Orchard Therapeutics plc Annual Report 2022

FY2022 Annual Report · Orchard Therapeutics plc
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Orchard Therapeutics plc 
Annual Report and Financial Statements  
for the Year Ended 31 December 2022 
Registered Number: 11494381  

INTRODUCTION AND CONTENTS 
Orchard Therapeutics plc (the “Company” or the “Parent Company”) is a public limited company 
incorporated under the laws of England and Wales and is listed on the Nasdaq Global Select Market. 
This section therefore covers the requirements for being a quoted company under the UK Companies 
Act 2006, as follows: 
Page 
•
Company Information
2 
•
Independent auditors’ reports to the members of Orchard Therapeutics plc
3 
•
Statement of Directors’ Responsibilities in Respect of the Financial Statements
15 
•
UK Statutory Strategic Report
17 
•
UK Statutory Directors’ Report
66 
•
Directors’ Remuneration Report
71 
•
Orchard Therapeutics plc Consolidated Financial Statements
101 
•
Orchard Therapeutics plc Parent Company Financial Statements
163 
UK FINANCIAL DOCUMENTS 
 
Orchard Therapeutics plc 1

Directors
James Geraghty, Chair of the Board of Directors  
Steven Altschuler 
Joanne Beck  
John Curnutte  
Marc Dunoyer 
Hubert Gaspar 
Charles Rowland  
Alicia Secor 
 
Secretary
Christopher York 
 
Registered Office
245 Hammersmith Road  
3rd Floor 
London 
 
United Kingdom 
 
Company Number
11494381 
 
Independent Auditors
PricewaterhouseCoopers LLP  
40 Clarendon Road 
Watford WD17 1JJ  
United Kingdom 
 
2 Orchard Therapeutics plc 
COMPANY INFORMATION 

 
Orchard Therapeutics plc 3
Report on the audit of the group ﬁnancial statements 
Opinion 
In our opinion, Orchard Therapeutics plc’s group ﬁnancial statements: 
•
give a true and fair view of the state of the group’s affairs as at 31 December 2022 and of its 
loss and cash ﬂows for the year then ended; 
•
have been properly prepared in accordance with UK-adopted international accounting standards; 
and 
•
have been prepared in accordance with the requirements of the Companies Act 2006. 
We have audited the ﬁnancial statements, included within the Annual Report and Financial Statements 
(the “Annual Report”), which comprise: the Consolidated Statement of Financial Position as at 
31 December 2022; the Consolidated Statement of Proﬁt or Loss, the Consolidated Statement of 
Comprehensive Loss, the Consolidated Statement of Changes in Equity, the Consolidated Cash Flow 
Statement for the year then ended; and the notes to the ﬁnancial statements, which include a 
description of the signiﬁcant accounting policies. 
Basis for opinion 
We conducted our audit in accordance with International Standards on Auditing (UK) (“ISAs (UK)”) 
and applicable law. Our responsibilities under ISAs (UK) are further described in the Auditors’ 
responsibilities for the audit of the ﬁnancial statements section of our report. We believe that the audit 
evidence we have obtained is sufﬁcient and appropriate to provide a basis for our opinion. 
Independence 
We remained independent of the group in accordance with the ethical requirements that are relevant 
to our audit of the ﬁnancial statements in the UK, which includes the FRC’s Ethical Standard, as 
applicable to listed entities, and we have fulﬁlled our other ethical responsibilities in accordance with 
these requirements. 
Our audit approach 
Overview 
Audit scope 
•
Of the group’s nine components, we identiﬁed three which, in our view, required an audit of their 
complete ﬁnancial information, either due to their size or their risk characteristics. In addition to 
the full scope audits, speciﬁc audit procedures were performed on selected consolidation 
adjustments made in relation to individually signiﬁcant balances. This, together with additional 
procedures performed at group level, gave us the evidence we needed. 
Key audit matters 
•
Expenses, accruals and prepayments for clinical research arrangements 
Materiality 
•
Overall materiality: $8,096,000 (2021: $7,250,000) based on 5% of loss before taxation. 
•
Performance materiality: $6,072,000 (2021: $8,000,000). 
The scope of  our audit 
As part of designing our audit, we determined materiality and assessed the risks of material 
misstatement in the ﬁnancial statements. 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC

 
4 Orchard Therapeutics plc 
Key audit matters 
Key audit matters are those matters that, in the auditors’ professional judgement, were of most 
signiﬁcance in the audit of the ﬁnancial statements of the current period and include the most 
signiﬁcant assessed risks of material misstatement (whether or not due to fraud) identiﬁed by the 
auditors, including those which had the greatest effect on: the overall audit strategy; the allocation 
of resources in the audit; and directing the efforts of the engagement team. These matters, and any 
comments we make on the results of our procedures thereon, were addressed in the context of our 
audit of the ﬁnancial statements as a whole, and in forming our opinion thereon, and we do not 
provide a separate opinion on these matters. 
This is not a complete list of all risks identiﬁed by our audit. 
Expenses, accruals and prepayments for clinical research arrangements is a new key audit matter 
this year. Orchard Therapeutics (Europe) Limited Research & Development Tax Credit Receivable, 
which was a key audit matter last year, is no longer included because of the value of the balance 
has reduced signiﬁcantly in the year such that the tax credit receivable and proﬁt and loss account 
credit is no longer material to the ﬁnancial statements. 
Key audit matter                                                      How our audit addressed the key audit matter 
  
Expenses, accruals and prepayments for clinical 
research arrangements 
As described in notes 1 and 2 to the consolidated 
ﬁnancial statements, the Group has entered into 
various research and development contracts with 
clinical research organisations (CROs) and clinical 
manufacturing organisations (CMOs). When billing 
terms under these contracts do not coincide with 
the timing of when the work is performed, 
management is ﬁrst required to make estimates of 
the expense to be recognised in respect of the 
contracts such that the expense reﬂects the 
pattern of work performed. Subsequently, 
management is required to calculate the 
associated accrual or prepayment balance for 
each contract, based on the difference between 
the cumulative amount expensed under the 
contract to date and the cumulative amount 
invoiced to date. Given the difﬁcult in estimating 
the stage of completion of a clinical trial, or with 
obtaining the required information from the 
CRO/CMO, this is considered an area of 
estimation uncertainty. The prepayment recorded 
for these arrangements as at 31 December 2022 
is not material at just $881k, however the accrual 
amounts to $11.2m, with the relevant expense 
classiﬁed within "Research and development 
expenses" in the Consolidated Statement of Proﬁt 
or Loss..
 
 
We have performed the following procedures to 
gain comfort over management’s estimate for the 
expenses, accruals and prepayments for clinical 
research arrangements:  
–
Reviewed contracts with CROs and CMOs to 
understand the arrangements and key terms.  
–
Recalculated the expense to be recognised for 
a sample of contracts in the year based on 
contractual terms, third party evidence and in 
some cases, third party conﬁrmation with the 
CRO.  
–
Tested a sample of invoices received in the 
year from CROs/CMOs for accuracy, and that 
they have been correctly applied to the 
appropriate CRO/CMO in management’s 
accounting model.  
–
Recalculated the prepayment/accrual based 
on the difference between cumulative expense 
and cumulative invoicing, and reconciled this 
to management’s workings.  
–
Tested the completeness of costs recognised 
through contract reviews, review of publicly 
available information such as press releases 
and discussions with clinical personnel 
regarding the progress towards meeting 
contractual milestones which could trigger 
additional expense to be recognised.  
No exceptions were noted from our procedures 
performed over the expenses, accruals and 
prepayments for clinical research arrangements.
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
Orchard Therapeutics plc 5
How we tailored the audit scope 
We tailored the scope of our audit to ensure that we performed enough work to be able to give an 
opinion on the ﬁnancial statements as a whole, taking into account the structure of the group, the 
accounting processes and controls, and the industry in which it operates. 
We tailored the scope of our audit to ensure that we performed enough work to be able to give an 
opinion on the ﬁnancial statements as a whole, taking into account the structure of the group, the 
accounting processes and controls, and the industry in which it operates. The group is structured 
such that the signiﬁcant majority of its business is comprised of two operating entities – Orchard 
Therapeutics (Europe) Limited and Orchard Therapeutics North America, both of which were scoped 
as signiﬁcant components. We also performed a full scope audit of Orchard Therapeutics plc, as the 
ultimate parent company in the group. The consolidated ﬁnancial statements are a consolidation of 
nine components, comprising the group’s operating subsidiaries and centralised functions, which 
are based throughout the UK, US and Europe. In establishing the overall approach to the audit of 
the consolidated ﬁnancial statements, we relied on the work performed by PwC US over Orchard 
Therapeutics North America and Orchard Therapeutics plc, along with certain procedures over 
Orchard Therapeutics (Europe) Limited, in addition to the work we performed over Orchard 
Therapeutics (Europe) Limited and the consolidation. We have directed, supervised and reviewed 
the work of PwC US throughout the audit and maintained regular communication via video calls and 
email, as well as a site visit to the UK from the PwC US team in December 2022. 
The impact of  climate risk on our audit 
As part of our audit we made enquiries of management to understand the extent of the potential 
impact of climate risk on the group’s ﬁnancial statements, and we remained alert when performing 
our audit procedures for any indicators of the impact of climate risk. Our procedures did not identify 
any material impact as a result of climate risk on the group’s ﬁnancial statements. 
Materiality 
The scope of our audit was inﬂuenced by our application of materiality. We set certain quantitative 
thresholds for materiality. These, together with qualitative considerations, helped us to determine the 
scope of our audit and the nature, timing and extent of our audit procedures on the individual ﬁnancial 
statement line items and disclosures and in evaluating the effect of misstatements, both individually 
and in aggregate on the ﬁnancial statements as a whole. 
Based on our professional judgement, we determined materiality for the ﬁnancial statements as a 
whole as follows: 
Overall group materiality
$8,096,000 (2021: 7,250,000). 
How we determined it
5% of loss before taxation 
Rationale for benchmark applied
The group is loss making, as expected given its status as an early 
stage life sciences company with only two commercialised 
products. As such, loss before tax is deemed to be the most 
appropriate benchmark on which to calculate materiality, as this is 
the metric on which the group’s ﬁnancial performance is assessed. 
For each component in the scope of our group audit, we allocated a materiality that is less than our 
overall group materiality. The range of materiality allocated across components was $5,050,000 to 
$6,400,000. Certain components were audited to a local statutory audit materiality that was also less 
than our overall group materiality. 
We use performance materiality to reduce to an appropriately low level the probability that the 
aggregate of uncorrected and undetected misstatements exceeds overall materiality. Speciﬁcally, 
we use performance materiality in determining the scope of our audit and the nature and extent of 
our testing of account balances, classes of transactions and disclosures, for example in determining 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
6 Orchard Therapeutics plc 
sample sizes. Our performance materiality was 75% (2021: 75%) of overall materiality, amounting to 
$6,072,000 (2021: $8,000,000) for the group ﬁnancial statements. 
In determining the performance materiality, we considered a number of factors - the history of 
misstatements, risk assessment and aggregation risk and the effectiveness of controls - and 
concluded that an amount in the middle of our normal range was appropriate. 
We agreed with those charged with governance that we would report to them misstatements identiﬁed 
during our audit above $405,000 (2021: $360,000) as well as misstatements below that amount that, 
in our view, warranted reporting for qualitative reasons. 
Conclusions relating to going concern 
Our evaluation of the directors’ assessment of the group’s ability to continue to adopt the going 
concern basis of accounting included: 
•
Assessing management’s latest cash ﬂow forecast, in which we have assessed the forecasts for 
reasonableness, understanding the planned cash outﬂows/inﬂows and considering 
management’s previous ability to forecast accurately. We also note that a signiﬁcant proportion 
of planned expenditure remains under management’s control for the foreseeable future, therefore 
if cash were to run short, management have a number of options under which discretionary 
expenditure could be reduced. 
Based on the work we have performed, we have not identiﬁed any material uncertainties relating to 
events or conditions that, individually or collectively, may cast signiﬁcant doubt on the group’s ability 
to continue as a going concern for a period of at least twelve months from when the ﬁnancial 
statements are authorised for issue. 
In auditing the ﬁnancial statements, we have concluded that the directors’ use of the going concern 
basis of accounting in the preparation of the ﬁnancial statements is appropriate. 
However, because not all future events or conditions can be predicted, this conclusion is not a 
guarantee as to the group’s ability to continue as a going concern. 
Our responsibilities and the responsibilities of the directors with respect to going concern are 
described in the relevant sections of this report. 
Reporting on other information 
The other information comprises all of the information in the Annual Report other than the ﬁnancial 
statements and our auditors’ report thereon. The directors are responsible for the other information. 
Our opinion on the ﬁnancial statements does not cover the other information and, accordingly, we do 
not express an audit opinion or, except to the extent otherwise explicitly stated in this report, any form 
of assurance thereon. 
In connection with our audit of the ﬁnancial statements, our responsibility is to read the other 
information and, in doing so, consider whether the other information is materially inconsistent with 
the ﬁnancial statements or our knowledge obtained in the audit, or otherwise appears to be materially 
misstated. If we identify an apparent material inconsistency or material misstatement, we are required 
to perform procedures to conclude whether there is a material misstatement of the ﬁnancial 
statements or a material misstatement of the other information. If, based on the work we have 
performed, we conclude that there is a material misstatement of this other information, we are 
required to report that fact. We have nothing to report based on these responsibilities. 
With respect to the UK Statutory Strategic Report and UK Statutory Directors’ Report, we also 
considered whether the disclosures required by the UK Companies Act 2006 have been included. 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
Orchard Therapeutics plc 7
Based on our work undertaken in the course of the audit, the Companies Act 2006 requires us also 
to report certain opinions and matters as described below. 
UK Statutory Strategic Report and UK Statutory Directors’ Report 
In our opinion, based on the work undertaken in the course of the audit, the information given in the 
UK Statutory Strategic Report and UK Statutory Directors’ Report for the year ended 31 December 
2022 is consistent with the ﬁnancial statements and has been prepared in accordance with applicable 
legal requirements. 
In light of the knowledge and understanding of the group and its environment obtained in the course 
of the audit, we did not identify any material misstatements in the UK Statutory Strategic Report and 
UK Statutory Directors’ Report. 
Responsibilities for the financial statements and the audit 
Responsibilities of  the directors for the ﬁnancial statements 
As explained more fully in the Statement of directors’ responsibilities in respect of the ﬁnancial 
statements, the directors are responsible for the preparation of the ﬁnancial statements in accordance 
with the applicable framework and for being satisﬁed that they give a true and fair view. The directors 
are also responsible for such internal control as they determine is necessary to enable the preparation 
of ﬁnancial statements that are free from material misstatement, whether due to fraud or error. 
In preparing the ﬁnancial statements, the directors are responsible for assessing the group’s ability 
to continue as a going concern, disclosing, as applicable, matters related to going concern and 
using the going concern basis of accounting unless the directors either intend to liquidate the group 
or to cease operations, or have no realistic alternative but to do so. 
Auditors’ responsibilities for the audit of  the ﬁnancial statements 
Our objectives are to obtain reasonable assurance about whether the ﬁnancial statements as a whole 
are free from material misstatement, whether due to fraud or error, and to issue an auditors’ report 
that includes our opinion. Reasonable assurance is a high level of assurance, but is not a guarantee 
that an audit conducted in accordance with ISAs (UK) will always detect a material misstatement 
when it exists. Misstatements can arise from fraud or error and are considered material if, individually 
or in the aggregate, they could reasonably be expected to inﬂuence the economic decisions of users 
taken on the basis of these ﬁnancial statements. 
Irregularities, including fraud, are instances of non-compliance with laws and regulations. We design 
procedures in line with our responsibilities, outlined above, to detect material misstatements in respect 
of irregularities, including fraud. The extent to which our procedures are capable of detecting 
irregularities, including fraud, is detailed below. 
Based on our understanding of the group and industry, we identiﬁed that the principal risks of non-
compliance with laws and regulations related to product safety and clinical regulatory compliance, 
and we considered the extent to which non-compliance might have a material effect on the ﬁnancial 
statements. We also considered those laws and regulations that have a direct impact on the ﬁnancial 
statements such as UK tax legislation and the Companies Act 2006. We evaluated management’s 
incentives and opportunities for fraudulent manipulation of the ﬁnancial statements (including the 
risk of override of controls), and determined that the principal risks were related to misappropriation 
of cash and potential management bias in accounting estimates. The group engagement team 
shared this risk assessment with the component auditors so that they could include appropriate audit 
procedures in response to such risks in their work. Audit procedures performed by the group 
engagement team and/or component auditors included: 
•
Discussions with management and internal legal counsel including consideration of known or 
suspected instances of non-compliance with laws and regulations and fraud. 
•
Review of minutes of meetings with the Board of Directors. 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
8 Orchard Therapeutics plc 
•
Performing audit procedures over expenses, accruals and prepayment balances associated with 
third party contract research organisations (CROs), who perform clinical trials on behalf of the 
company. 
•
Identifying and testing journal entries, in particular any journal entries posted with unusual account 
combinations impacting cash. 
There are inherent limitations in the audit procedures described above. We are less likely to become 
aware of instances of non-compliance with laws and regulations that are not closely related to events 
and transactions reﬂected in the ﬁnancial statements. Also, the risk of not detecting a material 
misstatement due to fraud is higher than the risk of not detecting one resulting from error, as fraud 
may involve deliberate concealment by, for example, forgery or intentional misrepresentations, or 
through collusion. 
Our audit testing might include testing complete populations of certain transactions and balances, 
possibly using data auditing techniques. However, it typically involves selecting a limited number of 
items for testing, rather than testing complete populations. We will often seek to target particular items 
for testing based on their size or risk characteristics. In other cases, we will use audit sampling to 
enable us to draw a conclusion about the population from which the sample is selected. 
A further description of our responsibilities for the audit of the ﬁnancial statements is located on the FRC’s 
website at: www.frc.org.uk/auditorsresponsibilities. This description forms part of our auditors’ report. 
Use of  this report 
This report, including the opinions, has been prepared for and only for the company’s members as 
a body in accordance with Chapter 3 of Part 16 of the Companies Act 2006 and for no other purpose. 
We do not, in giving these opinions, accept or assume responsibility for any other purpose or to any 
other person to whom this report is shown or into whose hands it may come save where expressly 
agreed by our prior consent in writing. 
Other required reporting 
Companies Act 2006 exception reporting 
Under the Companies Act 2006 we are required to report to you if, in our opinion: 
•
we have not obtained all the information and explanations we require for our audit; or 
•
certain disclosures of directors’ remuneration speciﬁed by law are not made. 
We have no exceptions to report arising from this responsibility. 
Other matter 
We have reported separately on the company ﬁnancial statements of Orchard Therapeutics plc for 
the year ended 31 December 2022 and on the information in the Directors’ Remuneration Report that 
is described as having been audited. 
 
 
 
Katherine Birch-Evans (Senior Statutory Auditor) 
for and on behalf of PricewaterhouseCoopers LLP 
Chartered Accountants and Statutory Auditors 
Watford 
27 April 2023 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
Orchard Therapeutics plc 9
Report on the audit of the parent company ﬁnancial statements 
Opinion 
In our opinion, Orchard Therapeutics plc’s parent company ﬁnancial statements: 
•
give a true and fair view of the state of the parent company’s affairs as at 31 December 2022 
and of its loss for the year then ended; 
•
have been properly prepared in accordance with United Kingdom Generally Accepted 
Accounting Practice (United Kingdom Accounting Standards, including FRS 101 “Reduced 
Disclosure Framework”, and applicable law); and 
•
have been prepared in accordance with the requirements of the Companies Act 2006. 
We have audited the ﬁnancial statements, included within the Annual Report and Financial Statements 
(the “Annual Report”), which comprise: the Parent Company Balance Sheet as at 31 December 2022; 
the Parent Company Statement of Changes in Equity for the year then ended; and the notes to the 
ﬁnancial statements, which include a description of the signiﬁcant accounting policies. 
Basis for opinion 
We conducted our audit in accordance with International Standards on Auditing (UK) (“ISAs (UK)”) 
and applicable law. Our responsibilities under ISAs (UK) are further described in the Auditors’ 
responsibilities for the audit of the ﬁnancial statements section of our report. We believe that the audit 
evidence we have obtained is sufﬁcient and appropriate to provide a basis for our opinion. 
Independence 
We remained independent of the parent company in accordance with the ethical requirements that 
are relevant to our audit of the ﬁnancial statements in the UK, which includes the FRC’s Ethical 
Standard, as applicable to listed entities, and we have fulﬁlled our other ethical responsibilities in 
accordance with these requirements. 
Our audit approach 
Overview 
Audit scope 
•
The audit comprised only the audit of the parent company, Orchard Therapeutics plc. 
Key audit matters 
•
Valuation of investment in Orchard Therapeutics (Europe) Limited and expected credit loss 
provision against intercompany receivables 
Materiality 
•
Overall materiality: $800,000 (2021: $2,042,000) based on 1% of total assets. 
•
Performance materiality: $600,000 (2021: $1,532,000). 
The scope of  our audit 
As part of designing our audit, we determined materiality and assessed the risks of material 
misstatement in the ﬁnancial statements. 
Key audit matters 
Key audit matters are those matters that, in the auditors’ professional judgement, were of most 
signiﬁcance in the audit of the ﬁnancial statements of the current period and include the most 
signiﬁcant assessed risks of material misstatement (whether or not due to fraud) identiﬁed by the 
auditors, including those which had the greatest effect on: the overall audit strategy; the allocation 
of resources in the audit; and directing the efforts of the engagement team. These matters, and any 
comments we make on the results of our procedures thereon, were addressed in the context of our 
audit of the ﬁnancial statements as a whole, and in forming our opinion thereon, and we do not 
provide a separate opinion on these matters. 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
10 Orchard Therapeutics plc 
This is not a complete list of all risks identiﬁed by our audit. 
The key audit matter below is consistent with last year. 
Key audit matter                                                      How our audit addressed the key audit matter 
 
Valuation of  investment in Orchard Therapeutics 
(Europe) Limited and expected credit loss 
provision against intercompany receivables 
As described in notes 1, 2 and 13 to the 
consolidated ﬁnancial statements, the parent 
company holds an investment in its subsidiary, 
Orchard Therapeutics (Europe) Limited, and also 
has an intercompany receivable due from this 
subsidiary, which is termed "Amounts owed by 
subsidiary 
undertakings", 
classiﬁed 
within 
"Debtors" on the Parent Company Balance Sheet. 
The reduction in the market capitalisation of 
Orchard Therapeutics plc, based on the Group’s 
share price at 31 December 2022, is an indicator 
of potential impairment of both the investment 
and the intercompany receivable held by the 
parent company. The market capitalisation of the 
Group at 31 December 2022 is below the 
carrying 
value 
of 
the 
investment 
and 
intercompany receivable due from Orchard 
Therapeutics (Europe) Limited.  
Having regard for the reduction in the market 
capitalisation of the Group, management has 
assessed that the investment in Orchard 
Therapeutics (Europe) Limited is not recoverable, 
and have therefore impaired the balance to nil as 
at 31 December 2022, with an impairment loss of 
$11m recognised in the year.  
In 
assessing 
the 
recoverability 
of 
the 
intercompany receivable due from Orchard 
Therapeutics (Europe) Limited, management has 
considered the probability of default and loss 
given default, if the amount was to be recalled at 
the Statement of ﬁnancial position date. Given the 
fall in the market capitalisation of the Group and 
the impairment of the investment management 
has assessed there to be a high probability of 
default. A provision for expected credit losses of 
$114m 
has 
been 
recorded 
against 
the 
intercompany receivable such that the balance 
that remains represents what is deemed to be 
recoverable.  
 
 
 
We have performed the following procedures 
over 
the 
impairment 
assessment 
which 
management has prepared:  
–
Assessed management’s impairment model 
and calculation for compliance with UK GAAP 
(FRS 101), including an assessment of the 
reasonableness of the probability of default 
and loss assessed by management. 
–
Corroborated the inputs to the model and 
validated these to external sources or our 
audit testing performed in other areas.  
–
Recalculated 
the 
impairment 
of 
the 
investment and expected credit loss in 
respect of the intercompany receivable to be 
recognised in the year. 
–
Reviewed the disclosures in the ﬁnancial 
statements. 
The methodology adopted by management and 
the conclusions reached are deemed to be 
reasonable and appropriate. 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
Orchard Therapeutics plc 11
How we tailored the audit scope 
We tailored the scope of our audit to ensure that we performed enough work to be able to give an 
opinion on the ﬁnancial statements as a whole, taking into account the structure of the parent 
company, the accounting processes and controls, and the industry in which it operates. 
We tailored the scope of our audit to ensure that we performed enough work to be able to give an 
opinion on the ﬁnancial statements as a whole, taking into account the structure of the parent 
company, the accounting processes and controls, and the industry in which it operates. Although 
the parent company is a UK company, certain procedures have been performed by PwC US as 
component auditors. We have instructed PwC US to report to us on the special purpose ﬁnancial 
information of the parent company under US GAAP, and we have performed testing on the 
adjustments posted by management to prepare the parent company ﬁnancial statements under 
FRS 101. 
The impact of  climate risk on our audit 
As part of our audit we made enquiries of management to understand the extent of the potential 
impact of climate risk on the parent company’s ﬁnancial statements, and we remained alert when 
performing our audit procedures for any indicators of the impact of climate risk. Our procedures did 
not identify any material impact as a result of climate risk on the parent company’s ﬁnancial 
statements. 
Materiality 
The scope of our audit was inﬂuenced by our application of materiality. We set certain quantitative 
thresholds for materiality. These, together with qualitative considerations, helped us to determine the 
scope of our audit and the nature, timing and extent of our audit procedures on the individual ﬁnancial 
statement line items and disclosures and in evaluating the effect of misstatements, both individually 
and in aggregate on the ﬁnancial statements as a whole. 
Based on our professional judgement, we determined materiality for the ﬁnancial statements as a 
whole as follows: 
Overall parent company materiality
$800,000 (2021: $2,042,000). 
How we determined it
1% of total assets 
Rationale for benchmark applied
We believe that total assets is the primary measure used by 
the shareholders in assessing the performance and position 
of the parent company and reﬂects the parent company’s 
principal activity as a holding company. 
We use performance materiality to reduce to an appropriately low level the probability that the 
aggregate of uncorrected and undetected misstatements exceeds overall materiality. Speciﬁcally, 
we use performance materiality in determining the scope of our audit and the nature and extent of 
our testing of account balances, classes of transactions and disclosures, for example in determining 
sample sizes. Our performance materiality was 75% (2021: 75%) of overall materiality, amounting to 
$600,000 (2021: $1,532,000) for the parent company ﬁnancial statements. 
In determining the performance materiality, we considered a number of factors - the history of 
misstatements, risk assessment and aggregation risk and the effectiveness of controls - and 
concluded that an amount in the middle of our normal range was appropriate. 
We agreed with those charged with governance that we would report to them misstatements identiﬁed 
during our audit above $40,000 (2021: $102,000) as well as misstatements below that amount that, 
in our view, warranted reporting for qualitative reasons. 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
12 Orchard Therapeutics plc 
Conclusions relating to going concern 
Our evaluation of the directors’ assessment of the parent company’s ability to continue to adopt the 
going concern basis of accounting included: 
•
Assessing management’s latest cash ﬂow forecast, in which we have assessed the forecasts for 
reasonableness, understanding the planned cash outﬂows/inﬂows and considering 
management’s previous ability to forecast accurately. We also note that a signiﬁcant proportion 
of planned expenditure remains under management’s control for the foreseeable future, therefore 
if cash were to run short, management have a number of options under which discretionary 
expenditure could be reined back. 
Based on the work we have performed, we have not identiﬁed any material uncertainties relating to 
events or conditions that, individually or collectively, may cast signiﬁcant doubt on the parent 
company’s ability to continue as a going concern for a period of at least twelve months from when 
the ﬁnancial statements are authorised for issue. 
In auditing the ﬁnancial statements, we have concluded that the directors’ use of the going concern 
basis of accounting in the preparation of the ﬁnancial statements is appropriate. 
However, because not all future events or conditions can be predicted, this conclusion is not a 
guarantee as to the parent company’s ability to continue as a going concern. 
Our responsibilities and the responsibilities of the directors with respect to going concern are 
described in the relevant sections of this report. 
Reporting on other information 
The other information comprises all of the information in the Annual Report other than the ﬁnancial 
statements and our auditors’ report thereon. The directors are responsible for the other information. 
Our opinion on the ﬁnancial statements does not cover the other information and, accordingly, we do 
not express an audit opinion or, except to the extent otherwise explicitly stated in this report, any form 
of assurance thereon. 
In connection with our audit of the ﬁnancial statements, our responsibility is to read the other 
information and, in doing so, consider whether the other information is materially inconsistent with 
the ﬁnancial statements or our knowledge obtained in the audit, or otherwise appears to be materially 
misstated. If we identify an apparent material inconsistency or material misstatement, we are required 
to perform procedures to conclude whether there is a material misstatement of the ﬁnancial 
statements or a material misstatement of the other information. If, based on the work we have 
performed, we conclude that there is a material misstatement of this other information, we are 
required to report that fact. We have nothing to report based on these responsibilities. 
With respect to the UK Statutory Strategic Report and UK Statutory Directors’ Report, we also 
considered whether the disclosures required by the UK Companies Act 2006 have been included. 
Based on our work undertaken in the course of the audit, the Companies Act 2006 requires us also 
to report certain opinions and matters as described below. 
UK Statutory Strategic Report and UK Statutory Directors’ Report 
In our opinion, based on the work undertaken in the course of the audit, the information given in the 
UK Statutory Strategic Report and UK Statutory Directors’ Report for the year ended 31 December 
2022 is consistent with the ﬁnancial statements and has been prepared in accordance with applicable 
legal requirements. 
In light of the knowledge and understanding of the parent company and its environment obtained in 
the course of the audit, we did not identify any material misstatements in the UK Statutory Strategic 
Report and UK Statutory Directors’ Report. 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
Orchard Therapeutics plc 13
Directors’ Remuneration 
In our opinion, the part of the Directors’ Remuneration Report to be audited has been properly 
prepared in accordance with the Companies Act 2006. 
Responsibilities for the financial statements and the audit 
Responsibilities of  the directors for the ﬁnancial statements 
As explained more fully in the Statement of directors’ responsibilities in respect of the ﬁnancial 
statements, the directors are responsible for the preparation of the ﬁnancial statements in accordance 
with the applicable framework and for being satisﬁed that they give a true and fair view. The directors 
are also responsible for such internal control as they determine is necessary to enable the preparation 
of ﬁnancial statements that are free from material misstatement, whether due to fraud or error. 
In preparing the ﬁnancial statements, the directors are responsible for assessing the parent 
company’s ability to continue as a going concern, disclosing, as applicable, matters related to going 
concern and using the going concern basis of accounting unless the directors either intend to 
liquidate the parent company or to cease operations, or have no realistic alternative but to do so. 
Auditors’ responsibilities for the audit of  the ﬁnancial statements 
Our objectives are to obtain reasonable assurance about whether the ﬁnancial statements as a whole 
are free from material misstatement, whether due to fraud or error, and to issue an auditors’ report 
that includes our opinion. Reasonable assurance is a high level of assurance, but is not a guarantee 
that an audit conducted in accordance with ISAs (UK) will always detect a material misstatement 
when it exists. Misstatements can arise from fraud or error and are considered material if, individually 
or in the aggregate, they could reasonably be expected to inﬂuence the economic decisions of users 
taken on the basis of these ﬁnancial statements. 
Irregularities, including fraud, are instances of non-compliance with laws and regulations. We design 
procedures in line with our responsibilities, outlined above, to detect material misstatements in respect 
of irregularities, including fraud. The extent to which our procedures are capable of detecting 
irregularities, including fraud, is detailed below. 
Based on our understanding of the parent company and industry, we identiﬁed that the principal 
risks of non-compliance with laws and regulations related to compliance with being a UK 
incorporated company which is listed in the US, and we considered the extent to which non-
compliance might have a material effect on the ﬁnancial statements. We evaluated management’s 
incentives and opportunities for fraudulent manipulation of the ﬁnancial statements (including the 
risk of override of controls), and determined that the principal risks were related to misappropriation 
of cash. Audit procedures performed by the engagement team included: 
•
Discussions with management and internal legal counsel including consideration of known or 
suspected instances of non-compliance with laws and regulations and fraud; 
•
Review of minutes of meetings with the Board of Directors; 
•
Identifying and testing journal entries, in particular any journal entries posted with unusual account 
combinations impacting cash. 
There are inherent limitations in the audit procedures described above. We are less likely to become 
aware of instances of non-compliance with laws and regulations that are not closely related to events 
and transactions reﬂected in the ﬁnancial statements. Also, the risk of not detecting a material 
misstatement due to fraud is higher than the risk of not detecting one resulting from error, as fraud 
may involve deliberate concealment by, for example, forgery or intentional misrepresentations, or 
through collusion. 
Our audit testing might include testing complete populations of certain transactions and balances, 
possibly using data auditing techniques. However, it typically involves selecting a limited number of 
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
14 Orchard Therapeutics plc 
items for testing, rather than testing complete populations. We will often seek to target particular items 
for testing based on their size or risk characteristics. In other cases, we will use audit sampling to 
enable us to draw a conclusion about the population from which the sample is selected. 
A further description of our responsibilities for the audit of the ﬁnancial statements is located on the 
FRC’s website at: www.frc.org.uk/auditorsresponsibilities. This description forms part of our auditors’ 
report. 
Use of  this report 
This report, including the opinions, has been prepared for and only for the parent company’s 
members as a body in accordance with Chapter 3 of Part 16 of the Companies Act 2006 and for no 
other purpose. We do not, in giving these opinions, accept or assume responsibility for any other 
purpose or to any other person to whom this report is shown or into whose hands it may come save 
where expressly agreed by our prior consent in writing. 
Other required reporting 
Companies Act 2006 exception reporting 
Under the Companies Act 2006 we are required to report to you if, in our opinion: 
•
we have not obtained all the information and explanations we require for our audit; or 
•
adequate accounting records have not been kept by the parent company, or returns adequate 
for our audit have not been received from branches not visited by us; or 
•
certain disclosures of directors’ remuneration speciﬁed by law are not made; or 
•
the ﬁnancial statements and the part of the Directors’ Remuneration Report to be audited are not 
in agreement with the accounting records and returns. 
We have no exceptions to report arising from this responsibility. 
Other matter 
We have reported separately on the group ﬁnancial statements of Orchard Therapeutics plc for the 
year ended 31 December 2022. 
 
Katherine Birch-Evans (Senior Statutory Auditor) 
for and on behalf of PricewaterhouseCoopers LLP 
Chartered Accountants and Statutory Auditors 
Watford 
27 April 2023
INDEPENDENT AUDITORS’ REPORT TO THE 
MEMBERS OF ORCHARD THERAPEUTICS PLC 
continued 

 
Orchard Therapeutics plc 15
The directors are responsible for preparing the Annual report and the ﬁnancial statements in 
accordance with applicable law and regulation. 
Company law requires the directors to prepare ﬁnancial statements for each ﬁnancial year. Under 
that law the directors have prepared the group ﬁnancial statements in accordance with UK-adopted 
international accounting standards and the parent company ﬁnancial statements in accordance with 
United Kingdom Generally Accepted Accounting Practice (United Kingdom Accounting Standards, 
comprising FRS 101 “Reduced Disclosure Framework”, and applicable law). 
Under company law, directors must not approve the ﬁnancial statements unless they are satisﬁed 
that they give a true and fair view of the state of affairs of the group and parent company and of the 
proﬁt or loss of the group for that period. In preparing the ﬁnancial statements, the directors are 
required to: 
•
select suitable accounting policies and then apply them consistently; 
•
state whether applicable UK-adopted international accounting standards have been followed for 
the group ﬁnancial statements and United Kingdom Accounting Standards, comprising FRS 101 
have been followed for the parent company ﬁnancial statements, subject to any material 
departures disclosed and explained in the ﬁnancial statements; 
•
make judgements and accounting estimates that are reasonable and prudent; and 
•
prepare the ﬁnancial statements on the going concern basis unless it is inappropriate to presume 
that the group and parent company will continue in business. 
The directors are responsible for safeguarding the assets of the group and parent company and 
hence for taking reasonable steps for the prevention and detection of fraud and other irregularities. 
The directors are also responsible for keeping adequate accounting records that are sufﬁcient to 
show and explain the group’s and parent company’s transactions and disclose with reasonable 
accuracy at any time the ﬁnancial position of the group and parent company and enable them to 
ensure that the ﬁnancial statements and the Directors’ Remuneration Report comply with the 
Companies Act 2006. 
The directors are responsible for the maintenance and integrity of the parent company’s website. 
Legislation in the United Kingdom governing the preparation and dissemination of ﬁnancial 
statements may differ from legislation in other jurisdictions. 
 
STATEMENT OF DIRECTORS’ RESPONSIBILITIES IN 
RESPECT OF THE FINANCIAL STATEMENTS

 
16 Orchard Therapeutics plc 
Directors’ conﬁrmations 
In the case of each director in ofﬁce at the date the directors’ report is approved: 
•
so far as the director is aware, there is no relevant audit information of which the group’s and 
parent company’s auditors are unaware; and 
•
they have taken all the steps that they ought to have taken as a director in order to make 
themselves aware of any relevant audit information and to establish that the group’s and parent 
company’s auditors are aware of that information. 
 
STATEMENT OF DIRECTORS’ RESPONSIBILITIES IN 
RESPECT OF THE FINANCIAL STATEMENTS 
continued 

 
Orchard Therapeutics plc 17
Introduction 
The Directors of Orchard Therapeutics plc (which together may be referred to as “Company”, 
“Orchard”, “we”, “us”, or “our”) present their UK Statutory Strategic Report on the Group and the 
audited consolidated ﬁnancial statements for the year ended 31 December 2022. 
Corporate Information 
We were originally incorporated under the laws of England and Wales in August 2018 as Orchard 
Rx Limited (now known as Orchard Therapeutics plc) to become a holding company for Orchard 
Therapeutics (Europe) Limited (previously known as Orchard Therapeutics Limited). Orchard Rx 
Limited subsequently re-registered as a public limited company and its name was changed from 
Orchard Rx Limited to Orchard Therapeutics plc in October 2018. Orchard Therapeutics (Europe) 
Limited was originally incorporated under the laws of England and Wales in September 2015 as 
Newincco 1387 Limited and subsequently changed its name to Orchard Therapeutics Limited in 
November 2015 and to Orchard Therapeutics (Europe) Limited in October 2018. 
To date, we have ﬁnanced our operations primarily with proceeds from the sale of American 
depositary shares (“ADSs”) in our Initial Public Offering (“IPO”) and follow-on offering, proceeds from 
the sale of ordinary shares in our private placement, proceeds from the sale of convertible preferred 
shares, proceeds associated with two UK research and development tax relief programs, the Small 
and Medium-sized Enterprises research and development tax credit (“SME”) program and the 
Research and Development Expenditure (“RDEC”) program, reimbursements from our research 
agreement with University of California Los Angeles (“UCLA”) and, following transfer of the ADA-SCID 
research program sponsorship from UCLA to us in July 2018, a grant from the California Institute of 
Regenerative Medicine (“CIRM”), upfront payments from our collaboration agreement with Pharming 
Group N.V., and our Original Credit Facility and our Amended Credit Facility. 
On 27 February 2020, we entered into a Sales Agreement with Cowen and Company, LLC, as agent, 
relating to an “at the market offering,” pursuant to which we may issue and sell ADSs representing 
our ordinary shares, having an aggregate offering price of up to $100.0 million. As of 31 December 
2021, we have not sold any shares under the Sales Agreement. On 24 March 2022, we delivered 
written notice to Cowen to terminate the Sales Agreement, effective as of 30 March 2022, pursuant 
to Section 11(b) thereof. We are not subject to any termination penalties related to the termination of 
the Sales Agreement. Prior to termination, we had not sold any ADSs pursuant to the Sales 
Agreement. As a result of the termination of the Sales Agreement, we will not offer or sell any ADSs 
under the Sales Agreement. 
On 9 February 2021, we issued and sold (i) 20,900,321 ordinary shares, nominal value £0.10 per share, 
at a purchase price of $6.22 per share (the “Purchase Price”), which was the closing sale price of our 
ADSs on the Nasdaq Global Select Market on 4 February 2021, and (ii) 3,215,434 non-voting ordinary 
shares, nominal value £0.10 per share, at the Purchase Price (the “Private Placement”). The Private 
Placement resulted in net proceeds to us of approximately $144.0 million after deducting placement 
agent fees. The ordinary shares and non-voting ordinary shares were sold pursuant to a securities 
purchase agreement we entered into with the purchasers named therein on 4 February 2021. 
UK STATUTORY STRATEGIC REPORT

 
18 Orchard Therapeutics plc 
Business Overview (including company strategy, business model, and key 
performance indicators) 
We are a global gene therapy company dedicated to transforming the lives of people affected by 
rare diseases through the development of innovative, potentially curative gene therapies. Our ex vivo 
autologous hematopoietic stem cell, or HSC, gene therapy approach harnesses the power of 
genetically modiﬁed blood stem cells and seeks to correct the underlying cause of disease in a 
single administration. We seek to achieve this outcome by utilizing a lentiviral vector to introduce a 
functional copy of a missing or faulty gene into the patient’s own, or autologous, HSCs through an 
ex vivo process, resulting in a gene-modiﬁed cellular drug product that can then be administered to 
the patient at the bedside.  
To date, over 170 patients have been treated with our current and former product candidates across 
seven different diseases, with follow-up periods of more than 11 years following a single 
administration. We believe the data observed across these development programs, in combination 
with our expertise in the development, manufacturing and commercialization of gene and cell 
therapies, position us to provide potentially curative therapies to people suffering from a broad range 
of diseases.  
We are currently focusing our ex vivo autologous HSC gene therapy approach on severe 
neurometabolic diseases and early research programs. Our lead program is OTL-200, which was 
approved in the European Union, the United Kingdom, Iceland, Liechtenstein and Norway under the 
brand name Libmeldy for eligible patients with early-onset metachromatic leukodystrophy, or MLD. 
In advance of a potential Biologics License Application (‘BLA’) submission, Orchard Therapeutics is 
conducting a meeting with the U.S. Food and Drug Administration involving several specialized 
functions within the company and agency. The primary purpose of a pre-BLA meeting is to discuss 
the planned content of the marketing application. Pending the outcome of the multidisciplinary pre-
BLA meeting scheduled for the second quarter of 2023, we anticipate a potential BLA submission in 
mid-2023. 
Our portfolio includes a commercial-stage product and research and development-stage product 
candidates. We believe our approach of using lentiviral vectors to genetically modify HSCs has 
wide-ranging applicability to a large number of indications. The ability of HSCs to differentiate into 
multiple cell types allows us to deliver gene-modiﬁed cells to multiple physiological systems, including 
the central nervous system, immune system and red blood cell and platelet lineage, thereby 
potentially enabling the correction of a wide range of diseases. By leveraging the innate self-renewing 
capability of HSCs that are engrafted in the bone marrow as well as the ability of lentiviral vectors to 
achieve stable integration of a modiﬁed gene into the chromosomes of HSCs, our gene therapies 
have the potential to provide a durable effect following a single administration.  
The diseases we target affect patients around the world, requiring an infrastructure to deliver gene 
therapies globally. In order to meet anticipated demand for our pipeline of approved products and 
product candidates still in development, we are utilizing our existing network of contract development 
and manufacturing organizations, or CDMOs, to manufacture lentiviral vectors and drug product. 
In addition, we have established process development capabilities in London, UK, and are leveraging 
technologies that will allow us to deliver our gene therapies globally.  
Cryopreservation of our gene-modiﬁed HSCs is a key component of our commercialization strategy 
to deliver potentially curative gene therapies to patients worldwide, facilitating both local treatment 
and local or cross-border product reimbursement. We developed a cryopreserved formulation of 
Libmeldy (OTL-200) and are collecting supportive clinical data from patients treated with 
cryopreserved formulations to support the analytical comparability to the fresh cell formulations used 
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 19
in our registrational clinical trials. The registrational trials for all our earlier stage product candidates 
are expected to be conducted using a cryopreserved formulation.  
With the exception of OTL-105, our product candidate for the potential treatment of hereditary 
angioedema, or HAE, which we are pursuing in partnership with Pharming Group N.V., we have global 
commercial rights to all our clinical product candidates and plan to commercialize our gene therapies 
in key markets worldwide, including in Europe and the U.S. initially, subject to obtaining the necessary 
marketing approvals for these jurisdictions. We are focused on deploying a commercial infrastructure 
to deliver Libmeldy and our product candidates, if approved, to patients and are focused on working 
closely with all relevant stakeholders, including patients, caregivers, specialist physicians and payors, 
to ensure the widest possible post-approval access for our product candidates. In addition, we may 
rely on third parties to assist with regulatory submissions, disease awareness, patient identiﬁcation 
and reimbursement in countries where local expertise is required or where we do not have a direct 
presence.  
As we continue to develop our portfolio, we believe that the experience of our management team 
and our extensive academic relationships are key strategic strengths. Our management team has 
extensive experience in rare diseases and in the manufacturing, pre-clinical and clinical development 
and commercialization of gene and cell therapies. In addition, we partner with leading academic 
institutions around the world, which are pioneers in ex vivo autologous HSC-based gene therapy. We 
plan to leverage our internal expertise combined with our relationships with leading academic 
institutions to transition our lead clinical-stage product candidates to commercialization and continue 
to expand our portfolio of ex vivo autologous HSC gene therapy products.  
Our ex vivo autologous HSC gene therapy approach  
Our ex vivo autologous HSC gene therapy approach seeks to transform a patient’s autologous HSCs 
into a gene-modiﬁed cellular drug product to treat the patient’s disease. HSCs are self-renewing cells 
that are capable of differentiating into all types of blood cells, including white blood cells, red blood 
cells, platelets and tissue resident macrophages, which include the microglia of the central nervous 
system. HSCs can be obtained directly from the bone marrow, which requires administration of a 
general anesthetic, or from the patient’s peripheral blood with the use of mobilizing agents, which 
are agents that can move HSCs from the bone marrow into the peripheral blood for easier collection. 
The HSCs collected are then manufactured to insert a functional copy of the missing or faulty gene. 
By delivering gene-modiﬁed HSCs back to patients, we seek to take advantage of the self-renewing 
capability of HSCs to enable a durable effect following a single administration, as has been seen in 
our commercial and development programs. Since these cells are recognized by the body as the 
patient’s own cells, the risks associated with using donor cells may be reduced. In addition, the ability 
of HSCs to differentiate into multiple different cell types has the potential to enable the delivery of 
gene-modiﬁed cells to different physiological systems and allow the correction of a broad range of 
different diseases.  
Clinical validation already exists for hematopoietic stem cell transplantation, or HSCT, an approach 
of treating a patient with a genetic disease with HSCs contributed by a healthy donor individual, 
thereby using HSCs that contain a functioning copy of the gene of interest. However, this approach 
has signiﬁcant limitations, including difﬁculties in ﬁnding appropriate genetically matched donors 
and the risk of graft-versus-host disease, transplant-related rejection and mortality from these and 
other complications, and is therefore typically only offered on a limited basis. Furthermore, genetically 
modiﬁed cells can be used to express enzyme activity at supra-physiological levels, which we believe 
has the potential to overcome the limitations of HSCT (where enzyme expression is generally limited 
to normal levels) to treat some neurometabolic disorders and improve the metabolic correction in 
UK STATUTORY STRATEGIC REPORT 
continued 

 
20 Orchard Therapeutics plc 
neuronal cells before irreversible degeneration occurs. Our approach is intended to address these 
signiﬁcant limitations of HSCT.  
In a pre-clinical study conducted by one of our scientiﬁc advisors and published in Proceedings of  
the National Academy of  Sciences of  the United States of  America, or PNAS, a sub population of 
gene-modiﬁed HSCs has evidenced the potential to cross the blood-brain barrier, engraft in the brain 
as microglia and express genes and proteins within the central nervous system, one of the important 
physiological systems targeted by our HSC gene therapy approach. As published in PNAS, images 
taken during the study show a cross-section of the brain of a mouse that was infused intravenously 
with HSCs, which had been genetically modiﬁed using a lentiviral vector carrying green ﬂuorescent 
protein, or GFP. The GFP expression observed throughout the brain illustrates the potential of 
gene-modiﬁed HSCs to cross the blood-brain barrier, engraft in the brain and express the functional 
protein throughout the brain, thereby potentially addressing a range of diseases that affect the central 
nervous system. Libmeldy (OTL-200), for instance, leverages this same mechanism of action to 
deliver gene-modiﬁed HSCs that can cross the blood-brain barrier and deliver a therapeutic gene 
that can prevent neuronal degeneration. The study demonstrated widespread distribution and 
expression of GFP in the brain of a mouse model following intravenous administration of HSCs 
transduced with GFP encoding vector. 
With respect to Libmeldy (OTL-200) and each of our product candidates, our ex vivo gene therapy 
approach utilizes a self-inactivating, or SIN, lentiviral vector to introduce a functional copy of the 
missing or faulty gene into the patient’s autologous HSCs through an ex vivo process called 
transduction, resulting in a cellular drug product that can then be re-introduced into the patient. Unlike 
some other viral vectors, such as adeno-associated viral, or AAV, vectors, lentiviral vectors integrate 
into the chromosomes of patients’ HSCs. We believe this allows us to achieve stable integration of 
the functional gene into the HSCs and can lead to durable expression of the target protein by the 
gene-modiﬁed HSCs and their progeny after a single administration of gene therapy. In contrast, 
because AAV vectors rarely integrate into the genome, the transgene is not passed on to all progeny 
when the cell divides, resulting in rapid dilution and loss of the transgene among frequently dividing 
cells such as HSCs. Regarding immunogenicity, because in vivo delivery of AAV places the vector 
into direct contact with the immune system and most individuals harbor some type of pre-existing 
immunity, including neutralizing antibodies, to one or more types of AAV vector, the incoming vector 
can be completely inactivated by the patient’s immune system. Furthermore, there have been reports 
that certain high dose applications of AAV have resulted in acute and severe innate immune 
responses that have proved lethal. With ex vivo delivery, however, the vector is not introduced directly 
into the body and vector elements are washed away in the laboratory such that there is little to no 
vector element left to present to the immune system. Our HSC gene therapies and product candidates 
are all manufactured ex vivo.  
Strimvelis for adenosine deaminase severe combined immunodeﬁciency, or ADA-SCID, is the only 
gammaretroviral vector-based gene therapy in our portfolio. In March 2022, we announced that we 
would discontinue our investment in and seek alternatives for Strimvelis. 
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 21
The image below illustrates the steps in our approach to transform a patient’s autologous HSCs 
ex vivo into therapeutic product.  
 
Initial clinical trials conducted using our product candidates utilized a fresh product formulation, 
resulting in a limited drug product shelf life. We market Libmeldy (OTL-200) and plan to market our 
current and any future product candidates, if approved, in a cryopreserved product formulation, 
which is designed to extend the drug product shelf life and enable the shipment of the drug product 
to specialized treatment centers, allowing patients to receive treatment closer to their home while 
leveraging more centralized manufacturing. Cryopreservation also allows us to conduct a number of 
quality control tests on the genetically modiﬁed HSCs prior to introducing them into the patient.  
In addition, certain of our clinical-stage product candidates have been evaluated in registrational 
trials using drug product derived from HSCs extracted from the patients’ bone marrow. To optimize 
our potential product label and the number of patients that we may be able to treat, as part of any 
BLA or Marketing Authorisation Application (‘MAA’) MAA submission for such product candidates, 
we plan to demonstrate comparability between drug product manufactured using HSCs derived from 
the patients’ peripheral blood and drug product manufactured using HSCs derived from the patients’ 
bone marrow. In cases where clinical trials were conducted using vector and/or drug product 
manufactured at academic centers, we plan to demonstrate comparability between vector and/or 
drug product manufactured by our third party commercial CDMOs with vector and drug product 
manufactured at such academic centers.  
We are currently focused on employing our ex vivo autologous HSC gene therapy approach in two 
therapeutic disease areas: neurodegenerative and immunological disorders. We also have a program 
focused on beta thalassemia, or TDT, a blood disorder, but new investments in this program are 
currently limited. Data from clinical trials suggest that ex vivo autologous HSC gene therapy has the 
potential to provide generally well-tolerated, sustainable and improved outcomes over existing 
standards of care for diseases in these areas. We believe that we can apply our approach beyond 
our current target indications to treat an even broader range of diseases.  
!
UK STATUTORY STRATEGIC REPORT 
continued 

 
22 Orchard Therapeutics plc 
Our strategy  
We are building a leading, global, fully-integrated gene therapy company focused on transforming the 
lives of people affected by severe diseases. To achieve this, we are pursuing the following strategies: 
•
Continue our commercialization efforts for Libmeldy (OTL-200) for treatment of eligible patients 
with early-onset MLD in Europe and expand geographically into new markets as regulatory 
approvals are obtained 
•
Advance our clinical-stage product candidates towards marketing approvals, including a potential 
BLA submission for OTL-200 in the U.S. in mid-2023 
•
Leverage the power of our therapeutic approach to investigate the potential of HSC gene therapy 
in larger indications  
•
Invest in new technologies and innovations to continue to improve our manufacturing processes 
for lentiviral vector and drug product and reduce costs of goods manufactured 
•
Establish end-to-end process development, manufacturing and supply chain capabilities, initially 
through third parties and internally over time 
•
Establish a patient-centric, global commercial infrastructure, including with third parties in certain 
regions where we do not have a direct presence    
•
Execute a business development strategy to leverage our HSC gene therapy approach, expand 
geographically, accelerate time-to-market or attract disease-area expertise to optimize the value 
of our portfolio of product candidates or expand into new indications 
On 30 March, 2022, the Company announced its commitment to focus on severe neurometabolic 
diseases and early research programs, and to discontinue its investment in and seek strategic 
alternatives for the Company’s programs in rare primary immune deﬁciencies, including OTL-103 for 
treatment of Wiskott Aldrich syndrome (“WAS”), OTL-102 for treatment of X-linked chronic granulomatous 
disease (“X-CGD”), and Strimvelis for adenosine deaminase severe combined immunodeﬁciency 
(“ADA-SCID”). During the year ended 31 December 2022, the Company recognized a one-time charge 
during of approximately $1.7 million, which relates to employee-related termination costs, of which 
$1.4 million and $0.3 million was recognized in research and development expenses and selling, general, 
and administrative expenses, respectively, in the Company's Consolidated statement of proﬁt or loss. 
Our pipeline  
Our pipeline spans multiple therapeutic areas where the disease burden on children, families and 
caregivers is immense and current treatment options are limited or do not exist. 
•
Our programs focused on neurodegenerative disorders consist of our commercial program 
approved in Europe, Libmeldy (OTL-200) for MLD, two clinical proof of concept-stage programs, 
OTL-203 for MPS-I and OTL-201 for mucopolysaccharidosis type IIIA, or MPS-IIIA, and one 
pre-clinical program, OTL-204 for frontotemporal dementia with progranulin mutations, or GRN-FTD.  
•
Our programs in immunological disorders consist of two pre-clinical programs, OTL-104 for 
Crohn’s disease with mutations in the nucleotide-binding oligomerization domain-containing 
protein 2, or NOD2-CD, and OTL-105 for HAE.  
–
In July 2021, we entered into a collaboration with Pharming Group N.V., or Pharming, pursuant 
to which we granted Pharming worldwide rights to OTL-105. Under our agreement with 
Pharming, we will lead the completion of IND-enabling activities of OTL-105 and oversee its 
manufacturing during pre-clinical and clinical development, which will be funded by 
Pharming. Pharming will be responsible for clinical development, regulatory ﬁlings and 
commercialization of OTL-105, if approved, including associated costs. 
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 23
–
We also have a commercial product approved in Europe, Strimvelis for ADA-SCID, an 
advanced registrational clinical program, OTL-103 for Wiskott Aldrich syndrome, or WAS, and 
one clinical proof of concept-stage program, OTL-102 for X-linked chronic granulomatous 
disease, or X-CGD. However, in March 2022, we announced that we would discontinue our 
investment in and seek alternatives for these programs.  
The nature of our autologous gene therapy product candidates precludes the conduct of Phase 1 
safety studies in healthy volunteers. Moreover, considering the indications our product candidates 
are intended to treat, which are often fatal without treatment and which are rare indications with high 
unmet medical need, we believe our clinical programs will generally be eligible to proceed to 
registration based on a single pivotal study given the bioethical considerations regarding the conduct 
of randomized, double-blind and placebo-controlled clinical trials with gene therapies for such 
indications. For purposes of this Annual Report, we refer to an exploratory study, which is sometimes 
referred to as a Phase 1 or Phase 1/2 clinical trial, as a proof of concept trial, and a conﬁrmatory 
efﬁcacy and safety study to support submission of a potential marketing application with the 
applicable regulatory authorities, which is sometimes referred to as a Phase 2/3 or Phase 3 clinical 
trial or a pivotal trial, as a registrational trial.  
Neurodegenerative Disorders  
Gene therapy for treatment of MLD  
Disease overview  
MLD is a rare and life-threatening inherited disease of the body’s metabolic system occurring in 
approximately one in every 100,000 live births in most regions of the world. Higher incidence rates 
are reported in geographies of higher consanguinity, such as Turkey and the Middle East. MLD is 
caused by a mutation in the arylsulfatase-A gene, or ARSA, that results in the accumulation of 
sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or 
spleen. Over time, the nervous system is damaged, leading to neurological problems such as motor, 
behavioral and cognitive regression, severe spasticity and seizures. Patients with MLD gradually lose 
the ability to move, talk, swallow, eat and see. In its late infantile form, mortality at ﬁve years from 
onset is estimated at 50% and 44% at 10 years for juvenile patients. 
Limitations of  current therapies  
Prior to the approval of Libmeldy (OTL-200) in Europe, there were no effective treatments or approved 
therapies for MLD. Palliative care options involve medications for seizures and pain, antibiotics and 
sedatives, on a case-by-case basis, as well as physiotherapy, hydrotherapy and tube feeding or 
gastrostomy when patients can no longer eat without assistance. Palliative care addresses the 
symptoms of MLD but does not slow or reverse the progression of the underlying disease. HSCT 
has limited and variable efﬁcacy in arresting disease progression and, as a result, HSCT is not 
considered to be a standard of care for this disease. MLD patients, their caregivers and families, 
and the healthcare system have faced signiﬁcant burdens given the severity of the disease and the 
lack of effective treatments.  
Our solution, Libmeldy (OTL-200) for treatment of  MLD 
OTL-200 is designed as a one-time therapy that aims to correct the underlying genetic cause of MLD, 
offering eligible patients the potential for long-term positive effects on cognitive development and 
maintenance of motor function at ages at which untreated patients show severe motor and cognitive 
impairments. With OTL-200, a patient’s own HSCs are selected, and functional copies of the ARSA 
gene are inserted into the genome of the HSCs using a lentiviral vector before these genetically 
modiﬁed cells are infused back into the patient. The ability of the gene-corrected HSCs to migrate 
across the blood-brain barrier into the brain, engraft, and express the functional enzyme has the 
potential to persistently correct the underlying disease with a single treatment.  
UK STATUTORY STRATEGIC REPORT 
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24 Orchard Therapeutics plc 
We obtained worldwide rights to this program through our asset purchase and license agreement 
with Glaxo Group Limited and GlaxoSmithKline Intellectual Property Development LTD, or, together, 
GSK. The clinical trials for this program have been conducted under a GSK-sponsored clinical trial 
authorization, which was transferred to us during the third quarter of 2018.  
Libmeldy approval in Europe as Orphan Drug 
In December 2020, the European Commission granted full, or standard, marketing authorization for 
Libmeldy (OTL-200) (autologous CD34+ cell enriched population that contains hematopoietic stem 
and progenitor cells transduced ex vivo using a lentiviral vector encoding the human arylsulfatase-A 
(ARSA) gene) for the treatment of early-onset MLD characterized by biallelic mutations in the ARSA 
gene leading to a reduction of the ARSA enzymatic activity in children with (i) late infantile or early 
juvenile forms, without clinical manifestations of the disease, or (ii) the early juvenile form, with early 
clinical manifestations of the disease, who still have the ability to walk independently and before the 
onset of cognitive decline. 
Libmeldy has received orphan drug designation from the EMA for the treatment of MLD and orphan 
drug status was maintained at the time of approval. We are continuing to follow patients in the clinical 
development program for up to 15 years, and data will be presented to regulators at agreed time 
points in order to further characterize the long-term efﬁcacy and safety of Libmeldy, particularly in 
the early symptomatic early juvenile population.  
Data Supporting the Clinical Proﬁle of  Libmeldy  
The European Commission (EC) approval is supported by clinical studies of Libmeldy in both pre-and 
early- symptomatic, early-onset MLD patients. Early-onset MLD encompasses the disease variants 
traditionally referred to as late infantile, or LI, and early juvenile, or EJ. 
Clinical efﬁcacy supporting EC approval was based on the integrated analysis of results from 
29 patients with early-onset MLD who were all treated with Libmeldy: 
•
20 patients were treated in a clinical study (median follow-up of 4 years); 9 patients were treated 
in expanded access programs (median follow-up of 1.5 years)  
•
16 patients had a diagnosis of LI MLD; 13 had a diagnosis of EJ MLD 
•
At the time of treatment, 20 patients were deemed pre-symptomatic; 9 were deemed 
early-symptomatic 
Clinical safety was evaluated in 35 patients with early-onset MLD: 
•
29 patients from the efﬁcacy analysis supporting EC approval (described above) 
•
6 additional patients treated in another clinical study of Libmeldy 
Co-primary endpoints 
The co-primary endpoints of the integrated efﬁcacy analysis were Gross Motor Function Measure, 
or GMFM, total score and ARSA activity, both evaluated at two years post-treatment. Results of this 
analysis indicate that a single-dose intravenous administration of Libmeldy is effective in modifying 
the disease course of early-onset MLD in most patients. 
Pre-symptomatic LI and EJ patients treated with Libmeldy experienced signiﬁcantly less deterioration 
in motor function at two years and three years post-treatment, as measured by GMFM total score, 
compared to age and disease subtype-matched untreated patients (p≤0.008). The mean difference 
between treated pre-symptomatic LI patients and age-matched untreated LI patients was 71.0% at 
year 2 and 79.8% at year 3. Similarly, the mean difference between treated pre-symptomatic 
UK STATUTORY STRATEGIC REPORT 
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Orchard Therapeutics plc 25
EJ patients and age-matched untreated EJ patients was 52.4% at year 2 and 74.9% at year 3. 
Although not statistically signiﬁcant, a clear difference in GMFM total score was also noted between 
treated early-symptomatic EJ patients and age-matched untreated EJ patients (28.7% at year 2; 
p=0.350 and 43.9% at year 3; p=0.054). 
A statistically signiﬁcant increase in ARSA activity in peripheral blood mononuclear cells was 
observed at 2 years post-treatment compared to pre-treatment in both pre-symptomatic patients 
(20.0-fold increase; p<0.001) and early-symptomatic patients (4.2-fold increase; p=0.004). 
At the time of the integrated data analysis, all treated LI patients were alive with a follow-up 
post-treatment of up to 7.5 years and 10 out of 13 treated EJ patients were alive with a follow-up 
post-treatment of up to 6.5 years. No treatment-related mortality has been reported in patients treated 
with Libmeldy. 
Key secondary endpoints 
For EJ patients who were early-symptomatic when treated with Libmeldy, meaningful effects on motor 
development were demonstrated when these patients were treated before entering the rapidly 
progressive phase of the disease (IQ≥85 and Gross Motor Function Classiﬁcation, or GMFC, ≤1). 
By 4 years post-disease onset, an estimated 62.5% of treated, early-symptomatic EJ MLD patients 
survived and maintained locomotion and ability to sit without support compared with 26.3% of 
untreated early-symptomatic EJ MLD patients, representing a delay in disease progression following 
treatment with Libmeldy. 
A secondary efﬁcacy endpoint that measured cognitive and language abilities as quantiﬁed by 
Intelligence Quotient/Development Quotient, or IQ/DQ, found in the treated LI subgroup, 12 out of 
15 assessed patients had a fairly constant IQ/DQ, within the normal range (IQ/DQ score of 100 +/- SD 
of 15) throughout follow-up. All but two of these patients (i.e., one pre-symptomatic and one 
early-symptomatic) remained above the threshold of severe mental disability (IQ/DQ>55) at 
chronological ages at which all 14 untreated comparator LI patients showed evidence of severe 
cognitive impairment, which is deﬁned as IQ/DQ below 55 and close to zero. Of the 10 surviving 
EJ patients, all 4 pre-symptomatic patients and 4 out of 6 early-symptomatic patients showed normal 
IQ/DQ throughout follow-up. In contrast, 11 out of 12 untreated EJ patients showed evidence of severe 
cognitive impairment during follow-up. 
Clinical trial with cryopreserved drug formulation 
The cryopreserved formulation of OTL-200 is being studied in a clinical trial of pediatric patients with 
pre-symptomatic LI, or pre- to early-symptomatic EJ in Milan, Italy. 
The primary goal of this clinical trial is to assess the safety and efﬁcacy of a cryopreserved 
formulation of OTL-200 in early-onset MLD patients, as measured by improvement in gross motor 
function and ARSA activity levels in the patients’ blood cells as well as overall survival. Secondary 
goals for this clinical trial include assessment of cognitive function through IQ.  
Ten patients were treated in this trial between April 2017 and April 2020. Data, which included six of 
these ten patients, was presented at WORLD Symposium in 2021. The median duration of follow up 
was 0.87 years as of November 2019. Administration was generally well tolerated in all patients, and 
for those with enough follow-up post-treatment, preliminary evidence of engraftment and restoration 
of ARSA activity in peripheral blood to supraphysiological levels and in cerebral spinal ﬂuid, or CSF, 
to normal levels has been shown. The short-term safety proﬁle was comparable between patients 
treated with the fresh formulation. 
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26 Orchard Therapeutics plc 
Data Supporting Safety Proﬁle of  Libmeldy 
The safety of Libmeldy was evaluated in 35 patients with MLD.  
The median duration of follow-up in the integrated safety data set, which included 29 patients treated 
with the fresh (investigational) formulation was 4.51 years. Three patients died and a total of 
26 patients remained in the follow-up phase. The median duration of follow-up in the 6 patients treated 
with the cryopreserved (commercial) formulation was 0.87 years. 
All treated LI patients were alive with a follow-up post-treatment of up to 7.5 years, and 10 out of 
13 treated EJ patients were alive with a follow-up post-treatment of up to 6.5 years. No treatment-related 
mortality has been reported in patients treated with Libmeldy. 
The most common adverse reaction attributed to Libmeldy was presence of anti-ARSA antibodies, 
or AAA. Five events of AAA were observed in four out of 35 patients and were related to treatment. 
Antibody titers were generally low and resolved either spontaneously or after a short course of 
rituximab. In all patients with positive AAA test results, no negative effects were observed in the 
post-treatment ARSA activity of peripheral blood or bone marrow cellular sub populations nor in the 
ARSA activity within the cerebrospinal ﬂuid. No impact on the clinical efﬁcacy or safety outcomes 
were observed.in any of the subjects who reported AAA. In addition to the risk associated with the 
gene therapy, treatment with Libmeldy is preceded by other medical interventions, namely bone 
marrow harvest or peripheral blood mobilization and apheresis, followed by myeloablative 
conditioning, which carry their own risks. During the clinical studies, the safety proﬁles of these 
interventions were consistent with their known safety and tolerability. 
A total of 39 patients have been treated as part of the clinical development program between 
April 2010 and April 2020. An integrated data analysis comparing 39 treated patients to a natural 
history study cohort was presented at WORLD Symposium in 2023. Consistent with previously 
published results (Fumagalli et al Lancet 2022), these results combining the original 29 subjects with 
the 10 treated patients from the study evaluating the cryopreserved formulation, with longer follow-up 
(median 6.15 years, max 11.03 years), show a continued favorable beneﬁt-risk proﬁle for arsa-cel in 
pre-symptomatic LI and EJ and early-symptomatic EJ MLD. Arsa-cel was generally well tolerated 
with no treatment-related SAEs or treatment-related deaths. 
OTL-200 development in the U.S. 
OTL-200 has received orphan drug designation for the treatment of MLD as well as Rare Pediatric 
Disease designation. In late 2020, the FDA cleared our IND application for OTL-200 in the U.S., and 
in January 2021, FDA granted regenerative medicine advanced therapy, or RMAT, designation for 
OTL-200. Based on feedback received from the FDA, we are preparing for a BLA ﬁling for OTL-200 
in pre-symptomatic, early-onset MLD patients, expected in mid-2023, using data from existing 
OTL-200 patients. This approach and timeline are subject to the successful completion of activities 
remaining in advance of a pre-BLA meeting with the FDA, scheduled for the second quarter of 2023. 
Gene therapy for treatment of MPS-IH 
Disease overview  
Mucopolysaccharidosis type I is a lysosomal storage disease caused by a deﬁciency of the lysosomal 
enzyme alpha-L-iduronidase, or IDUA. Inherited deﬁciency of IDUA is responsible for MPS-I. Without 
treatment, clinical manifestations of this severe disease include skeletal abnormalities with severe 
orthopedic manifestations, hepatosplenomegaly, neurodevelopmental decline, sight and hearing 
disturbances, cardiovascular and respiratory problems leading to death in early childhood. IDUA 
deﬁciency can result in a wide range of clinical severity, with three major recognized clinical entities: 
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Orchard Therapeutics plc 27
(1) Hurler, or MPS-IH, (2) Scheie, or MPS-IS (3) and Hurler-Scheie, or MPS-IH/S, syndromes. MPS-IH is 
the most severe form of MPS-I. 
The median age of diagnosis for MPS-IH is 12 months, and most affected children are diagnosed before 
18 months of age. Infants affected by MPS-IH may appear normal at birth, but progress to develop 
symptoms such as kyphosis of the spine, and inguinal or umbilical hernias in the ﬁrst six months, 
developing the characteristic somatic phenotype over the ﬁrst few years of life.  
The approximate incidence of MPS-I is of one in 100,000 live births. Approximately 60 percent of children 
born with MPS-I have MPS-IH. 
Limitations of  current therapies  
Allogeneic-HSCT, or allo-HSCT, which is commonly accompanied by pre- and peri-transplant enzyme 
replacement therapy, or ERT, from diagnosis to engraftment, has been established as the standard 
of care for MPS-IH patients with preserved cognition. The recommendation of allo-HSCT as the 
standard of care for MPS-IH patients is endorsed by the European Society for Blood and Marrow 
Transplantation and the American Society for Transplantation and Cellular Therapy. 
Despite its established position in treatment algorithms, allogeneic-HSCT can result in alloreactive 
complications, including and graft versus host disease or death, particularly when the degree of 
matching between graft donor and recipient is poor. Additionally, there remains a signiﬁcant disease 
burden in those treated, even if treated early in life, including severely debilitating cognitive, 
neurological, growth, orthopedic, cardiac, respiratory and ophthalmic manifestations, all of which 
are reported during long-term post-HSCT follow-up.  
Our solution, OTL-203 for treatment of  MPS-IH 
Ex vivo autologous HSC gene therapy strategies aimed at correcting the genetic defect in patients 
could represent a signiﬁcant improvement for the treatment of MPS-I, notably MPS-IH, the most severe 
and prevalent phenotype with the highest unmet medical need, when compared to current treatments.  
OTL-203 is a single administration, gene therapy product candidate consisting of autologous CD34+ 
enriched HSPCs, derived from mobilized peripheral blood, genetically modiﬁed ex vivo with the 
lentiviral vector encoding for the IDUA complementary DNA, or cDNA. It is being developed as a 
cryopreserved formulation. Ex vivo autologous gene therapies, such as OTL-203, are designed to 
correct the genetic defect in patients’ own HSCs and their progeny by addition of functional cDNA. 
The OTL-203 mechanism of action, or MOA, addresses the disease pathophysiology by restoring 
enzymatic IDUA expression in peripheral and central body compartments as well as restoring 
microglia homeostasis in the central nervous system, or CNS, to confer neuroprotective effects 
against the neurotoxic effects of glycosaminoglycan, or GAG, accumulation in affected cells.  
The achievement of long-term sustained correction of the manifestations of MPS-IH occurs via local 
secretion of functional IDUA enzyme, which facilitates the efﬁcient clearance of GAGs. This MoA is 
based on the local release of IDUA enzyme from genetically corrected cells containing functional 
copies of the IDUAgene into the extracellular space, which is in turn taken up by neighboring cells 
in a process referred to as “cross-correction.” Animal models have shown that genetically modiﬁed 
cells are able to cross the blood brain barrier and can provide cross-correction within the CNS. 
Engraftment of these cells within the CNS gives rise to monocyte-derived microglia-like cells that 
secrete the functional IDUA enzyme, which is taken up by neuronal and glial cells via 
cross-correction.  
One way in which OTL-203 differs from allo-HSCT is the ability of the transduced autologous cells to 
produce supraphysiological levels of IDUA enzyme in peripheral compartments and increased IDUA 
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28 Orchard Therapeutics plc 
levels in central compartments in both non-clinical and clinical settings. This difference may be 
important because multivariate analyses have consistently identiﬁed higher post-HSCT IDUA levels 
as predictors of outcomes with lower residual disease burden in multiple organ systems, including 
skeletal, ophthalmic, cardiac, auditory and respiratory. It is therefore hypothesized that the presence 
of supraphysiological levels of IDUA enzyme in peripheral compartments may help overcome the 
limitations of allo-HSCT by enhancing the cross-correction process, by enabling presence of greater 
quantities of available enzyme in difﬁcult-to-reach protected (i.e., brain) or avascular compartments 
(i.e., eye and joint tissue) and better enable clearance of GAGs in hard-to-reach tissues.  
In addition, OTL-203 has the potential to overcome safety issues associated with the current standard 
of care. Compared to allogeneic transplantation, which is the current standard of care for MPS-IH 
treatment, the autologous nature of OTL-203 is associated with a signiﬁcantly reduced transplant-related 
morbidity and mortality and avoidance of graft versus host (both acute and chronic) and immune 
mediated graft rejection. 
We have obtained worldwide development and commercialization rights to OTL-203 from Telethon 
Foundation and San Raffaele Hospital. 
OTL-203 has received orphan drug and PRIME designation from the EMA as well as orphan drug 
designation and rare pediatric disease designation from the FDA for the treatment of MPS-I.  
Ongoing clinical trials 
OTL-203 is currently being investigated in an ongoing, academic-sponsored clinical trial at the 
San Raffaele Hospital in Milan, Italy to establish proof of concept. The study is a prospective, single 
dose, single center, non-randomized, open label study involving a single administration of OTL-203 
in eight patients with a conﬁrmed diagnosis of MPS-IH. The study is fully enrolled using a 
cryopreserved formulation of OTL-203.  
The patients evaluated in this trial include pediatric MPS-IH patients from 14 to 34 months of age at 
the time of treatment and will be followed for at least ﬁve years post-treatment in the context of the 
proof of concept study and then continue to be evaluated in a long-term follow-up study.  
In September 2022, we announced the presentation of the interim clinical results from the ongoing 
academic-sponsored clinical trial at the San Raffaele Hospital. For this presentation’s last follow up 
of all patients (range: 24 and 36 months), interim data supporting clinical proof-of-concept illustrated 
that treatment with OTL-203 was generally well-tolerated with a safety proﬁle consistent with the 
selected conditioning regimen. IDUA antibodies present prior to gene therapy as a result of ERT 
were not seen in any patient within three months following treatment. In addition, ERT was 
discontinued at least three weeks prior to any patient receiving gene therapy treatment, and no 
patients had re-started ERT post-treatment. 
In December 2022 we received IND clearance of OTL-203 from the FDA, which allows us to initiate 
a global registrational study in MPS-IH. We plan to initiate the study, which will include centers across 
the US and Europe, in the second half of 2023.  
The study will be a multi-center, randomized, active controlled clinical trial designed to evaluate the 
efﬁcacy and safety of OTL-203 in patients with MPS-IH compared to standard of care with allogeneic 
hematopoietic stem cell transplant. A total of 40 patients with a conﬁrmed diagnosis of MPS-IH who 
meet the study inclusion criteria will be randomized 1:1 to receive either OTL-203 or allogeneic HSCT. 
The study is powered to demonstrate superiority of OTL-203 over allo-HSCT. 
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Orchard Therapeutics plc 29
Gene therapy for treatment of MPS-IIIA  
Disease overviews  
MPS-IIIA, also known as Sanﬁlippo syndrome type A, is a life-threatening metabolic disease that 
causes accumulation of glycosaminoglycan in cells, tissues and organs, particularly in the brain. 
Within the ﬁrst years after birth, MPS-IIIA and MPS-IIIB patients begin to experience progressive 
neurodevelopmental delay and decline, including speech delay and eventual loss of language, 
behavioral disturbances and potentially severe dementia. Ultimately, most patients with MPS-IIIA 
progress to a vegetative state. Life expectancy for patients with MPS-IIIA is between 10 to 25 years.  
The incidence of MPS-IIIA is currently estimated to be one in 100,000 live births per year.  
Limitations of  current therapies  
Currently, there are no effective treatments or approved therapies for MPS-IIIA. Palliative care options 
involve medications for seizures and pain, antibiotics and sedatives, on a case-by-case basis, as 
well as physiotherapy, hydrotherapy and tube feeding or gastrostomy when patients can no longer 
eat without assistance. Palliative care addresses the symptoms of MPS-IIIA but does not slow or 
reverse the progression of the underlying disease. Systemic ERT is not an approved treatment option 
and HSCT is not considered to be an effective treatment option for these diseases. The severity of 
symptoms and lack of an effective treatment option to manage these symptoms is a signiﬁcant 
burden to MPS-IIIA patients, their caregivers and families and healthcare systems.  
Our solutions, OTL-201 for treatment of  MPS-IIIA 
We are developing OTL-201 as an ex vivo autologous HSC gene therapy for treatment of patients 
with MPS-IIIA. We believe pre-clinical studies in mice have shown that ex vivo autologous gene 
therapy has the potential to address the neurological manifestations of MPS-IIIA. We have obtained 
worldwide development and commercialization rights to OTL-201 from The University of Manchester.  
OTL-201 has received orphan drug designation from the EMA and FDA for the treatment of MPS-IIIA 
and has received rare pediatric disease designation from the FDA.  
Proof  of  concept trial in MPS-IIIA  
We are supporting a proof-of-concept trial for the treatment of MPS-IIIA, which started enrollment in 
January 2020. The trial, which is being conducted by the Royal Manchester Children’s Hospital and 
sponsored by the Manchester University NHS Foundation Trust, completed enrollment in 2021 with 
the ﬁfth patient treated in September 2021.  
Early clinical ﬁndings, including the ﬁrst neurocognitive results, from the proof-of-concept trial were 
presented at the American Society of Hematology (ASH) Annual Meeting in December 2022 and at 
the WORLD Symposium in February 2023. The data, which encompassed follow-up ranging from 
9 to 24 months, showed robust, prompt, sustained, multi-lineage engraftment of genetically modiﬁed 
cells. Supraphysiological levels of SGSH enzyme were seen in leukocytes, plasma and CSF and 
rapid and reduction of substrate (glycosaminoglycans, GAGs) observed in all compartments.  
Early neurocognitive outcomes also indicated that since receiving OTL-201, four out of ﬁve patients 
showed gain of cognitive skills in line with development in healthy children. The oldest patient at last 
follow up has maintained this normal cognitive development since treatment, despite reaching a 
chronological age where cognition is observed to decline in natural history patients, showing 
improvement from this comparator. Three additional patients are currently within the normal 
development quotient (DQ) range at 9 to 18 months post-treatment but require longer follow-up to 
assess outcomes. 
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30 Orchard Therapeutics plc 
Treatment with OTL-201 was generally well-tolerated in the initial study population. Of the six serious 
adverse events (SAEs) reported to date, four were determined to be due to conditioning or 
leukapheresis and one was related to background disease. One patient had delayed platelet 
engraftment until day 52 post-treatment, likely due to Cytomegalovirus infection around the time of 
infusion. 
Research program in FTD  
Disease overview  
Frontotemporal Dementia, or FTD, is the second most common cause of dementia after Alzheimer 
Disease in people under the age of 65. FTD is due to the atrophy of the frontal and temporal lobes 
of the brain. The disease manifests with progressive changes in behavior and personality, starting 
with symptoms such as decline in social and personal interactions, depression, apathy, emotional 
blunting, disinhibition and language disorders, and then progressing to general cognitive impairment 
at a later stage. In ~5% of patients, FTD is caused by mutations in one copy (haploinsufﬁciency) of 
the gene that codes for progranulin, or GRN. GRN is a neurotrophic, anti-inﬂammatory factor that is 
produced and secreted among others by specialized cells in the brain called microglia cells. 
GRN produced by microglia cells can be taken up by neighboring neurons, helping them to be 
healthy and functional. Since GRN-FTD patients’ cells do not produce enough GRN, brain 
inﬂammation develops with time and neurons become progressively dysfunctional until they eventually 
die, leading to brain atrophy and the aforementioned symptoms.  
We believe there are currently up to 2,500 people affected by GRN-FTD in Europe and the U.S., with 
approximately 800 new cases per year. 
Limitations of  current therapies  
There are no treatments available for FTD and death occurs six to nine years after onset. 
Our solution, OTL-204 for treatment of  FTD 
OTL-204 is an ex vivo autologous HSC gene therapy being developed to replace the defective 
microglia cells in the brain of GRN-FTD patients with genetically modiﬁed microglia cells that produce 
and secrete a corrective amount of GRN. These cells develop naturally from HSCs, which are 
collected from the patient and modiﬁed by using a viral vector that brings a functional copy of the 
GRN gene. When they are infused in the patient, the genetically modiﬁed HSCs naturally reach the 
brain and become resident microglia cells. OTL-204 is being developed in partnership with Professor 
Alessandra Bifﬁ at the University of Padua in Italy. As part of the collaboration, we initiated a 
sponsored research agreement with the University of Padua and obtained an exclusive option with 
Boston Children’s Hospital to develop and exclusively license the program. 
Pre-clinical development of  OTL-204 
Preliminary in vitro data obtained in 2020 have demonstrated that human cell lines and mouse HSCs 
can be efﬁciently transduced to produce GRN. GRN is then secreted in the culture medium and can 
be taken up by other types of cells that do not produce GRN themselves. 
Preliminary in vivo data from the pre-clinical proof-of-concept study showed that murine GRN-/- 
HSPCs, transduced with an LV expressing progranulin under the control of a novel promoter, are able 
to engraft and repopulate the brain myeloid compartment of FTD mice and to locally deliver the GRN 
enzyme. 
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Orchard Therapeutics plc 31
Immunological Disorders  
Research program in NOD2-Crohn’s Disease  
Disease overview  
Crohn’s Disease, or CD, is a form of Inﬂammatory Bowel Disease, or IBD, a condition affecting the 
gastrointestinal tract caused by an uncontrolled and chronic inﬂammatory process directed against 
intestinal bacteria. Mutations in a number of genes are known to confer susceptibility to the risk of 
CD, and among these the NOD2 gene (nucleotide-binding oligomerization domain-containing protein 
2) is known to be the most common genetic factor, with 20-40% of Crohn’s patients carrying mutations 
causing defective NOD2 activity. NOD2 encodes a cell receptor which controls bacterial elimination 
by innate immune cells such as macrophages through recognition of bacterial peptide (MDP) and 
induction of a pro-inﬂammatory immune response. NOD2 deﬁciency results in an impaired detection 
and clearance of bacteria penetrating the gut during gastrointestinal infection, creating an unchecked 
and relapsing inﬂammation within the intestinal tissues characterized by intestinal granuloma 
formation. This leads to recurrent clinical symptoms of chronic abdominal pain, diarrhea, weight loss, 
fatigue, malnutrition and for some patients, more severe intestinal damage requiring surgical 
resection. NOD2-CD patients typically present with more severe symptoms and are reported to be 
more refractory to existing therapies. 
The incidence of CD is high compared to our other indications, with estimates of 100 to 200 patients 
per million in Europe and North America. Epidemiological studies suggest NOD2 genetic variants 
causing functional defects are associated with 7 to 10% of all cases of CD, with up to 200,000 patients 
in the U.S. and Europe with two NOD2 mutated alleles. 
Limitations of  current therapies  
Current clinical management for Crohn’s disease includes use of immune-suppressive medications, 
biological agents such as anti-TNF, steroids and surgical resection. There is currently no cure for 
Crohn's disease, and long-term, effective treatment options are limited. Several clinical trials have 
evaluated autologous HSCT in Crohn’s disease, although with limited success. There remains a need 
for therapeutic modalities that target underlying causes of Crohn’s disease to achieve effective 
amelioration of symptoms and disease remission. 
Our solution, OTL-104 for treatment of  NOD2-CD 
We are developing OTL-104 to evaluate its therapeutic efﬁcacy as an ex vivo autologous HSC gene 
therapy to treat patients with NOD2-CD through a single administration. As the pathogenesis of 
NOD2-CD is associated with the function of cells of the hematopoietic system, ex vivo autologous 
HSC gene therapy may therefore be used to restore NOD2 function to immune cells such as tissue 
resident macrophages within the gastrointestinal tract. Our OTL-104 program is being designed to 
introduce the NOD2 gene into cells of the hematopoietic system by lentiviral transduction of a 
patient’s own blood or bone marrow derived HSCs, and the gene-modiﬁed cells can then be infused 
back into the patient. Clinical observations in the allogeneic transplant setting, where HSCT has 
resulted in the clinical reversion of Crohn’s Disease and other monogenic forms of IBD, supports the 
scientiﬁc rationale and mode of action of OTL-104. We own patent applications in the United States 
and other jurisdictions and all other intellectual property rights associated with the OTL-104 program.  
Pre-clinical development of  OTL-104 
OTL-104 pre-clinical work has shown that restoration of NOD2 gene expression in murine and human 
stem cells can rescue a defective myeloid immune response to MDP. NOD2 defective inﬂammatory 
functions in primary human myeloid cells can be restored by both lentiviral and gene editing 
approaches. The OTL-104 lentiviral vector is designed to express NOD2 under the chimeric 
CathepsinG/cFES promoter to deliver myeloid directed transgene expression. Pre-clinical studies to 
evaluate the safety of this approach show that NOD2-LV gene modiﬁcation of human CD34+stem 
UK STATUTORY STRATEGIC REPORT 
continued 

 
32 Orchard Therapeutics plc 
cells and murine lineage negative stem cells does not affect HSC engraftment or immune subset 
development and differentiation following transplantation into NSG or NOD2-KO mice, respectively. 
Transplantation of NOD2-LV gene modiﬁed murine stem cells further demonstrates that HSC derived 
cells can efﬁciently migrate and reconstitute the myeloid cell compartments of intestinal tissue, 
restoring a normal biodistribution of NOD2 expression within the gut. 
Pre-clinical proof-of-concept studies include in vivo colitis disease modeling and a non-interventional 
clinical research study using NOD2-genetically deﬁned patients with Crohn’s Disease. We have 
generated in vivo evidence that defective monocyte functions in NOD2-KO mice can be corrected 
by OTL-104 gene therapy, restoring NOD2-dependent systemic cytokine responses and innate 
immune cell mobilization. In vitro, myeloid cells differentiated from CD34+ cells obtained from 
peripheral blood of genetically characterized NOD2 deﬁcient CD patients, are refractory to MDP 
stimulation and unable to generate a normal cytokine response proﬁle. LV transduction of 
NOD2-deﬁcient patient cells restores MDP-induced cytokine responses to levels comparable to those 
observed in monocytes derived from CD34+ cells from healthy donors, correcting a NOD2-defective 
phenotype. Orchard’s OTL-104 program is currently under development towards IND-/ CTA- enabling 
toxicology / biodistribution studies. 
Other programs 
In March 2022, we announced that we would discontinue our investment in and seek alternatives for 
Strimvelis, OTL-103 for treatment of WAS and OTL-102 for treatment of X-CGD.  
Future applications of our ex vivo autologous HSC gene therapy approach  
We believe that our versatile ex vivo autologous HSC gene therapy approach has the potential to 
deliver promising gene therapies to patients across a broad range of diseases. Although our 
near-term focus is on delivering our commercial and clinical-stage gene therapies to patients suffering 
from several rare diseases described above, we believe we can leverage our signiﬁcant research 
and development experience and partnerships with academic institutions to identify other diseases 
in our target areas, including neurodegenerative, immunological and blood disorders, where ex vivo 
gene therapy may have a comparably higher probability of success as compared to other 
approaches our mid- to long-term strategy is to leverage our HSC gene therapy approach in 
additional larger indications, seeking development partnerships as the programs advance towards 
the clinic. One partnership already established in 2021 is our collaboration with Pharming on OTL-105, 
as referenced above. 
Our regulatory strategy  
The nature of our autologous gene therapy product candidates precludes the conduct of Phase 1 
safety studies in healthy volunteers. Moreover, considering the indications our product candidates 
are intended to treat, which are often fatal without treatment and which are rare indications with high 
unmet medical need, we believe our clinical programs will generally be eligible to proceed to 
registration based on a single pivotal study given the bioethical considerations regarding the conduct 
of randomized, double-blind and placebo-controlled clinical trials with gene therapies for such 
indications. Both the FDA and EMA provide expedited pathways for the development of drug product 
candidates for the treatment of rare diseases, particularly life-threatening diseases with high unmet 
medical need. Such drug product candidates may be eligible to proceed to registration following 
one or more clinical trials in a limited patient population, following review of the trial’s design, 
endpoints and clinical data by the applicable regulatory agencies. These determinations are based 
on the applicable regulatory agency’s scientiﬁc judgment and these determinations may differ in the 
United States and the European Union.  
UK STATUTORY STRATEGIC REPORT 
continued 

In some cases applicable regulatory agency may require us to perform analytical studies or conduct 
additional clinical trials to support analytical comparability of drug product, for example by 
demonstrating comparability of drug product manufactured using HSCs derived from a patient’s 
mobilized peripheral blood and drug product manufactured using HSCs derived from a patient’s 
bone marrow and/or comparability of drug product that has been cryopreserved and fresh drug 
product. For the purposes of this Annual Report we refer to these clinical trials as supportive clinical 
trials. In addition, certain of our product candidates may be evaluated in clinical trials for which clinical 
data is not intended to be pooled with data from our registrational trials for the purposes of a 
regulatory submission but will be submitted to the applicable regulatory agencies for informational 
purposes. For the purposes of this Annual Report we refer to these trials as additional clinical trials. 
In addition, in some cases patients may be ineligible for participation in our clinical trials and may 
receive treatment under a compassionate use program or an expanded access program. We expect 
that the available safety and efﬁcacy results from all these trials would be included in any regulatory 
submission we may submit, and the applicable regulatory agency with respect to each clinical 
program will make a determination as to whether the available data is sufﬁcient to support a regulatory 
submission.  
Manufacturing  
The diseases we are targeting affect patients across the world. Therefore, we are implementing plans 
to enhance our partnerships with CDMOs and leverage technologies that will allow us to deliver our 
gene therapies globally.  
Global supply network with experienced CDMOs  
We currently partner with a network of experienced CDMOs, including AGC Biologics S.p.A. (formerly 
MolMed S.p.A.) and Oxford BioMedica, for the supply of our vectors and drug products, including 
Libmeldy. We have established relationships with commercial CDMO partners with the resources and 
capacity to meet our clinical and existing and expected initial commercial needs. Our CDMO partners 
also provide us with access to their state-of-the art manufacturing technologies.  
Manufacturing efficiencies and scalability  
We are investing in human capital and advancing manufacturing technologies for HSC-based 
autologous ex vivo gene therapies. We have licensed lentiviral vector stable cell line technologies 
from GSK, completed transduction enhancer screening processes, established a vector process 
development lab at a Catapult Network facility in the UK, and are in the process of building cell 
therapy and analytical development capabilities at our London, UK global headquarters. We seek to 
enhance our product and process understanding while actively exploring and developing innovative 
technologies for vector and drug product manufacturing to improve the efﬁciency and scalability of 
manufacturing processes with an ultimate goal to reliably manufacture high quality products for rare 
diseases and larger indications at lower cost. For example, we have identiﬁed and validated several 
transduction enhancing compounds in order to facilitate lentiviral vector entry into HSCs, showing a 
greater than 50% reduction in vector requirements. We continue to invest in our people to support 
the commercialization and life cycle management of our pipeline products.  
Cryopreservation of our gene therapy programs  
Cryopreservation of gene-modiﬁed cells is a key component of our strategy to deliver innovative, 
potentially curative gene therapies to patients worldwide. We have developed cryopreserved 
formulations of our OTL-200 program and expect to demonstrate comparability of our cryopreserved 
formulations to earlier manufactured fresh formulations in support of future submissions for marketing 
 
Orchard Therapeutics plc 33
UK STATUTORY STRATEGIC REPORT 
continued 

 
34 Orchard Therapeutics plc 
approval in the United States and Europe. Our programs in OTL-203 and OTL-201 have already 
started or will start with cryopreserved formulations. We plan to establish cryopreserved product 
formulations as the standard for all of our future gene therapy candidates.  
In the cryopreservation process, a patient’s gene-modiﬁed HSCs are frozen at extremely low 
temperatures and then stored to allow quality control testing and release to be performed before 
introducing the gene-modiﬁed cells back into the patient. Our cryopreserved formulations are 
expected to have shelf-lives of months to years, enabling us to potentially distribute our products 
and product candidates from a few centralized manufacturing facilities to geographically dispersed 
treatment sites. Our ability to ultimately distribute our product candidates globally will facilitate access 
of the therapies to patients and reduce the logistical burden on patients and their families.  
Commercial operations 
We have launched Libmeldy (OTL-200) for the treatment of early-onset MLD following receipt of full, 
or standard, marketing approval from the European Commission in December 2020. We have secured 
agreements with several major European markets, including the U.K., Italy, Germany and Sweden, to 
enable access and reimbursement for all eligible patients with MLD. In addition, we have secured 
the renewal of the early access program in France, under which the Company receives 
reimbursement for the treatment of any eligible patient with MLD. We have recognized revenue from 
commercial treatments from markets with reimbursement agreements, early access mechanisms, 
treatment abroad programs and European cross-border (S2) pathways. Subject to approval of 
OTL-200 by the FDA, we also plan to put in place commercial operations and treatment centers in 
the U.S.  
We are building our commercial capabilities by employing individuals with broad experience in quality 
assurance and compliance, medical education, marketing, supply chain, sales, public policy, patient 
services, market access and product reimbursement. We will need to expand these capabilities as 
we continue to implement appropriate quality systems, compliance policies, systems and procedures, 
as well as internal systems and infrastructure in order to support our supply chain, qualify and train 
additional treatment centers, establish patient-focused programs, educate healthcare professionals, 
and secure reimbursement. The timing and conduct of these commercial activities will be dependent 
upon regulatory approvals and on agreements we have made or may make in the future with strategic 
collaborators.  
As part of the commercialization process, we are engaged in discussions with stakeholders across 
the healthcare system, including public and private payors, patient advocates and organizations, 
and healthcare providers, to drive more timely patient identiﬁcation through education, newborn 
screening, and diagnostic initiatives and to explore new payment models that we hope will enable 
broader patient access. We have initiated over a dozen newborn screening studies in Europe, the 
Middle East and the U.S., six of which are actively screening. To date, there have been three 
genetically conﬁrmed cases of MLD after screening of approximately 96,000 newborns globally. One 
of these cases has been assessed clinically and referred for treatment with Libmeldy with the other 
two more recently identiﬁed patients pending clinical assessment. 
We are engaging with European country- and regional-level payment authorities to negotiate further 
reimbursement and access for Libmeldy.  
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 35
Intellectual property and barriers to entry  
Our commercial success depends, in part, upon our ability to protect commercially important and 
proprietary aspects of our business, defend and enforce our intellectual property rights, preserve 
the conﬁdentiality of our know-how and trade secrets, and operate without infringing, 
misappropriating and otherwise violating valid and enforceable intellectual property rights of others. 
In particular, we strive to protect the proprietary aspects of our business and to develop barriers to 
entry that we believe are important to the development and commercialization of our gene therapies. 
For example, where appropriate, we develop, or acquire exclusive rights to, clinical data, patents, 
know-how and trade secrets associated with each of our products and product candidates. However, 
we do not own any patents or patent applications that cover Libmeldy or any of our lead product 
candidates. We cannot guarantee that patents will issue from any of existing patent applications or 
from any patent applications that we or our licensors may ﬁle in the future, nor can we guarantee that 
any patents that may issue in the future from such patent applications will be commercially useful in 
protecting our products and product candidates. In addition, we plan to rely on regulatory protection 
based on orphan drug exclusivities, data exclusivities and market exclusivities. See “—Government 
regulation” for additional information.  
We currently rely primarily on know-how and trade secret protection for aspects of our proprietary 
technologies that we or our licensors believe are not amenable to or appropriate for patent protection, 
including, for example, clinical data and production information for Libmeldy, Strimvelis and each of 
our product candidates. Nonetheless, know-how and trade secrets can be difﬁcult to protect. 
Although we take steps to protect our know-how, trade secrets and other proprietary information, 
including restricting access to our premises and our conﬁdential information, as well as entering into 
agreements with our employees, consultants, advisors and potential collaborators, third parties may 
independently develop the same or similar know-how, trade secrets or proprietary information or may 
otherwise gain access to such know-how, trade secrets and other proprietary information or such 
know-how, trade secrets or other proprietary information may otherwise become known. Moreover, 
we cannot guarantee that our conﬁdentiality agreements will provide meaningful protection or that 
they will not be breached, and we may not have an adequate remedy for any such breach. As a 
result, we may be unable to meaningfully protect our know-how, trade secrets and other proprietary 
information.  
In addition, with regard to patent protection, the scope of coverage being sought in a patent 
application may be reduced signiﬁcantly before a patent is issued, and even after issuance the scope 
of coverage may be challenged. As a result, we cannot guarantee that any of our product candidates 
will be protectable or remain protected by enforceable patents. We cannot predict whether the patent 
applications we are currently pursuing will issue as patents in any particular jurisdiction or whether 
the claims of any issued patents will provide sufﬁcient proprietary protection from competitors. Any 
patents that we hold may be challenged, circumvented or invalidated by third parties.  
With regards to OTL-200 and as discussed in detail in “—License agreements”, we have exclusive, 
worldwide, sublicensable licenses pursuant to our asset purchase and license agreement with GSK, 
or the GSK Agreement, and the R&D Agreement to anonymized patient-level data arising from the 
clinical trials of OTL-200 and know-how, including other clinical data and production information 
relating to OTL-200. 
The term of individual patents depends upon the legal term of the patents in the countries in which 
they are obtained. In most countries in which we are seeking patent protection for our product 
candidates, the patent term is 20 years from the earliest date of ﬁling a non-provisional patent 
application. In the United States, the term of a patent may be lengthened by a patent term adjustment 
UK STATUTORY STRATEGIC REPORT 
continued 

 
36 Orchard Therapeutics plc 
to accommodate for administrative delays caused at the U.S. Patent and Trademark Ofﬁce, or USPTO, 
or may be shortened if another patent has a terminal disclaimer with an earlier expiration date. 
Furthermore, in the United States, the term of a patent covering an FDA-approved drug may be 
eligible for a patent term extension under the Hatch-Waxman Amendments as compensation for the 
loss of patent term during the FDA regulatory review process. The period of extension may be up to 
ﬁve years beyond the expiration of the patent but cannot extend the remaining term of a patent 
beyond a total of 14 years from the date of product approval. Only one patent among those eligible 
for an extension may be extended. Similar provisions are available in Europe and in certain other 
jurisdictions to extend the term of a patent that covers an approved drug. In the future, if we obtain 
any additional issued U.S. patents covering one of our present or future product candidates, and if 
such product candidate receives FDA approval, we expect to apply for a patent term extension, 
if available, to extend the term of the patent covering such approved product candidate. We also 
expect to seek patent term extensions in any jurisdictions where they are available, but there is no 
guarantee that the applicable authorities, including the FDA, will agree with our assessment of 
whether such an extension should be granted, and even if granted, they may disagree with our 
assessment of the appropriate length of such an extension.  
License agreements  
GSK asset purchase and license agreement  
In April 2018, we entered into the GSK Agreement, pursuant to which GSK transferred its portfolio of 
approved and investigational rare disease gene therapies to us, which included Strimvelis and 
OTL-200 for MLD, among other programs. GSK also simultaneously novated to us their 
R&D Agreement with Telethon-OSR. 
Under the GSK Agreement, we are subject to certain diligence obligations to develop and advance 
certain of the acquired product candidates. For example, we were required to use best endeavors 
to ﬁle an MAA for OTL-200 for MLD in either Europe or a BLA for MLD in the United States and to 
subsequently use commercially reasonable efforts to ﬁle an MAA or BLA, as applicable, in the other 
jurisdiction and to market, sell and promote OTL-200 in such jurisdictions. In December 2020, we 
received full, or standard, marketing authorization for Libmeldy in the European Union as well as the 
United Kingdom, Iceland, Liechtenstein and Norway. 
We are also required to use commercially reasonable efforts to obtain a priority review voucher, or 
PRV, from the FDA for certain programs, including OTL-200, and to transfer the ﬁrst such PRV to GSK. 
GSK also has an option to acquire at a deﬁned price any PRVs granted to us thereafter for certain 
programs. In the event that GSK does not exercise this option with respect to any PRV, we may sell 
the PRV to a third party and must share any proceeds in excess of a speciﬁed sale price equally 
with GSK.  
Under the GSK Agreement we are also obligated to pay non-refundable royalties and milestone 
payments in relation to the gene therapy programs acquired. For example, for Libmeldy, we pay a 
tiered royalty rate at percentages from the mid-teens to the low twenties. These royalties owed to 
GSK are in addition to any royalties owed to other third parties under various license agreements for 
the GSK programs. In aggregate, we may pay up to £90.0 million in milestone payments upon 
achievement of certain sales milestones. Our royalty obligations with respect to OTL-200 may be 
deferred for a certain period in the interest of prioritizing available capital to develop each product. 
Our royalty obligations are subject to reduction on a product-by-product basis in the event of market 
control by biosimilars and will expire in April 2048.  
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 37
We may terminate our development or commercialization activities of any of the programs under the 
GSK Agreement upon the occurrence of a serious adverse event, or SAE, if we believe such program 
poses a safety risk to patients and in certain additional situations. GSK may require us to grant a 
third party a non-exclusive license under the intellectual property we have acquired from GSK under 
the GSK Agreement if we materially breach our obligations to use best endeavors or commercially 
reasonable efforts, as applicable, to develop and commercialize the acquired programs and fail to 
develop and implement a mutually agreeable plan to cure such material breach within a speciﬁed 
time period. The foregoing hypothetical license would only continue until such time as we cured our 
material breach, and we would be required to pay GSK all amounts we received from the third party 
in connection with such license.  
Telethon-OSR research and development collaboration and license agreement  
In April 2018, in connection with our entering into the GSK Agreement, we entered into a deed of novation 
with GSK, Telethon Foundation and San Raffaele Hospital, together referred to as Telethon-OSR, 
pursuant  to which we acquired and assumed all of GSK’s rights and obligations under the 
R&D Agreement with Telethon-OSR for the research, development and commercialization of ex vivo HSC 
gene therapies for certain programs, including OTL-200 and Strimvelis. 
Pursuant to the R&D Agreement, Telethon-OSR granted to GSK an exclusive, worldwide, 
sublicensable license under certain intellectual property rights to develop and commercialize ex vivo 
gene therapy products for the treatment of ADA-SCID. In addition, Telethon-OSR had granted to GSK 
an exclusive option for an exclusive, sublicensable, worldwide license under certain intellectual 
property rights to develop and commercialize certain vectors and gene therapy products from 
disease-speciﬁc development programs for the treatment of certain other diseases, including MLD. 
At the time we entered into the novation agreement, GSK had completed development, launched 
and commercialized Strimvelis for ADA-SCID in the European Union, and had exercised its exclusive 
option to obtain exclusive licenses from Telethon-OSR to certain programs, including MLD. We 
acquired Strimvelis and GSK’s exclusive licenses relating to the ADA-SCID and MLD programs, 
among others, pursuant to the GSK Agreement and the deed of novation.  
Under the R&D Agreement, Telethon-OSR is required to use commercially reasonable efforts to 
conduct each of the collaboration programs in accordance with development plans approved by a 
joint steering committee. With respect to those programs in relation to which our option has been 
exercised, we are required to use commercially reasonable efforts to develop, obtain regulatory 
approval, launch and promote in both the European Union and the United States all licensed products 
and to commercialize and manufacture such products at levels sufﬁcient to meet commercial 
demands. We are required to use best efforts to renew the European Union marketing authorization 
for Strimvelis to enable patients to be treated at the San Raffaele hospital from all referring centers 
globally, as permitted by applicable law. We are responsible for the costs and activities associated 
with the continued development of Strimvelis and each program for which an option under the R&D 
Agreement is exercised.  
As consideration for the licenses and options granted under the R&D Agreement, we are required to 
make payments to Telethon-OSR upon achievement of certain product development milestones. We 
are obligated to pay up to an aggregate of €31.0 million in connection with product development 
milestones with respect to those programs for which we have exercised an option under this 
agreement, including OTL-200. Additionally, we are required to pay to Telethon-OSR a tiered 
mid-single to low-double digit royalty percentage on net annual sales of licensed products on a 
UK STATUTORY STRATEGIC REPORT 
continued 

country-by-country basis, as well as a low double-digit percentage of sublicense income received 
from any certain third party sublicensees of the collaboration programs. Our royalty obligation expires 
on a licensed product-by-licensed product and country-by-country basis upon the latest to occur of 
the expiration of the last valid claim under the licensed patent rights in such country, the 10th 
anniversary of the ﬁrst commercial sale of such licensed product in such country, and the expiration 
of any applicable regulatory exclusivity in such country, provided that our royalty obligation will 
terminate immediately in the event signiﬁcant generic or biosimilar competition to a licensed product 
achieves a certain threshold percentage of the market share.  
Unless terminated earlier, the R&D Agreement will expire (i) on a product-by-product and 
country-by-country basis upon the expiration of all payment obligations with respect to such product 
in such country, (ii) in its entirety upon the expiration of all payment obligations with respect to the 
last product in all countries in the world, and (iii) on a program-by-program basis when no vector or 
gene therapy product is being researched, developed or commercialized. Either we or Telethon-OSR 
may terminate the R&D Agreement in its entirety or on a program-by-program basis if the other party 
commits a material breach and fails to cure such breach within a certain period of time. Additionally, 
either we or Telethon-OSR may terminate involvement in a collaboration program for compelling safety 
reasons, and either we or Telethon-OSR may terminate the R&D Agreement if the other party 
becomes insolvent. We may also terminate the R&D Agreement either in its entirety or on a 
program-by-program basis for any reason upon notice to Telethon-OSR.  
Oxford BioMedica license and development agreement  
In November 2016, we entered into a license and development agreement, or the Oxford 
Development Agreement, with Oxford BioMedica (UK) Limited, or Oxford BioMedica, for the 
development of gene therapies for ADA-SCID, MPS-IIIA and certain other diseases that we may 
request be included under the Oxford Development Agreement, such other diseases referred to as 
Subsequent Indications. The Oxford Development Agreement was amended on multiple occasions 
and most recently in April 2020. 
Pursuant to the Oxford Development Agreement, Oxford BioMedica granted us an exclusive, 
worldwide license under certain intellectual property rights for the purposes of research, 
development and commercialization of ex vivo gene therapy products for the treatment of ADA-SCID, 
MPS-IIIA and Subsequent Indications, except that such license is non-exclusive to the extent the 
treatment of a Subsequent Indication is the subject of a certain previous license granted by Oxford 
BioMedica. Oxford BioMedica also granted us a non-exclusive, worldwide license under certain 
intellectual property rights for the purposes of research, development, commercialization and 
manufacture of ex vivo gene therapy products for the treatment of certain diseases other than 
ADA-SCID, MPS-IIIA and Subsequent Indications. Under the Oxford Development Agreement, Oxford 
BioMedica is required to use commercially reasonable efforts to perform the activities set forth in a 
collaboration plan approved by a joint steering committee, and we are responsible for certain costs 
of the activities set forth in such collaboration plan.  
As consideration for the licenses granted under the agreement, we issued 588,220 of our ordinary 
shares to Oxford BioMedica. We are also obligated to issue additional equity upon the achievement 
of certain milestones, pursuant to which we issued 150,826 ordinary shares upon the achievement 
of the ﬁrst milestone in November 2017 and 150,826 ordinary shares were issued upon the 
achievement of further milestones in August 2018. In April 2020, the ﬁfth milestone was deemed to 
have been met upon execution of the amended agreement in April 2020, and the Company issued 
another 75,413 ordinary shares to Oxford BioMedica. Additionally, we are obligated to pay low 
 
38 Orchard Therapeutics plc 
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 39
single-digit percentage royalties on net sales of licensed products until January 31, 2039. The 
foregoing royalties are reduced by a mid-double digit percentage in the case of compassionate use 
of a licensed product in a country until the ﬁrst commercial sale following marketing authorization in 
such country. We are also required to pay a set monthly fee to Oxford BioMedica in the event we use 
a certain Oxford BioMedica system for generating stable cell lines.  
Unless terminated earlier, the Oxford Development Agreement will expire when no further payments 
are due to Oxford BioMedica. We may terminate the performance of the collaboration plan upon 
notice to Oxford BioMedica, and either party may terminate the performance of the collaboration 
plan or the Oxford Development Agreement if the other party commits a material breach that is not 
cured within a certain period of time. Either party may also terminate the Oxford Development 
Agreement in the event the other party becomes insolvent.  
Telethon-OSR license agreement 
In May 2019, we entered into a license agreement with Telethon-OSR under which Telethon-OSR 
granted us an exclusive worldwide license for the research, development, manufacture and 
commercialization of ex vivo autologous HSC lentiviral based gene therapy products for the treatment 
of MPS-I, including MPS IH. Under the terms of the agreement, Telethon-OSR is entitled to receive 
an upfront payment, and we may be required to make milestone payments if certain development, 
regulatory and commercial milestones are achieved. Additionally, we will be required to pay 
Telethon-OSR a tiered mid-single to low-double digit royalty percentage on annual net sales of 
licensed products. 
Competition 
The biotechnology and pharmaceutical industries are characterized by intense and rapidly changing 
competition to develop new technologies and proprietary products. While we believe that our portfolio 
of product candidates and scientiﬁc expertise in gene therapy provides us with competitive 
advantages, we face potential competition from many different sources.  
We face competition not only from gene therapy companies, but also from companies that are 
developing novel, non-gene therapy approaches or improving existing treatment approaches. 
Depending on how successful these efforts are, it is possible they may increase the barriers to 
adoption and success for our product candidates, if approved.  
We are currently aware of the following competitive approaches among our products and clinical 
programs:  
•
MLD: To our knowledge, beyond Libmeldy in Europe, there is currently no other effective treatment 
option for patients with MLD. HSCT, for example, has demonstrated limited efﬁcacy in halting 
disease progression and is therefore not considered a standard of care for this disease. A number 
of alternative approaches to HSCT are under investigation. For instance, Homology Medicines is 
at the pre-clinical stage of developing an in vivo AAV gene therapy for MLD delivered 
intravenously, Passage Bio has a pre-clinical development program for MLD, and Afﬁnia has a 
pre-clinical program for in vivo AAV gene therapy for MLD through lumbar puncture (LP) 
administration. We are also aware that Takeda is investigating an ERT for MLD with a biweekly 
intrathecal infusion, and Denali Therapeutics is at the pre-clinical stage of developing a 
recombinant ARSA enzyme engineered to cross the blood-brain barrier. 
UK STATUTORY STRATEGIC REPORT 
continued 

•
MPS-I: The current standard of care for MPS-IH patients is HSCT before the age of 30 months. 
We are aware that REGENXBIO is developing an AAV-based gene therapy, which is in Phase I 
trials and to be delivered intracisternally. bluebird bio and Immusoft have both reported that they 
are developing ex vivo cell therapies in the pre-clinical stage. For MPS-I patients that are not 
suitable candidates for HSCT because they lack a suitable donor, were diagnosed later in life, or 
have a less severe subtype of MPS-I, the current standard of care for the treatment of MPS-I 
involves regular intravenous injections of laronidase (Aldurazyme), an ERT commercialized by 
BioMarin and Sanoﬁ Genzyme. A formulation of laronidase for intrathecal administration is 
currently under evaluation. JCR Pharmaceuticals is developing an ERT, which is in Phase I trials. 
Denali Therapeutics has an ERT program in the discovery stage. 
•
MPS-IIIA: There are currently no effective disease modifying treatment options for patients with 
MPS-IIIA. We are aware of three gene therapy candidates in clinical development. Lysogene is 
developing an AAV gene therapy product administered through intracerebral injections and 
regained global commercial rights after its collaboration with Sarepta Therapeutics terminated in 
July 2022; Abeona Therapeutics has been developing an AAV gene therapy product administered 
intravenously, which was licensed to Ultragenyx in May 2022 for further clinical development; and 
Esteve is developing an AAV gene therapy administered through intracerebroventricular injection. 
Amicus Therapeutics is at the pre-clinical stage of developing an AAV gene therapy for MPS-IIIA. 
JCR Pharmaceuticals and Denali Therapeutics each have a pre-clinical stage ERT program for 
MPS-IIIA. 
•
GRN-FTD: There are no approved disease modifying treatments for GRN-FTD. Each of Prevail 
Therapeutics (now owned by Eli Lilly & Company) and Passage Bio is developing in early-stage 
clinical trials an AAV gene therapy to be delivered intra-cisterna magna. Alector is developing a 
monoclonal antibody designed to increase levels of GRN in the brain in late-stage clinical trials, 
and Denali Therapeutics is developing a modiﬁed protein designed to penetrate across the 
blood-brain barrier at the pre-clinical stage in collaboration with Takeda. 
•
NOD2-Crohn’s: There are no approved treatment options speciﬁcally for the NOD-2 form of 
Crohn’s disease, and many patients with Crohn’s disease have uncontrolled symptoms despite 
treatment with standard of care, including multiple anti-inﬂammatory biologics and surgical 
interventions. We are not aware of any other treatments in development speciﬁcally for the NOD-2 
form of Crohn’s disease.  
Many of our potential competitors, alone or with their strategic partners, have substantially greater 
ﬁnancial, technical and other resources than we do, such as larger research and development, 
clinical, marketing and manufacturing organizations. Mergers and acquisitions in the biotechnology 
and pharmaceutical industries may result in even more resources being concentrated among a 
smaller number of competitors. Our commercial opportunity could be reduced or eliminated if 
competitors develop and commercialize products that are safer, more effective, have fewer or less 
severe side effects, are more convenient or are less expensive than any products that we may 
develop. Competitors also may obtain FDA, EMA or other regulatory approval for their products more 
rapidly than we may obtain approval for ours, which could result in our competitors establishing a 
strong market position before we are able to enter the market. Additionally, technologies developed 
by our competitors may render our potential product candidates uneconomical or obsolete, and we 
may not be successful in marketing our product candidates against competitors. 
 
40 Orchard Therapeutics plc 
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 41
Government regulation  
In the United States, biological products, including gene therapy products, are subject to regulation 
under the Federal Food, Drug, and Cosmetic Act, or FD&C Act, and the Public Health Service Act, 
or PHS Act, and other federal, state, local and foreign statutes and regulations. Both the FD&C Act 
and the PHS Act and their corresponding regulations govern, among other things, the research, 
development, clinical trial, testing, manufacturing, safety, efﬁcacy, labeling, packaging, storage, 
record keeping, distribution, reporting, advertising and other promotional practices involving 
biological products. Each clinical trial protocol for a gene therapy product must be reviewed by the 
FDA. FDA approval must be obtained before the marketing of biological products. The process of 
obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local 
and foreign statutes and regulations require the expenditure of substantial time and ﬁnancial 
resources and we may not be able to obtain the required regulatory approvals.  
Ethical, social and legal concerns about gene therapy, genetic testing and genetic research could 
result in additional laws and regulations restricting or prohibiting the processes we may use. Federal 
and state legislatures, agencies, congressional committees and foreign governments have expressed 
interest in further regulating biotechnology. More restrictive laws and regulations or interpretations 
of existing laws or regulations, or claims that our products are unsafe or pose a hazard, could prevent 
us from commercializing any products. New government requirements may be established that could 
delay or prevent regulatory approval of our product candidates under development. It is impossible 
to predict whether legislative changes will be enacted, regulations, policies or guidance changed, 
or interpretations by agencies or courts changed, or what the impact of such changes, if any, may be.  
U.S. biological products development process  
The process required by the FDA before a biological product may be marketed in the United States 
generally involves the following:  
•
completion of nonclinical laboratory tests and animal studies according to good laboratory 
practices, or GLPs, unless justiﬁed, and applicable requirements for the humane use of laboratory 
animals or other applicable regulations;  
•
submission to the FDA of an application for an investigational new drug application, or IND, which 
must become effective before human clinical trials may begin;  
•
approval of the protocol and related documentation by an independent institutional review board, 
or IRB, or ethics committee at each clinical trial site before each study may be initiated;  
•
performance of adequate and well-controlled human clinical trials according to the FDA’s 
regulations commonly referred to as good clinical practices, or GCPs, and any additional 
requirements for the protection of human research subjects and their health information, to 
establish the safety and efﬁcacy of the proposed biological product for its intended use;  
•
submission to the FDA of a biologics license application, or BLA, for marketing approval that 
includes sufﬁcient evidence of establishing the safety, purity, and potency of the proposed 
biological product for its intended indication, including from results of nonclinical testing and 
clinical trials;  
•
satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the 
biological product is produced to assess compliance with current good manufacturing practice, 
or cGMP, to assure that the facilities, methods and controls are adequate to preserve the biological 
product’s identity, strength, quality and purity and, if applicable, the FDA’s current good tissue 
practices, or CGTPs, for the use of human cellular and tissue products;  
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•
potential FDA audit of the nonclinical study and clinical trial sites that generated the data in 
support of the BLA in accordance with any applicable expedited programs or designations;  
•
review of the product candidate by an FDA advisory committee, where appropriate or if 
applicable; 
•
payment of user fees for FDA review of the BLA (unless a fee waiver applies); and  
•
FDA review and approval, or licensure, of the BLA.  
Before testing any biological product candidate, including a gene therapy product, in humans, the 
product candidate enters the pre-clinical testing stage. Pre-clinical tests, also referred to as 
nonclinical studies, include laboratory evaluations of product biological characteristics, chemistry, 
toxicity and formulation, as well as animal studies to assess the potential safety and activity of the 
product candidate. The conduct of the pre-clinical tests must comply with federal regulations and 
requirements including GLPs.  
An IND is an exemption from the FD&C Act that allows an unapproved product candidate to be 
shipped in interstate commerce for use in an investigational clinical trial and a request for FDA 
authorization to administer such investigational product to humans. Such authorization must be 
secured prior to interstate shipment and administration of any product candidate that is not the 
subject of an approved BLA. In support of a request for an IND, applicants must submit a protocol 
for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as 
part of the IND. In addition, the results of the pre-clinical tests, together with manufacturing 
information, analytical data, any available clinical data or literature and plans for clinical trials, among 
other things, must be submitted to the FDA as part of an IND. The FDA requires a 30-day waiting 
period after the ﬁling of each IND before clinical trials may begin. This waiting period is designed to 
allow the FDA to review the IND to determine whether human research subjects will be exposed to 
unreasonable health risks. At any time during this 30-day period the FDA may raise concerns or 
questions about the conduct of the trials as outlined in the IND and impose a clinical hold or partial 
clinical hold. In this case, the IND sponsor and the FDA must resolve any outstanding concerns before 
clinical trials can begin.  
Following commencement of a clinical trial, the FDA may also place a clinical hold or partial clinical 
hold on that trial. A clinical hold is an order issued by the FDA to the sponsor to delay a proposed 
clinical investigation or to suspend an ongoing investigation. A partial clinical hold is a delay or 
suspension of only part of the clinical work requested under the IND. No more than 30 days after 
imposition of a clinical hold or partial clinical hold, the FDA will provide the sponsor a written 
explanation of the basis for the hold. Following issuance of a clinical hold or partial clinical hold, an 
investigation may only resume after the FDA has notiﬁed the sponsor that the investigation 
may proceed.  
A sponsor may choose, but is not required, to conduct a foreign clinical trial under an IND. When a 
foreign clinical trial is conducted under an IND, all FDA IND requirements must be met unless waived. 
When a foreign clinical trial is not conducted under an IND, the sponsor must ensure that the study 
complies with certain regulatory requirements of the FDA in order to use the study as support for an 
IND or application for marketing approval or licensing. In particular, such studies must be conducted 
in accordance with GCP, including review and approval by an independent ethics committee, or IEC, 
and informed consent from subjects. The FDA must be able to validate the data through an onsite 
inspection, if deemed necessary by the FDA.  
 
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Orchard Therapeutics plc 43
An IRB representing each institution participating in the clinical trial must review and approve the 
plan for any clinical trial before it commences at that institution, and the IRB must conduct continuing 
review and re-approve the study at least annually. The IRB must review and approve, among other 
things, the study protocol and informed consent information to be provided to study subjects. An IRB 
must operate in compliance with FDA regulations. An IRB can suspend or terminate approval of a 
clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in 
accordance with the IRB’s requirements or if the product candidate has been associated with 
unexpected serious harm to patients.  
Some trials are overseen by an independent group of qualiﬁed experts organized by the trial sponsor, 
known as a data safety monitoring board or committee, or DSMB. This group provides authorization 
as to whether or not a trial may move forward at designated check points based on access that only 
the group maintains to available data from the study.  
In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United 
States, certain human clinical trials involving recombinant or synthetic nucleic acid molecules are 
subject to oversight of institutional biosafety committees, or IBCs, as set forth in the NIH Guidelines 
for Research Involving Recombinant or Synthetic Nucleic Acid Molecules, or NIH Guidelines. Under 
the NIH Guidelines, recombinant and synthetic nucleic acids are deﬁned as: (i) molecules that are 
constructed by joining nucleic acid molecules and that can replicate in a living cell (i.e., recombinant 
nucleic acids); (ii) nucleic acid molecules that are chemically or by other means synthesized or 
ampliﬁed, including those that are chemically or otherwise modiﬁed but can base pair with naturally 
occurring nucleic acid molecules (i.e., synthetic nucleic acids); or (iii) molecules that result from the 
replication of those described in (i) or (ii). Speciﬁcally, under the NIH Guidelines, supervision of 
human gene transfer trials includes evaluation and assessment by an IBC, a local institutional 
committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid 
molecules at that institution. The IBC assesses the safety of the research and identiﬁes any potential 
risk to public health or the environment, and such review may result in some delay before initiation of 
a clinical trial. While the NIH Guidelines are not mandatory unless the research in question is being 
conducted at or sponsored by institutions receiving NIH funding of recombinant or synthetic nucleic 
acid molecule research, many companies and other institutions not otherwise subject to the 
NIH Guidelines voluntarily follow them. 
Information about clinical trials must be submitted within speciﬁc time frames to the NIH for public 
dissemination on its ClinicalTrials.gov website.  
Clinical trials typically are conducted in three sequential phases that may overlap or be combined:  
•
Phase 1. The biological product is initially introduced into healthy human subjects and tested for 
safety. In the case of some products for severe or life-threatening diseases, especially when the 
product may be too inherently toxic to ethically administer to healthy volunteers, the initial human 
testing is often conducted in patients.  
•
Phase 2. The biological product is evaluated in a limited patient population to identify possible 
adverse effects and safety risks, to preliminarily evaluate the efﬁcacy of the product for speciﬁc 
targeted diseases and to determine dosage tolerance, optimal dosage and dosing schedule.  
•
Phase 3. Clinical trials are undertaken to further evaluate dosage, clinical efﬁcacy, potency, and 
safety in an expanded patient population at geographically dispersed clinical trial sites. These 
clinical trials are intended to establish the overall risk/beneﬁt ratio of the product and provide an 
adequate basis for approval and product labeling.  
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44 Orchard Therapeutics plc 
Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after 
initial marketing approval. These clinical trials are used to gain additional experience from the 
treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-up. 
The FDA generally recommends that sponsors of human gene therapy products integrating vectors 
such as gammaretroviral and lentiviral vectors and transposon elements observe subjects for potential 
gene therapy-related delayed adverse events for a 15-year period, including a minimum of ﬁve years 
of annual examinations followed by ten years of annual queries, either in person or by questionnaire, 
of study subjects.  
Both the FDA and the EMA provide expedited pathways for the development of drug product 
candidates for treatment of rare diseases, particularly life-threatening diseases with high unmet 
medical need. Such drug product candidates may be eligible to proceed to registration following a 
single clinical trial in a limited patient population, sometimes referred to as a Phase 1/2 trial, but which 
may be deemed a pivotal or registrational trial following review of the trial’s design and primary 
endpoints by the applicable regulatory agencies. Determination of the requirements to be deemed 
a pivotal or registrational trial is subject to the applicable regulatory authority’s scientiﬁc judgment 
and these requirements may differ in the U.S. and the European Union.  
During all phases of clinical development, regulatory agencies require extensive monitoring and 
auditing of all clinical activities, clinical data, and clinical trial investigators. Annual progress reports 
detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must 
be promptly submitted to the FDA, the NIH and the investigators for serious and unexpected adverse 
events, any ﬁndings from other studies, tests in laboratory animals or in vitro testing that suggest a 
signiﬁcant risk for human subjects, or any clinically important increase in the rate of a serious 
suspected adverse reaction over that listed in the protocol or investigator brochure. The sponsor must 
submit an IND safety report within 15 calendar days after the sponsor determines that the information 
qualiﬁes for reporting. The sponsor also must notify the FDA of any unexpected fatal or life-threatening 
suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the 
information. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within 
any speciﬁed period, if at all. The FDA or the sponsor, acting on its own or based on a recommendation 
from the sponsor’s data safety monitoring board may suspend a clinical trial at any time on various 
grounds, including a ﬁnding that the research subjects or patients are being exposed to an 
unacceptable health risk. Similarly, an IRB can suspend or terminate approval of a clinical trial at its 
institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if 
the biological product has been associated with unexpected serious harm to patients.  
Human gene therapy products are a new category of therapeutics. Because this is a relatively new 
and expanding area of novel therapeutic interventions, there can be no assurance as to the length 
of the study period, the number of patients the FDA will require to be enrolled in the studies in order 
to establish the safety, purity and potency of human gene therapy products, or that the data generated 
in these studies will be acceptable to the FDA to support marketing approval.  
Concurrent with clinical trials, companies usually complete additional animal studies and also must 
develop additional information about the physical characteristics of the biological product as well as 
ﬁnalize a process for manufacturing the product in commercial quantities in accordance with cGMP 
requirements. To help reduce the risk of the introduction of adventitious agents with use of biological 
products, the PHS Act emphasizes the importance of manufacturing control for products whose 
attributes cannot be precisely deﬁned. The manufacturing process must be capable of consistently 
producing quality batches of the product candidate and, among other things, the sponsor must 
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develop methods for testing the identity, strength, quality, potency and purity of the ﬁnal biological 
product. Additionally, appropriate packaging must be selected and tested and stability studies must 
be conducted to demonstrate that the biological product candidate does not undergo unacceptable 
deterioration over its shelf life.  
U.S. review and approval processes  
After the completion of clinical trials of a biological product, FDA approval of a BLA must be obtained 
before commercial marketing of the biological product. The BLA must include results of product 
development, laboratory and animal studies, human studies, information on the manufacture and 
composition of the product, proposed labeling and other relevant information. The testing and approval 
processes require substantial time and effort and there can be no assurance that the FDA will accept 
the BLA for ﬁling and, even if ﬁled, that any approval will be granted on a timely basis, if at all.  
Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine 
if it is substantially complete before the FDA accepts it for ﬁling. The FDA may refuse to ﬁle any BLA 
that it deems incomplete or not properly reviewable at the time of submission and may request 
additional information. In this event, the BLA must be resubmitted with the additional information. The 
resubmitted application also is subject to review before the FDA accepts it for ﬁling. In most cases, 
the submission of a BLA is subject to a substantial application user fee, although the fee may be 
waived under certain circumstances. Under the performance goals and policies implemented by the 
FDA under the Prescription Drug User Fee Act, or PDUFA, for original BLAs, the FDA targets ten months 
from the ﬁling date in which to complete its initial review of a standard application and respond to the 
applicant, and six months from the ﬁling date for an application with priority review. The FDA does not 
always meet its PDUFA goal dates, and the review process is often signiﬁcantly extended by FDA 
requests for additional information or clariﬁcation. This review typically takes twelve months from the 
date the BLA is submitted to the FDA because the FDA has approximately two months to make a 
‘‘ﬁling’’ decision. The review process and the PDUFA goal date may be extended, for example, by 
three months if the BLA sponsor submits a major new clinical study report, a major re-analysis of a 
previously submitted study or other major amendment at any time during the review cycle.  
Once the submission is accepted for ﬁling, the FDA begins an in-depth substantive review of the BLA. 
The FDA reviews the BLA to determine, among other things, whether the proposed product is safe, 
pure and potent, for its intended use, and whether the product is being manufactured in accordance 
with cGMP to ensure the continued safety, purity and potency of such product. The FDA may refer 
applications for novel biological products or biological products that present difﬁcult or novel questions 
of safety or efﬁcacy to an advisory committee, typically a panel that includes clinicians and other 
experts, for review, evaluation and a recommendation as to whether the application should be 
approved and under what conditions. The FDA is not bound by the recommendations of an advisory 
committee, but it considers such recommendations carefully when making decisions. During the 
biological product approval process, the FDA also will determine whether a Risk Evaluation and 
Mitigation Strategy, or REMS, is necessary to assure the safe use of the biological product. If the FDA 
concludes a REMS is needed, the sponsor of the BLA must submit a proposed REMS; the FDA will 
not approve the BLA without a REMS, if required.  
Before approving a BLA, the FDA typically will inspect the facilities at which the product is 
manufactured. The FDA will not approve the product unless it determines that the manufacturing 
processes and facilities are in compliance with cGMP requirements and adequate to assure consistent 
production of the product within required speciﬁcations. For a gene therapy product, the FDA also 
will not approve the product if the manufacturer is not in compliance with the CGTPs. These are FDA 
 
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regulations that govern the methods used in, and the facilities and controls used for, the manufacture 
of human cells, tissues, and cellular and tissue-based products, or HCT/Ps, which are human cells or 
tissue intended for implantation, transplant, infusion, or transfer into a human recipient. The primary 
intent of the CGTP requirements is to ensure that cell and tissue-based products are manufactured 
in a manner designed to prevent the introduction, transmission and spread of communicable disease. 
FDA regulations also require tissue establishments to register and list their HCT/Ps with the FDA and, 
when applicable, to evaluate donors through appropriate screening and testing. Additionally, before 
approving a BLA, the FDA will typically inspect one or more clinical sites to assure that the clinical 
trials were conducted in compliance with IND study requirements and GCP requirements. During the 
COVID-19 pandemic, restrictions preventing the conduct or completion of facility or clinical site 
inspections have led to FDA deferred action on marketing applications or the issuance of complete 
response letters. To assure cGMP, CGTP and GCP compliance, an applicant must incur signiﬁcant 
expenditure of time, money and effort in the areas of training, record keeping, production and quality 
control.  
Under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA for a novel product 
(e.g., new active ingredient, new indication, etc.) must contain data to assess the safety and 
effectiveness of the biological product for the claimed indications in all relevant pediatric 
subpopulations and to support dosing and administration for each pediatric subpopulation for which 
the product is safe and effective. The FDA may grant deferrals for submission of data or full or partial 
waivers. Unless otherwise required by regulation, PREA does not apply to any biological product for 
an indication for which orphan designation has been granted.  
Notwithstanding the submission of relevant data and information, the FDA may ultimately decide that 
the BLA does not satisfy its regulatory criteria for approval and deny approval. Data obtained from 
clinical trials are not always conclusive and the FDA may interpret data differently than we interpret 
the same data. If the FDA decides not to approve the BLA in its present form, the FDA will issue a 
complete response letter that usually describes all of the speciﬁc deﬁciencies in the BLA identiﬁed 
by the FDA. The deﬁciencies identiﬁed may be minor, for example, requiring labeling changes, or 
major, for example, requiring additional clinical trials. Additionally, the complete response letter may 
include recommended actions that the applicant might take to place the application in a condition for 
approval. If a complete response letter is issued, the applicant may either resubmit the BLA, 
addressing all of the deﬁciencies identiﬁed in the letter, or withdraw the application.  
If a product receives regulatory approval, the approval may be signiﬁcantly limited to speciﬁc diseases 
and dosages or the indications for use may otherwise be limited, including to subpopulations of 
patients, which could restrict the commercial value of the product. Further, the FDA may require that 
certain contraindications, warnings precautions or interactions be included in the product labeling. 
The FDA may impose restrictions and conditions on product distribution, prescribing, or dispensing 
in the form of a REMS, or otherwise limit the scope of any approval. In addition, the FDA may require 
post-marketing clinical trials, sometimes referred to as Phase 4 clinical trials, designed to further assess 
a biological product’s safety and effectiveness, and testing and surveillance programs to monitor the 
safety of approved products that have been commercialized.  
Orphan drug designation  
Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product 
intended to treat a rare disease or condition, which is generally a disease or condition that affects 
fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United 
States and for which there is no reasonable expectation that the cost of developing and making a 
 
46 Orchard Therapeutics plc 
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drug or biological product available in the United States for this type of disease or condition will be 
recovered from sales of the product. Orphan product designation must be requested before submitting 
a BLA. After the FDA grants orphan product designation, the identity of the therapeutic agent and its 
potential orphan use are disclosed publicly by the FDA. Orphan product designation does not convey 
any advantage in or shorten the duration of the regulatory review and approval process.  
Orphan drug designation entitles a party to ﬁnancial incentives such as opportunities for grant funding 
towards clinical trial costs, tax advantages and user-fee waivers. If a product that has orphan 
designation subsequently receives the ﬁrst FDA approval for the disease or condition for which it has 
such designation, the product is entitled to orphan product exclusivity, which means that the FDA may 
not approve any other applications to market the same drug or biological product for the same 
indication for seven years, except in limited circumstances, such as a showing of clinical superiority 
to the product with orphan exclusivity. Competitors, however, may receive approval of different 
products for the indication for which the orphan product has exclusivity or obtain approval for the same 
product but for a different indication for which the orphan product has exclusivity. Orphan product 
exclusivity also could block the approval of one of our products for seven years if a competitor obtains 
approval of the same biological product for the same use or indication, and we are unable to 
demonstrate that our product is clinically superior to the previously approved drug for the same use 
or indication. If a drug or biological product designated as an orphan product receives marketing 
approval for an indication broader than what is designated, it may not be entitled to orphan product 
exclusivity. Orphan drug status in the European Union has similar, but not identical, beneﬁts. 
Rare Pediatric Disease Designation and Priority Review Vouchers  
Under the FD&C Act, the FDA incentivizes the development of drugs and biological products that 
meet the deﬁnition of a “rare pediatric disease,” deﬁned to mean a serious or life-threatening disease 
in which the serious of life-threatening manifestations primarily affect individuals aged from birth to 
18 years and the disease affects fewer than 200,000 individuals in the United States or affects more 
than 200,000 in the United States and for which there is no reasonable expectation that the cost of 
developing and making in the United States a drug or biological product for such disease or condition 
will be received from sales in the United States of such drug or biological product. The sponsor of a 
product candidate for a rare pediatric disease may be eligible for a voucher that can be used to 
obtain a priority review for a subsequent human drug or biological product application after the date 
of approval of the rare pediatric disease drug or biological product, referred to as a priority review 
voucher, or PRV. A sponsor may request rare pediatric disease designation from the FDA prior to the 
submission of its BLA. A rare pediatric disease designation does not guarantee that a sponsor will 
receive a PRV upon approval of its BLA. Moreover, a sponsor who chooses not to submit a rare 
pediatric disease designation request may nonetheless receive a PRV upon approval of their 
marketing application if they request such a voucher in their original marketing application and meet 
all of the eligibility criteria. If a PRV is received, it may be sold or transferred an unlimited number of 
times. Congress has extended the PRV program through 30 September 2024, with the potential for 
PRVs to be granted through 30 September 2026. 
Expedited development and review programs  
The FDA has various programs, including Fast Track designation, breakthrough therapy designation, 
accelerated approval and priority review, that are intended to expedite or simplify the process for the 
development and FDA review of drugs and biologics that are intended for the treatment of serious 
or life-threatening diseases or conditions. These programs do not change the standards for approval 
but may help expedite the development or approval process. To be eligible for fast track designation, 
new drugs and biological products must be intended to treat a serious or life-threatening condition 
 
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and demonstrate the potential to address unmet medical needs for the condition. Fast Track 
designation applies to the combination of the product and the speciﬁc indication for which it is being 
studied. The sponsor of a new drug or biologic may request the FDA to designate the drug or biologic 
as a Fast Track product at any time during the clinical development of the product. One beneﬁt of 
fast track designation, for example, is that the FDA may consider for review sections of the marketing 
application for a product that has received Fast Track designation on a rolling basis before the 
complete application is submitted.  
Under the FDA’s breakthrough therapy program, products intended to treat a serious or 
life-threatening disease or condition may be eligible for the beneﬁts of the Fast Track program when 
preliminary clinical evidence demonstrates that such product may have substantial improvement on 
one or more clinically signiﬁcant endpoints over existing therapies. Additionally, the FDA will seek to 
ensure the sponsor of a breakthrough therapy product receives timely advice and interactive 
communications to help the sponsor design and conduct a development program as efﬁciently as 
possible.  
Any product is eligible for priority review if it has the potential to provide safe and effective therapy 
where no satisfactory alternative therapy exists or a signiﬁcant improvement in the treatment, 
diagnosis or prevention of a disease compared to marketed products. The FDA will attempt to direct 
additional resources to the evaluation of an application for a new drug or biological product 
designated for priority review in an effort to facilitate the review. Under priority review, the FDA’s goal 
is to review an application in six months once it is ﬁled, compared to ten months for a standard review.  
Additionally, a product may be eligible for accelerated approval. Drug or biological products studied 
for their safety and effectiveness in treating serious or life-threatening illnesses and that provide 
meaningful therapeutic beneﬁt over existing treatments may receive accelerated approval, which 
means that they may be approved on the basis of adequate and well-controlled clinical trials 
establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict 
a clinical beneﬁt, or on the basis of an effect on an intermediate clinical endpoint other than survival 
or irreversible morbidity. As a condition of approval, the FDA may require that a sponsor of a drug or 
biological product receiving accelerated approval perform adequate and well-controlled 
post-marketing clinical trials. Under the Food and Drug Omnibus Reform Act of 2022, or FDORA, the 
FDA is permitted to require, as appropriate, that a post-approval conﬁrmatory study or studies be 
underway prior to approval or within a speciﬁed time period after the date of accelerated approval 
was granted. FDORA also requires sponsors to send updates to the FDA every 180 days on the 
status of such studies, including progress toward enrollment targets, and the FDA must promptly 
post this information publicly. FDORA also gives the FDA increased authority to withdraw approval of 
a drug or biologic granted accelerated approval on an expedited basis if the sponsor fails to conduct 
such studies in a timely manner, send the necessary updates to the FDA, or if such post-approval 
studies fail to verify the drug’s predicted clinical beneﬁt. Under FDORA, the FDA is empowered to 
take action, such as issuing ﬁnes, against companies that fail to conduct with due diligence any 
post-approval conﬁrmatory study or submit timely reports to the agency on their progress. In addition, 
for products being considered for accelerated approval, the FDA generally requires, unless otherwise 
informed by the agency, that all advertising and promotional materials intended for dissemination or 
publication within 120 days of marketing approval be submitted to the agency for review during the 
pre-approval review period.  
 
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RMAT designation  
As part of the 21st Century Cures Act, enacted in December 2016, Congress amended the FD&C 
Act to facilitate an efﬁcient development program for, and expedite review of RMAT, which include 
cell and gene therapies, therapeutic tissue engineering products, human cell and tissue products, 
and combination products using any such therapies or products. RMAT do not include those HCT/Ps 
regulated solely under section 361 of the PHS Act and 21 CFR Part 1271. This program is intended 
to facilitate efﬁcient development and expedite review of regenerative medicine therapies, which are 
intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition and qualify 
for RMAT designation. A drug sponsor may request that FDA designate a drug as a RMAT 
concurrently with or at any time after submission of an IND. FDA has 60 calendar days to determine 
whether the drug meets the criteria, including whether there is preliminary clinical evidence indicating 
that the drug has the potential to address unmet medical needs for a serious or life-threatening 
disease or condition. A BLA for a regenerative medicine therapy that has received RMAT designation 
may be eligible for priority review or accelerated approval through use of surrogate or intermediate 
endpoints reasonably likely to predict long-term clinical beneﬁt, or reliance upon data obtained from 
a meaningful number of sites. Beneﬁts of RMAT designation also include early interactions with FDA 
to discuss any potential surrogate or intermediate endpoint to be used to support accelerated 
approval. A regenerative medicine therapy with RMAT designation that is granted accelerated 
approval and is subject to post-approval requirements may fulﬁll such requirements through the 
submission of clinical evidence from clinical trials, patient registries, or other sources of real world 
evidence, such as electronic health records; the collection of larger conﬁrmatory data sets; or 
post-approval monitoring of all patients treated with such therapy prior to its approval. Like some of 
FDA’s other expedited development programs, RMAT designation does not change the standards for 
approval but may help expedite the development or approval process.  
Post-approval requirements  
Maintaining substantial compliance with applicable federal, state, and local statutes and regulations 
requires the expenditure of substantial time and ﬁnancial resources. Rigorous and extensive FDA 
regulation of biological products continues after approval, particularly with respect to cGMP. We 
currently rely, and may continue to rely, on third parties for the production of clinical and commercial 
quantities of any products that we may commercialize. Manufacturers of our products are required 
to comply with applicable requirements in the cGMP regulations, including quality control and quality 
assurance and maintenance of records and documentation. Other post-approval requirements 
applicable to biological products, include reporting of cGMP deviations that may affect the identity, 
potency, purity and overall safety of a distributed product, record-keeping requirements, reporting 
of adverse effects, reporting updated safety and efﬁcacy information, and complying with electronic 
record and signature requirements. After a BLA is approved, the product also may be subject to 
ofﬁcial lot release. As part of the manufacturing process, the manufacturer is required to perform 
certain tests on each lot of the product before it is released for distribution. If the product is subject 
to ofﬁcial release by the FDA, the manufacturer submits samples of each lot of product to the FDA 
together with a release protocol showing a summary of the history of manufacture of the lot and the 
results of all of the manufacturer’s tests performed on the lot. The FDA also may perform certain 
conﬁrmatory tests on lots of some products, such as viral vaccines, before releasing the lots for 
distribution by the manufacturer. In addition, the FDA conducts laboratory research related to the 
regulatory standards on the safety, purity, potency, and effectiveness of biological products.  
We also must comply with the FDA’s advertising and promotion requirements, such as those related 
to direct-to-consumer advertising, the prohibition on promoting products for uses or in patient 
populations that are not described in the product’s approved labeling (known as “off-label use”), 
 
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industry-sponsored scientiﬁc and educational activities, and promotional activities involving the 
internet. Discovery of previously unknown problems or the failure to comply with the applicable 
regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the 
product from the market as well as possible civil or criminal sanctions. Failure to comply with the 
applicable U.S. requirements at any time during the product development process, approval process 
or after approval, may subject an applicant or manufacturer to administrative or judicial civil or criminal 
sanctions and adverse publicity. FDA sanctions could include refusal to approve pending 
applications, withdrawal of an approval, clinical holds, warning or untitled letters, product recalls, 
product seizures, total or partial suspension of production or distribution, injunctions, ﬁnes, refusals 
of government contracts, mandated corrective advertising or communications with doctors or other 
stakeholders, debarment, restitution, disgorgement of proﬁts, or civil or criminal penalties. Any agency 
or judicial enforcement action could have a material adverse effect on us.  
Biological product manufacturers and other entities involved in the manufacture and distribution of 
approved biological products and those supplying products, ingredients and components of them, 
are required to register their establishments with the FDA and certain state agencies, and are subject 
to periodic unannounced inspections by the FDA and certain state agencies for compliance with 
cGMP and other laws. Accordingly, manufacturers must continue to expend time, money, and effort 
in the area of production and quality control to maintain cGMP compliance. Discovery of problems 
with a product after approval may result in restrictions on a product, manufacturer, or holder of an 
approved BLA, including withdrawal of the product from the market. In addition, changes to the 
manufacturing process or facility generally require prior FDA approval before being implemented 
and other types of changes to the approved product, such as adding new indications and additional 
labeling claims, are also subject to further FDA review and approval.  
U.S. patent term restoration and marketing exclusivity  
Depending upon the timing, duration and speciﬁcs of the FDA approval of the use of our product 
candidates, some of our U.S. patents may be eligible for limited patent term extension under the 
Hatch-Waxman Amendments. The Hatch-Waxman Amendments permit a patent restoration term of 
up to ﬁve years as compensation for patent term lost during product development and the FDA 
regulatory review process. However, patent term restoration cannot extend the remaining term of a 
patent beyond a total of 14 years from the product’s approval date. The patent term restoration period 
is generally one-half the time between the effective date of an IND and the submission date of a BLA 
plus the time between the submission date of a BLA and the approval of that application. Only one 
patent applicable to an approved biological product is eligible for the extension and the application 
for the extension must be submitted prior to the expiration of the patent. In addition, a patent can 
only be extended once and only for a single product. The USPTO, in consultation with the FDA, 
reviews and approves the application for any patent term extension or restoration. In the future, we 
may intend to apply for restoration of patent term for one of our patents, if and as applicable, to add 
patent life beyond its current expiration date, depending on the expected length of the clinical trials 
and other factors involved in the ﬁling of the relevant BLA.  
A biological product can obtain pediatric market exclusivity in the United States. Pediatric exclusivity, 
if granted, adds six months to existing exclusivity periods. This six-month exclusivity, which runs from 
the end of other exclusivity protection, may be granted based on the voluntary completion of a 
pediatric study in accordance with an FDA-issued “Written Request” for such a study.  
The ACA, signed into law on 23 March 2010, includes a subtitle called the Biologics Price Competition 
and Innovation Act of 2009 which created an abbreviated approval pathway for biological products 
 
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shown to be similar to, or interchangeable with, an FDA-licensed reference biological product. This 
amendment to the PHS Act attempts to minimize duplicative testing. Biosimilarity, which requires that 
there be no clinically meaningful differences between the biological product and the reference 
product in terms of safety, purity, and potency, can be shown through analytical studies, animal 
studies, and a clinical trial or trials. Interchangeability requires that a product is biosimilar to the 
reference product and the product must demonstrate that it can be expected to produce the same 
clinical results as the reference product and, for products administered multiple times, the biologic 
and the reference biologic may be switched after one has been previously administered without 
increasing safety risks or risks of diminished efﬁcacy relative to exclusive use of the reference 
biologic.  
A reference biological product is granted four- and 12-year exclusivity periods from the time of ﬁrst 
licensure of the product. FDA will not accept an application for a biosimilar or interchangeable 
product based on the reference biological product until four years after the date of ﬁrst licensure of 
the reference product, and FDA will not approve an application for a biosimilar or interchangeable 
product based on the reference biological product until twelve years after the date of ﬁrst licensure 
of the reference product. “First licensure” typically means the initial date the particular product at 
issue was licensed in the United States. Date of ﬁrst licensure does not include the date of licensure 
of (and a new period of exclusivity is not available for) a biological product if the licensure is for a 
supplement for the biological product or for a subsequent application by the same sponsor or 
manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) 
for a change (not including a modiﬁcation to the structure of the biological product) that results in a 
new indication, route of administration, dosing schedule, dosage form, delivery system, delivery 
device or strength, or for a modiﬁcation to the structure of the biological product that does not result 
in a change in safety, purity, or potency. Therefore, one must determine whether a new product 
includes a modiﬁcation to the structure of a previously licensed product that results in a change in 
safety, purity, or potency to assess whether the licensure of the new product is a ﬁrst licensure that 
triggers its own period of exclusivity. Whether a subsequent application, if approved, warrants 
exclusivity as the “ﬁrst licensure” of a biological product is determined on a case-by-case basis with 
data submitted by the sponsor.  
Additional regulation  
In addition to the foregoing, state and federal laws regarding environmental protection and hazardous 
substances, including the Occupational Safety and Health Act, the Resource Conservancy and 
Recovery Act and the Toxic Substances Control Act, affect our business. These and other laws govern 
our use, handling and disposal of various biological, chemical and radioactive substances used in, 
and wastes generated by, our operations. If our operations result in contamination of the environment 
or expose individuals to hazardous substances, we could be liable for damages and governmental 
ﬁnes. We believe that we are in material compliance with applicable environmental laws and that 
continued compliance therewith will not have a material adverse effect on our business. We cannot 
predict, however, how changes in these laws may affect our future operations. 
U.S. Foreign Corrupt Practices Act  
The U.S. Foreign Corrupt Practices Act, to which we are subject, prohibits corporations and 
individuals from engaging in certain activities to obtain or retain business or to inﬂuence a person 
working in an ofﬁcial capacity. It is illegal to pay, offer to pay or authorize the payment of anything of 
value to any foreign government ofﬁcial, government staff member, political party or political 
candidate in an attempt to obtain or retain business or to otherwise inﬂuence a person working in an 
ofﬁcial capacity. 
 
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Government regulation outside of the United States  
In addition to regulations in the United States, we are subject to a variety of regulations in other 
jurisdictions governing, among other things, research and development, clinical trials, testing, 
manufacturing, safety, efﬁcacy, labeling, packaging, storage, record keeping, distribution, reporting, 
advertising and other promotional practices involving biological products as well as authorization 
and approval of our products. Because biologically sourced raw materials are subject to unique 
contamination risks, their use may be restricted in some countries.  
The requirements and process governing the conduct of clinical trials, product licensing, pricing and 
reimbursement vary from country to country. In all cases, the clinical trials must be conducted in 
accordance with GCP and the applicable regulatory requirements and the ethical principles that 
have their origin in the Declaration of Helsinki. If we fail to comply with applicable foreign regulatory 
requirements, we may be subject to, among other things, ﬁnes, suspension of clinical trials, 
suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating 
restrictions and criminal prosecution. 
Clinical trials regulation 
Whether or not we obtain FDA approval for a product, we must obtain the requisite approvals from 
regulatory authorities in foreign countries prior to the commencement of clinical trials or marketing 
of the product in those countries. Certain countries outside of the United States have a similar process 
that requires the submission of a clinical trial application much like the IND prior to the 
commencement of human clinical trials.  
In April 2014, the EU adopted the new Clinical Trials Regulation (EU) No 536/2014, or Regulation, 
which replaced the Clinical Trials Directive 2001/20/EC, or Directive, on 31 January 2022. The 
transitory provisions of the new Regulation provide that, by 31 January 2025, all ongoing clinical trials 
must have transitioned to the new Regulation. The new Regulation overhauled the system of approvals 
for clinical trials in the EU. Speciﬁcally, the new Regulation, which is directly applicable in all Member 
States (meaning that no national implementing legislation in each EU Member State is required), aims 
at simplifying and streamlining the approval of clinical trials in the EU. The main characteristics of 
the regulation include: a streamlined application procedure via a single-entry point through the 
Clinical Trials Information System, or CTIS; a single set of documents to be prepared and submitted 
for the application as well as simpliﬁed reporting procedures for clinical trial sponsors; and a 
harmonized procedure for the assessment of applications for clinical trials, which is divided in two 
parts (Part I contains scientiﬁc and medicinal product documentation and Part II contains the national 
and patient-level documentation). Part I is assessed by a coordinated review by the competent 
authorities of all EU Member States in which an application for authorization of a clinical trial has 
been submitted (Member States concerned) of a draft report prepared by a Reference Member 
State. Part II is assessed separately by each Member State concerned. Strict deadlines have been 
established for the assessment of clinical trial applications. The role of the relevant ethics committees 
in the assessment procedure will continue to be governed by the national law of the concerned EU 
Member State. However, overall related timelines will be deﬁned by the Clinical Trials Regulation. 
Drug review and approval  
In the EU, medicinal products, including advanced therapy medicinal products, or ATMPs, are subject 
to extensive pre- and post-market regulation by regulatory authorities at both the EU and national 
levels. ATMPs comprise gene therapy products, somatic cell therapy products and tissue engineered 
products. Gene therapy products deliver genes into the body that lead to a therapeutic, prophylactic 
 
52 Orchard Therapeutics plc 
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continued 

or diagnostic effect. Libmeldy is authorized as a gene therapy product in the EU, and we anticipate 
that our gene therapy development products would also be regulated as ATMPs in the EU.  
To obtain regulatory approval of an ATMP under EU regulatory systems, we must submit an MAA 
under the centralized procedure administered by the EMA. The application used to submit the BLA 
in the United States is similar to that required in the EU, with the exception of, among other things, 
certain speciﬁc requirements set out in Regulation (EC) No 1394/2007 on advanced therapy 
medicinal products, or the ATMP Regulation, for example certain particulars to be contained in the 
summary of product characteristics. The centralized procedure provides for the grant of a single 
marketing authorization by the European Commission that is valid across all of the EU, and in the 
additional Member States of the European Economic Area (Iceland, Liechtenstein and Norway), 
or EEA. As provided for in the ATMP Regulation, the scientiﬁc evaluation of MAAs for ATMPs is 
primarily performed by a specialized scientiﬁc committee called the Committee for Advanced 
Therapies, or CAT. The CAT prepares a draft opinion on the quality, safety and efﬁcacy of the ATMP 
which is the subject of the MAA, which is sent for ﬁnal approval to the Committee for Medicinal 
Products for Human Use, or CHMP. The CHMP recommendation is then sent to the European 
Commission, which adopts a decision binding in all EU Member States. The maximum time frame for 
the evaluation of an MAA for an ATMP is 210 days from receipt of a valid MAA, excluding clock stops 
when additional information or written or oral explanation is to be provided by the applicant in 
response to questions asked by the CAT and/or CHMP. Clock stops may extend the time frame of 
evaluation of an MAA considerably beyond 210 days. Where the CHMP gives a positive opinion, the 
EMA provides the opinion together with supporting documentation to the European Commission, 
who make the ﬁnal decision to grant a marketing authorization, which is issued within 67 days of 
receipt of the EMA’s recommendation. Accelerated assessment may be granted by the CHMP in 
exceptional cases, when a medicinal product is of major public health interest, particularly from the 
viewpoint of therapeutic innovation. If the CHMP accepts such a request, the time frame of 210 days 
for assessment will be reduced to 150 days (excluding clock stops), but it is possible that the CHMP 
may revert to the standard time limit for the centralized procedure if it determines that the application 
is no longer appropriate to conduct an accelerated assessment. 
Now that the UK (which comprises Great Britain and Northern Ireland) has left the EU, Great Britain 
is no longer covered by centralized marketing authorizations (under the Northern Ireland Protocol, 
centralized marketing authorizations continue to be recognized in Northern Ireland). All medicinal 
products with an existing centralized marketing authorization were automatically converted to Great 
Britain marketing authorizations on 1 January 2021. For a period of three years from 1 January 2021, 
the Medicines and Healthcare products Regulatory Agency, or MHRA, the UK medicines regulator, 
could rely on a decision taken by the European Commission on the approval of a new marketing 
authorization in the centralized procedure, in order to more quickly grant a new Great Britain 
marketing authorization. A separate application will, however, still be required. On 24 January 2023, 
the MHRA announced that a new international recognition framework will be put in place from 
1 January 2024, which will have regard to decisions on the approval of marketing authorizations 
made by the European Medicines Agency and certain other regulators when determining an 
application for a new Great Britain marketing authorization. 
Data and marketing exclusivity 
The EU also provides opportunities for market exclusivity. Upon receiving a marketing authorization 
in the EU, innovative medicinal products generally receive eight years of data exclusivity and an 
additional two years of market exclusivity. If granted, data exclusivity prevents generic or biosimilar 
applicants from referencing the innovator’s pre-clinical and clinical trial data contained in the dossier 
 
Orchard Therapeutics plc 53
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of the reference product when applying for a generic or biosimilar marketing authorization during a 
period of eight years from the date on which the reference product was ﬁrst authorized in the EU. 
During the additional two-year period of market exclusivity, a generic or biosimilar marketing 
authorization can be submitted, and the innovator’s data may be referenced, but no generic or 
biosimilar product can be marketed until the expiration of the market exclusivity period. The overall 
ten-year period will be extended to a maximum of eleven years if, during the ﬁrst eight years of those 
ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic 
indications which, during the scientiﬁc evaluation prior to authorization, is held to bring a signiﬁcant 
clinical beneﬁt in comparison with existing therapies. Even if an innovative medicinal product gains 
the prescribed period of data exclusivity, another company may market another version of the product 
if such company obtained marketing authorization based on an MAA with a complete and 
independent data package of pharmaceutical tests, pre-clinical tests and clinical trials. There is, 
however, no guarantee that a product will be considered by the EU’s regulatory authorities to be an 
innovative medicinal product, and products may therefore not qualify for data exclusivity.  
Orphan designation and exclusivity 
Products with an orphan designation in the EU can receive ten years of market exclusivity, during 
which time “no similar medicinal product” for the same indication may be placed on the market. 
A “similar medicinal product” is deﬁned as a medicinal product containing a similar active substance 
or substances as contained in an authorized orphan medicinal product, and which is intended for 
the same therapeutic indication. An orphan medicinal product can also obtain an additional two years 
of market exclusivity in the EU where an agreed pediatric investigation plan for pediatric studies has 
been complied with. No extension to any supplementary protection certiﬁcate can be granted on the 
basis of pediatric studies for orphan indications. 
The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in 
the United States. Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated 
as an orphan medicinal product if it meets the following criteria: (1) it is intended for the diagnosis, 
prevention or treatment of a life-threatening or chronically debilitating condition; and (2) either (i) the 
prevalence of such condition must not be more than ﬁve in 10,000 persons in the EU when the 
application is made, or (ii) without the beneﬁts derived from orphan status, it must be unlikely that the 
marketing of the medicine would generate sufﬁcient return in the EU to justify the investment needed 
for its development; and (3) there exists no satisfactory method of diagnosis, prevention or treatment 
of such condition authorized for marketing in the EU, or if such a method exists, the product will be of 
signiﬁcant beneﬁt to those affected by the condition, as deﬁned in Regulation (EC) 847/2000. Orphan 
medicinal products are eligible for ﬁnancial incentives such as reduction of fees or fee waivers and 
are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved 
therapeutic indication. The application for orphan designation must be submitted before the application 
for marketing authorization. The applicant will receive a fee reduction for the MAA if the orphan 
designation has been granted, but not if the designation is still pending at the time the marketing 
authorization is submitted. Orphan designation does not convey any advantage in, or shorten the 
duration of, the regulatory review and approval process. A marketing authorization may be granted to 
a “similar medicinal product” for the same orphan indication at any time if:  
•
a second applicant can establish that its product, although similar, is safer, more effective or 
otherwise clinically superior;  
•
the marketing authorization holder of the authorized orphan product consents to a second orphan 
medicinal product application; or  
 
54 Orchard Therapeutics plc 
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•
the marketing authorization holder of the authorized orphan product cannot supply enough 
orphan medicinal product.  
Since 1 January 2021, a separate process for orphan designation has applied in Great Britain. There 
is now no pre-marketing authorization orphan designation (as there is in the EU) in Great Britain and 
the application for orphan designation will be reviewed by the MHRA at the time of an MAA for a UK 
or Great Britain marketing authorization. The criteria for orphan designation are the same as in the 
EU, save that they apply to Great Britain only (e.g., there must be no satisfactory method of diagnosis, 
prevention or treatment of the condition concerned in Great Britain, as opposed to the EU, and the 
prevalence of the condition must not be more than ﬁve in 10,000 persons in Great Britain). 
Pediatric development  
In the EU, companies developing a new medicinal product must agree upon a pediatric investigation 
plan, or PIP, with the EMA’s Pediatric Committee, or PDCO, and must conduct pediatric clinical trials 
in accordance with that PIP, unless a waiver applies, (e.g., because the relevant disease or condition 
occurs only in adults). The PIP sets out the timing and measures proposed to generate data to 
support a pediatric indication of the product for which a marketing authorization is being sought. 
The MAA for the product must include the results of pediatric clinical trials conducted in accordance 
with the PIP, unless a waiver applies, or a deferral has been granted by the PDCO of the obligation 
to implement some or all of the measures of the PIP until there are sufﬁcient data to demonstrate the 
efﬁcacy and safety of the product in adults, in which case the pediatric clinical trials must be 
completed at a later date. Products that are granted a marketing authorization with the results of the 
pediatric clinical trials conducted in accordance with the PIP are eligible for a six-month extension 
of the protection under a supplementary protection certiﬁcate, or SPC (provided an application for 
such extension is made at the same time as ﬁling the SPC application for the product, or at any point 
up to 2 years before the SPC expires) even where the trial results are negative. In the case of orphan 
medicinal products, a two-year extension of the orphan market exclusivity may be available. This 
pediatric reward is subject to speciﬁc conditions and is not automatically available when data in 
compliance with the PIP are developed and submitted.  
PRIME Designation  
In March 2016, the EMA launched an initiative to facilitate development of product candidates in 
indications, often rare, for which few or no therapies currently exist. The PRIority MEdicines, or PRIME, 
scheme is intended to encourage drug development in areas of unmet medical need and provides 
accelerated assessment of products representing substantial innovation, where the MAA will be 
made through the centralized procedure. Eligible products must target conditions for which there is 
an unmet medical need (there is no satisfactory method of diagnosis, prevention or treatment in the 
EU or, if there is, the new medicine will bring a major therapeutic advantage) and they must 
demonstrate the potential to address the unmet medical need by introducing new methods of therapy 
or improving existing ones. Products from small- and medium-sized enterprises may qualify for earlier 
entry into the PRIME scheme than larger companies. Many beneﬁts accrue to sponsors of product 
candidates with PRIME designation, including but not limited to, early and proactive regulatory 
dialogue with the EMA, frequent discussions on clinical trial designs and other development program 
elements, and accelerated MAA assessment once a dossier has been submitted. Importantly, 
a dedicated EMA contact and rapporteur from the CHMP or CAT are appointed early in the PRIME 
scheme facilitating increased understanding of the product at the EMA’s Committee level. A kick-off 
meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to 
provide guidance on the overall development and regulatory strategies. Where, during the course of 
 
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development, a medicine no longer meets the eligibility criteria, support under the PRIME scheme 
may be withdrawn. 
Post-approval controls  
Following approval, the holder of the marketing authorization is required to comply with a range of 
requirements applicable to the manufacturing, marketing, promotion and sale of the medicinal 
product. These include the following: 
•
The holder of a marketing authorization must establish and maintain a pharmacovigilance system 
and appoint an individual qualiﬁed person for pharmacovigilance, who is responsible for oversight 
of that system. Key obligations include expedited reporting of suspected serious adverse 
reactions and submission of periodic safety update reports, or PSURs.  
•
All new MAAs must include a risk management plan, or RMP, describing the risk management 
system that the company will put in place and documenting measures to prevent or minimize the 
risks associated with the product. The regulatory authorities may also impose speciﬁc obligations 
as a condition of the marketing authorization. Such risk-minimization measures or 
post-authorization obligations may include additional safety monitoring, more frequent submission 
of PSURs, or the conduct of additional clinical trials or post-authorization safety studies. RMPs 
and PSURs are routinely available to third parties requesting access, subject to limited redactions.  
•
All advertising and promotional activities for the product must be consistent with the approved 
SmPC and therefore all off-label promotion is prohibited. Direct-to-consumer advertising of 
prescription medicines is also prohibited in the EU. Although general requirements for advertising 
and promotion of medicinal products are established under EU directives, the details are 
governed by regulations in each EU Member State and can differ from one country to another.  
The aforementioned EU rules are generally applicable in the EEA. 
Brexit and the Regulatory Framework in the UK  
The UK left the EU (commonly referred to as “Brexit”) in January 2020. The UK and EU entered a 
trade and cooperation agreement, or TCA, which has been formally applicable since May 2021. The 
TCA includes speciﬁc provisions concerning pharmaceuticals, which include the mutual recognition 
of GMP, inspections of manufacturing facilities for medicinal products and GMP documents issued, 
but does not provide for wholesale mutual recognition of UK and EU pharmaceutical regulations. 
At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of 
medicinal products through the Human Medicines Regulations 2012 (as amended) (under the 
Northern Ireland Protocol, the EU regulatory framework continues to apply in Northern Ireland). 
Except in respect of the new EU Clinical Trials Regulation, the regulatory regime in Great Britain 
therefore largely aligns with current EU regulations. However, it is possible that these regimes will 
diverge more signiﬁcantly in future now that Great Britain’s regulatory system is independent from 
the EU and the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation. 
However, notwithstanding that there is no wholesale recognition of EU pharmaceutical legislation 
under the TCA, under the new framework mentioned above which will be put in place by the MHRA 
from 1 January 2024, the MHRA has stated that it will take into account decisions on the approval of 
marketing authorizations from the EMA (and certain other regulators) when considering an application 
for a Great Britain marketing authorization.  
Other healthcare laws and compliance requirements  
In the United States, our current and future operations are subject to regulation by various federal, 
state and local authorities in addition to the FDA, including but not limited to, the Centers for Medicare 
 
56 Orchard Therapeutics plc 
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Orchard Therapeutics plc 57
and Medicaid Services, or CMS, other divisions of the U.S. Department of Health and Human 
Services, or HHS (such as the Ofﬁce of Inspector General, Ofﬁce for Civil Rights and the Health 
Resources and Service Administration), the U.S. Department of Justice, or DOJ, and individual 
U.S. Attorney ofﬁces within the DOJ, and state and local governments. For example, our clinical 
research, sales, marketing and scientiﬁc/educational grant programs may have to comply with the 
anti-fraud and abuse provisions of the Social Security Act, the false claims laws, the privacy and 
security provisions of the federal Health Insurance Portability and Accountability Act of 1996, 
or HIPAA, and similar state laws, each as amended, as applicable: 
•
the federal Anti-Kickback Statute, which prohibits, among other things, knowingly and willfully 
soliciting, receiving, offering or paying any remuneration (including any kickback, bribe, or rebate), 
directly or indirectly, overtly or covertly, in cash or in kind, to induce, or in return for, either the 
referral of an individual, or the purchase, lease, order, arrangement or recommendation of any 
good, facility, item or service for which payment may be made, in whole or in part, under a federal 
healthcare program, such as the Medicare and Medicaid programs; a person or entity does not 
need to have actual knowledge of the federal Anti-Kickback Statute or speciﬁc intent to violate it 
to have committed a violation. In addition, the government may assert that a claim including items 
or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or 
fraudulent claim for purposes of the federal False Claims Act or federal civil money penalties 
statute;  
•
the federal civil and criminal false claims laws and civil monetary penalty laws, including the False 
Claims Act, which prohibit, among other things, individuals or entities from knowingly presenting, 
or causing to be presented, false or fraudulent claims for payment to, or approval by Medicare, 
Medicaid, or other federal healthcare programs, knowingly making, using or causing to be made 
or used a false record or statement material to a false or fraudulent claim or an obligation to pay 
or transmit money to the federal government, or knowingly concealing or knowingly and 
improperly avoiding or decreasing or concealing an obligation to pay money to the federal 
government. Manufacturers can be held liable under the False Claims Act even when they do 
not submit claims directly to government payers if they are deemed to “cause” the submission 
of false or fraudulent claims. The False Claims Act also permits a private individual acting as a 
“whistle blower” to bring actions on behalf of the federal government alleging violations of the 
False Claims Act and to share in any monetary recovery;  
•
the anti-inducement law, which prohibits, among other things, the offering or giving of 
remuneration, which includes, without limitation, any transfer of items or services for free or for 
less than fair market value (with limited exceptions), to a Medicare or Medicaid beneﬁciary that 
the person knows or should know is likely to inﬂuence the beneﬁciary’s selection of a particular 
supplier of items or services reimbursable by a federal or state governmental program;  
•
HIPAA, which created new federal criminal statutes that prohibit knowingly and willfully executing, 
or attempting to execute, a scheme to defraud any healthcare beneﬁt program or obtain, by 
means of false or fraudulent pretenses, representations, or promises, any of the money or 
property owned by, or under the custody or control of, any healthcare beneﬁt program, regardless 
of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering 
up by any trick or device a material fact or making any materially false, ﬁctitious, or fraudulent 
statements or representations in connection with the delivery of, or payment for, healthcare 
beneﬁts, items or services relating to healthcare matters; similar to the federal Anti-Kickback 
Statute, a person or entity does not need to have actual knowledge of the statute or speciﬁc intent 
to violate it in order to have committed a violation;  
•
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act 
of 2009, and their respective implementing regulations, which impose requirements on certain 
covered healthcare providers, health plans, and healthcare clearinghouses as well as their 
UK STATUTORY STRATEGIC REPORT 
continued 

 
58 Orchard Therapeutics plc 
respective business associates that perform services for them that involve the use, or disclosure 
of, individually identiﬁable health information, relating to the privacy, security and transmission of 
individually identiﬁable health information;  
•
the federal transparency requirements under the ACA, including the provision commonly referred 
to as the Physician Payments Sunshine Act, and its implementing regulations, which requires 
applicable manufacturers of drugs, devices, biologics and medical supplies for which payment 
is available under Medicare, Medicaid or the Children’s Health Insurance Program to report 
annually to the U.S. Department of Health and Human Services, CMS, information related to 
payments or other transfers of value made to physicians (deﬁned to include doctors, dentists, 
optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and 
investment interests held by the physicians described above and their immediate family members. 
Effective 1 January 2022, these reporting obligations extend to include transfers of value made 
to certain non-physician providers such as physician assistants and nurse practitioners;  
•
federal government price reporting laws, which require us to calculate and report complex pricing 
metrics in an accurate and timely manner to government programs; and  
•
federal consumer protection and unfair competition laws, which broadly regulate marketplace 
activities and activities that potentially harm consumers.  
Additionally, we are subject to state and foreign equivalents of each of the healthcare laws and 
regulations described above, among others, some of which may be broader in scope and may apply 
regardless of the payor. Many U.S. states have adopted laws similar to the federal Anti-Kickback 
Statute and False Claims Act, and may apply to our business practices, including, but not limited to, 
research, distribution, sales or marketing arrangements and claims involving healthcare items or 
services reimbursed by non-governmental payors, including private insurers. In addition, some states 
have passed laws that require pharmaceutical companies to comply with the April 2003 Ofﬁce of 
Inspector General Compliance Program Guidance for Pharmaceutical Manufacturers and/or the 
Pharmaceutical Research and Manufacturers of America’s Code on Interactions with Healthcare 
Professionals. Several states also impose other marketing restrictions or require pharmaceutical 
companies to make marketing or price disclosures to the state. There are ambiguities as to what is 
required to comply with these state requirements and if we fail to comply with an applicable state 
law requirement, we could be subject to penalties. Finally, there are state and foreign laws governing 
the privacy and security of health information (e.g., the California Consumer Privacy Act), many of 
which differ from each other in signiﬁcant ways and often are not preempted by HIPAA, thus 
complicating compliance efforts.  
We may also be subject to additional privacy restrictions. The collection, use, storage, disclosure, 
transfer, or other processing of personal data regarding individuals in the European Economic Area, 
or EEA, including personal health data, is subject to the General Data Protection Regulation 2016/679 
(EU GDPR), which became effective in May 2018. Following Brexit and the expiration of the 
subsequent transition period on 31 December 2020, the EU GDPR has been brought into UK law as 
the “UK GDPR” which, along with the UK Data Protection Act 2018, governs the collection, use, 
storage, disclosure, transfer, or other processing of personal data regarding individuals in the UK. 
In the present document, references to “GDPR” are meant to include both the EU GDPR and the 
UK  GDPR, unless speciﬁed. The GDPR is wide-ranging in scope and imposes numerous 
requirements on companies that process personal data.  
Because of the breadth of these laws and the narrowness of the statutory exceptions and safe 
harbors available, it is possible that some of our business activities could be subject to challenge 
under one or more of such laws.  
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 59
Violations of fraud and abuse laws may be punishable by criminal and/or civil sanctions, including 
penalties, ﬁnes, imprisonment and/or exclusion or suspension from federal and state healthcare 
programs such as Medicare and Medicaid and debarment from contracting with the U.S. government. 
In addition, private individuals have the ability to bring actions on behalf of the U.S. government 
under the federal False Claims Act as well as under the false claims laws of several states.  
Law enforcement authorities are increasingly focused on enforcing fraud and abuse laws, and it is 
possible that some of our practices may be challenged under these laws. Efforts to ensure that our 
current and future business arrangements with third parties, and our business generally, will comply 
with applicable healthcare laws and regulations will involve substantial costs. If our operations, 
including our arrangements with physicians and other healthcare providers are found to be in violation 
of any of such laws or any other governmental regulations that apply to us, we may be subject to 
penalties, including, without limitation, administrative, civil and criminal penalties, damages, ﬁnes, 
disgorgement, contractual damages, reputational harm, diminished proﬁts and future earnings, the 
curtailment or restructuring of our operations, exclusion from participation in federal and state 
healthcare programs (such as Medicare and Medicaid), and imprisonment, any of which could 
adversely affect our ability to operate our business and our ﬁnancial results. In addition, our gene 
therapy programs for Strimvelis and Libmeldy were approved by the EMA in 2016 and 2020, 
respectively, and the approval and commercialization of Strimvelis and Libmeldy subjects us to 
foreign equivalents of the healthcare laws mentioned above, among other foreign laws. The approval 
and commercialization of any of our other gene therapies outside the United States will also likely 
subject us to foreign equivalents of the healthcare laws mentioned above, among other foreign laws.  
If any of the physicians or other healthcare providers or entities with whom we expect to do business 
are found to be not in compliance with applicable laws, they may be subject to criminal, civil or 
administrative sanctions, including exclusions from government funded healthcare programs, which 
may also adversely affect our business.  
The risk of our being found in violation of these laws is increased by the fact that many of these laws 
have not been fully interpreted by the regulatory authorities or the courts, and their provisions are 
open to a variety of interpretations. Any action against us for violation of these laws, even if we 
successfully defend against it, could cause us to incur signiﬁcant legal expenses and divert our 
management’s attention from the operation of our business. The shifting compliance environment 
and the need to build and maintain a robust system to comply with multiple jurisdictions with different 
compliance and reporting requirements increases the possibility that a healthcare company may 
violate one or more of the requirements. Efforts to ensure that our business arrangements with third 
parties will comply with applicable healthcare laws and regulations will involve substantial cost. 
Healthcare reform 
The United States and many foreign jurisdictions have enacted or proposed legislative and regulatory 
changes that affect the healthcare system and which could prevent or delay marketing approval of 
our potential products, restrict or regulate post-approval activities and affect our ability to proﬁtably 
sell products, if approved.  
In the United States, there have been and continue to be a number of legislative initiatives to contain 
healthcare costs. As one example, in March 2010, the Patient Protection and Affordable Care Act, as 
amended by the Health Care and Education Reconciliation Act of 2010, or the ACA, was passed, 
which substantially changed the way health care is ﬁnanced by both governmental and private 
insurers, and signiﬁcantly impacted the U.S. pharmaceutical industry. Since its enactment, there have 
been numerous judicial, administrative, executive and legislative challenges to certain aspects of 
the ACA, as we expect there will be additional challenges and amendments to the ACA in the future.  
UK STATUTORY STRATEGIC REPORT 
continued 

 
60 Orchard Therapeutics plc 
In Europe, delivery of healthcare is largely a matter of national law and policy. National governments 
and health service providers have different priorities and approaches to the delivery of health care 
and the pricing and reimbursement of products in that context. Budgetary constraints could affect 
our ability to proﬁtably sell approved products in certain jurisdictions.  
We expect that healthcare reform measures may result in more rigorous coverage criteria and 
downward pressure on the price that we receive for approved products. There have been, and likely 
will continue to be, legislative and regulatory proposals at the foreign, federal and state levels directed 
at lowering the cost of healthcare. The implementation of cost containment measures or other 
healthcare reforms may prevent us from generating sufﬁcient revenue, attaining proﬁtability or 
commercializing additional products. 
Coverage and reimbursement  
Signiﬁcant uncertainty exists as to the coverage and reimbursement status of any gene therapies for 
which we obtain regulatory approval. In the United States and markets in other countries, sales of 
any gene therapies for which we receive regulatory approval for commercial sale will depend, in part, 
on the availability of coverage and reimbursement from payors. Payors include government 
authorities, managed care providers, private health insurers and other organizations. Patients who 
are prescribed treatments for their conditions and providers generally rely on these third-party payors 
to reimburse all or part of the associated healthcare. The process for determining whether a payor 
will provide coverage for a product may be separate from the process for setting the reimbursement 
rate that the payor will pay for the product. Payors may limit coverage to speciﬁc products on an 
approved list, or formulary, which might not include all of the FDA-approved products for a particular 
indication. A decision by a payor not to cover our gene therapies could reduce physician utilization 
of our products once approved and have a material adverse effect on our sales, results of operations 
and ﬁnancial condition. Moreover, a payor’s decision to provide coverage for a product does not imply 
that an adequate reimbursement rate will be approved. Adequate third-party reimbursement may 
not be available to enable us to maintain price levels sufﬁcient to realize an appropriate return on our 
investment in product development and manufacturing costs.  
The Inﬂation Reduction Act of 2022, or IRA, includes several provisions that may impact our business 
to varying degrees, including provisions that reduce the out-of-pocket cap for Medicare Part D 
beneﬁciaries to $2,000 starting in 2025; impose new manufacturer ﬁnancial liability on certain drugs 
under Medicare Part D, allow the U.S. government to negotiate Medicare Part B and Part D price 
caps for certain high-cost drugs and biologics without generic or biosimilar competition, require 
companies to pay rebates to Medicare for certain drug prices that increase faster than inﬂation, and 
delay the rebate rule that would limit the fees that pharmacy beneﬁt managers can charge. Further, 
under the IRA, orphan drugs are exempted from the Medicare drug price negotiation program, but 
only if they have one rare disease designation and for which the only approved indication is for that 
disease or condition. If a product receives multiple rare disease designations or has multiple 
approved indications, it may not qualify for the orphan drug exemption. The effects of the IRA on our 
business and the healthcare industry in general is not yet known. 
In addition, coverage and reimbursement for products can differ signiﬁcantly from payor to payor. 
One payor’s decision to cover a particular medical product or service does not ensure that other 
payors will also provide coverage for the medical product or service, or will provide coverage at an 
adequate reimbursement rate. In the United States, the principal decisions about reimbursement for 
new medicines are typically made by the Centers for Medicare & Medicaid Services, or CMS, an 
agency within the U.S. Department of Health and Human Services. CMS decides whether and to 
what extent a new medicine will be covered and reimbursed under Medicare and private payors tend 
to follow CMS to a substantial degree. 
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 61
Additionally, the coverage determination process will require us to provide scientiﬁc and clinical 
support for the use of our products to each payor separately and will be a time-consuming process.  
Payors are increasingly challenging the price and examining the medical necessity and 
cost-effectiveness of medical products and services, in addition to their safety and efﬁcacy. In order 
to obtain and maintain coverage and reimbursement for any product, we may need to conduct 
expensive evidence generation studies in order to demonstrate the medical necessity and 
cost-effectiveness of such a product, in addition to the costs required to obtain regulatory approvals. 
If payors do not consider a product to be cost-effective compared to current standards of care, they 
may not cover the product as a beneﬁt under their plans or, if they do, the level of payment may not 
be sufﬁcient to allow a company to cover its costs or make a proﬁt.  
Outside of the United States, the pricing of pharmaceutical products is subject to governmental 
control in many countries. For example, in the EU, pricing and reimbursement schemes vary widely 
from country to country. Some countries provide that products may be marketed only after a 
reimbursement price has been agreed with the government authority. Furthermore, some countries 
may require the completion of additional studies that compare the effectiveness and/or 
cost-effectiveness of a particular therapy to current standards of care as part of so-called health 
technology assessments, or HTAs, in order to obtain reimbursement or pricing approval. Additionally, 
there may be a need for activities to secure reimbursement for procedures associated with products 
administered in a hospital setting, such as Libmeldy, under the diagnosis-related group, or DRG, 
system, whereby a billing code may not exist or may be currently insufﬁcient to cover the cost of the 
procedure. In other instances, countries may monitor and control product volumes and issue 
guidance to physicians to limit prescriptions in the form of treatment policies. Efforts to control prices 
and utilization of pharmaceutical products will likely continue as countries attempt to manage 
healthcare expenditures. 
Key Performance Indicators (KPIs) 
Management closely monitors cash position and runway. As of 31 December 2022, we had cash, 
cash equivalents, short-term investments, and restricted cash of $148.0 million down from $224.4 
million in 2021. As a result of the Private Placement in March 2023 the Company received $34.0 million, 
this has extended the Group’s cash runway into 2025. Our research and development expenses are 
also closely monitored and have decreased from $153.6 million in 2021 to $104.8 million in 2022. In 
addition, we assess our performance through clinical and regulatory advancement of our programs. 
Following the approval of our lead program, OTL-200, by the European Union, the United Kingdom, 
Iceland, Liechtenstein and Norway under the brand name Libmeldy for eligible patients with early-
onset metachromatic leukodystrophy, or MLD, in December 2020, we initiated commercial launch 
activities in 2021. In the ﬁrst quarter of 2022 we made our ﬁrst commercial sale of Libmeldy. On March 
30, 2022, the Company announced its commitment to focus on severe neurometabolic diseases and 
early research programs, and to discontinue its investment in and seek strategic alternatives for the 
Company’s programs in rare primary immune deﬁciencies, including OTL-103 for treatment of Wiskott 
Aldrich syndrome (“WAS”), OTL-102 for treatment of X-linked chronic granulomatous disease (“X-
CGD”), and Strimvelis for adenosine deaminase severe combined immunodeﬁciency (“ADA-SCID”). 
In the third quarter of 2022 we announced that the ﬁrst conﬁrmed case of a patient with metachromatic 
leukodystrophy (MLD) has been identiﬁed from the ARCHIMEDlife newborn screening (NBS) pilot 
study in collaboration with Hannover Screening Laboratory. In November 2022 we announced that we 
had secured clinical Type B meeting with U.S. FDA to take place in early 2023 prior to OTL-200 BLA 
submission.  
UK STATUTORY STRATEGIC REPORT 
continued 

 
62 Orchard Therapeutics plc 
Employees and Human Capital Resources 
As of 31 December 2022 we had 166 full-time employees (2021: 250). We have no collective 
bargaining agreements with our employees, and we have not experienced any work stoppages. 
We consider our relationship with our employees to be positive. We monitor employee engagement 
through an annual survey and develop a prioritized action plan on an annual basis to address any 
areas in need of attention. Our human capital objectives include, as applicable, identifying, recruiting, 
developing, retaining, and incentivizing our existing and prospective employees, as well as optimizing 
the overall employee experience. The principal purposes of our incentive plans are to attract, retain 
and motivate our employees. The granting of share-based compensation awards is designed to 
reward selected employees for long-term shareholder value creation and our cash-based 
performance bonus awards reward the achievement of annual performance goals. The health and 
safety of our employees, customers and communities are of primary concern. During the COVID-19 
pandemic, we have taken signiﬁcant steps to protect our workforce, including, but not limited to, 
implementing a hybrid work model and social distancing protocols consistent with guidelines issued 
by federal, state and local laws.  
Summary of the Principal Risks and Uncertainties 
Our business is subject to numerous risks and uncertainties that you should be aware of in evaluating 
our business. These risks include, but are not limited to, the following: 
•
We have incurred net losses since inception. We expect to incur net losses for the foreseeable 
future and may never achieve or maintain proﬁtability. 
•
We will need additional funding, which may not be available on acceptable terms or at all. 
•
Our gene therapy product candidates are based on a novel technology, which makes it difﬁcult 
to predict the time and cost of product candidate development and of subsequently obtaining 
regulatory approval. 
•
The results from our clinical trials for any of our product candidates may not be sufﬁciently robust 
to support marketing approval or the submission of marketing approval. Before we submit our 
product candidates for marketing approval, the U.S. Food and Drug Administration or the 
European Medicines Agency may require us to conduct additional clinical trials or evaluate 
patients for an additional follow-up period. 
•
Interim data and ad hoc analyses are preliminary in nature. Success in pre-clinical studies or 
early clinical trials may not be indicative of results obtained in later trials. 
•
Gene therapies are novel, complex and difﬁcult to manufacture. We have limited manufacturing 
experience, and we rely on third-party manufacturers that are often our single source of supply.  
•
Libmeldy™, Strimvelis® and our product candidates and the process for administering Libmeldy, 
Strimvelis and our product candidates may cause serious or undesirable side effects or adverse 
events.  
•
We may ﬁnd it difﬁcult to enroll patients in our clinical trials, which could delay or prevent us from 
proceeding with clinical trials of our product candidates. 
•
We may be unable to establish effective sales and marketing capabilities, which would negatively 
impact our revenue.  
•
If the size and value of the market opportunities for our commercial products or product 
candidates are smaller than our estimates, or if we have difﬁculty in ﬁnding patients that meet 
eligibility requirements for Libmeldy or any of our product candidates, if approved, our product 
revenues may be adversely affected.  
UK STATUTORY STRATEGIC REPORT 
continued 

 
Orchard Therapeutics plc 63
•
We face signiﬁcant competition in our industry and there can be no assurance that our 
commercial products or our product candidates, if approved, will achieve acceptance in the 
market.  
•
We may be unable to protect our intellectual property rights throughout the world. 
•
We may become subject to claims that we are infringing certain third-party patents. 
•
We have in the past, and in the future we may, enter into collaborations with third parties to develop 
or commercialize product candidates. These collaborations may not be successful. 
•
The market price of our ADSs may be highly volatile and may ﬂuctuate due to factors beyond our 
control. 
Information on Environmental Matters 
The Company is required to measure and report its greenhouse gas emissions in accordance with 
the provisions of the UK Companies Act 2006 (UK Statutory Strategic Report and UK Statutory 
Directors’ Report) Regulations 2013. Our greenhouse gas emissions estimates for 2022 have been 
prepared in accordance with the U.K. Government’s Department for Environment, Food and Rural 
Affairs (Defra) guidance document “Environmental Reporting Guidelines: Including Mandatory GHG 
emissions reporting guidance, from March 2019”. 
                                                                                                                                                          2022                      2021 
Estimated greenhouse gas emissions from purchased electricity, 
heat, steam, or cooling for our own use (tCO2e)                                                       61.1                  64.6 
Underlying global energy use (‘000 kWh)                                                                  304                   316 
Proportion of emissions related to the UK                                                                37%                  59% 
Intensity ratio: Total greenhouse gas emissions per employee on the 
basis of a monthly average of 204 full-time equivalent employees (2021: 238)       0.30                  0.27 
We have used evidence and estimates derived from information provided by our energy supply 
partners and lessors to generate our disclosure of emissions for the year. These include the purchase 
of electricity, heat, steam or cooling either directly from our energy supply partners, or through utility 
bills from our lessors. Standard emission factors from Defra’s GHG Conversion Factors Repository 
were applied to estimate emissions. The Group considers that the intensity ratio of tonnes of carbon 
dioxide per full-time equivalent employee is a suitable metric for its operations. 
Electricity, heating, and cooling usage at our leased facilities in the United States and United Kingdom 
drive the majority of our greenhouse gas emissions. Greenhouse gas emissions generated by 
company-owned facilities remained roughly constant as we remained a primarily remote  workforce. 
During 2022 we moved premises to new ofﬁces and laboratories in Hammersmith, London, during 
which we focused on choosing energy efﬁcient options to reduce our future emissions. 
UK STATUTORY STRATEGIC REPORT 
continued 

 
64 Orchard Therapeutics plc 
Diversity 
Appointments within the Group are made on merit according to the balance of skills and experience 
offered by prospective candidates. While acknowledging the beneﬁts of diversity, individual 
appointments are made irrespective of personal characteristics such as race, disability, gender, 
sexual orientation, religion, or age. A breakdown of employment statistics as of 31 December 2022 
and 2021 is as follows: 
31 December 2022: 
Male
Female                  Total 
Company Directors
6                       2                    8 
Executives/Vice Presidents 
14                       5                  19 
Other Employees
58                     89                147 
Total Employees
78                     96                174 
31 December 2021: 
Male
Female                  Total 
Company Directors
6                       2                    8 
Executives/Vice Presidents 
15                     10                  25 
Other Employees
88                   145                233 
Total Employees
103                   155                258 
Section 172(1) UK Companies Act 2006 
The Directors are required by law to act in good faith to promote the success of the Company for the 
beneﬁt of the shareholders as a whole and are also required to have regard for the following areas: 
The board has had  
regard to the following  
matters:                                  More information 
   Refer to the “Business Overview” section of this UK Statutory Strategic Report 
(page 18). 
   The Group will need substantial additional funding to support continuing 
operations and pursue a growth strategy as outlined in our Business overview 
within this Strategic Report. Until such time the Group can generate signiﬁcant 
revenue from product sales, if ever, the Group expects to ﬁnance operations 
through a combination of equity offerings, debt ﬁnancings, collaborations, 
government contracts or other strategic transactions. The Group may be 
unable to raise additional funds or enter into such other agreements or 
arrangements when needed on favourable terms, or at all. 
   Refer to the “Employees and Human Capital Resources” (page 62) and 
“Diversity” (page 64) sections of this UK Statutory Strategic Report. 
   The Board and Company management have a good relationship with the 
Group’s employees. The Board maintains constructive dialogue with 
employees through the Company’s Executive Leadership. Appropriate 
remuneration and incentive schemes are maintained to align employees’ 
objectives with those of the Group. 
 
 
– the likely 
consequences of 
any decision in the 
long-term;
– the interests of the 
Company’s 
employees;
UK STATUTORY STRATEGIC REPORT 
continued 

The board has had  
regard to the following  
matters:                                  More information 
   Refer to the “Summary of the Principal Risks and Uncertainties” section of 
this UK Statutory Strategic Report (page 62). 
 
 
 
 
   Refer to the “Employees and Human Capital Resources” (page 62), 
“Diversity” (page 64), and “Information on Environmental Matters” (page 63) 
sections of this UK Statutory Strategic Report. 
 
 
   The Board sets high standards for the Company’s employees, ofﬁcers and 
Directors. Implicit in this philosophy is the importance of sound corporate 
governance. The Group has established a Code of Business Conduct and 
Ethics (the “Code”), which is posted in the Corporate Governance section of 
the Group’s website and includes mechanisms for reporting suspected 
violations of the Code and other policies and procedures of the Company. 
The Company’s employees, ofﬁcers and Directors must review the Code 
periodically and are required to comply with its terms. 
   The Board endeavors to maintain good relationships with its shareholders and 
treat them equally. The Board values good relations with the Company’s 
shareholders and understands the importance of effectively communicating 
the Company’s operational and ﬁnancial performance as well as its future 
strategy. The Company’s website provides ﬁnancial information as well as 
historical news releases and matters relating to corporate governance. 
   Annual and interim results are communicated via press releases, and are ﬁled 
with the U.S. Securities and Exchange Commission, as are certain operational 
and regulatory press releases. Shareholders may also attend the Annual 
General Meeting where they can discuss matters with the Board. 
This report was approved by the Board of Directors on 27 April 2023 and signed on behalf of the 
Board of Directors by: 
 
Hubert Gaspar  
Director 
27 April 2023 
 
– the impact of the 
Company’s 
operations on the 
community and the 
environment;
– the importance of 
developing the 
Company’s business 
relationships with 
suppliers, customers 
and others;
– the desirability of the 
Company 
maintaining a 
reputation for high 
standards of 
business conduct;
– The need to act fairly 
as between 
shareholders of the 
Company
 
Orchard Therapeutics plc 65
UK STATUTORY STRATEGIC REPORT 
continued 

The Directors of Orchard Therapeutics plc (the “Company”, “Parent Company”, or the “Group”) 
submit this report and the audited consolidated ﬁnancial statements as of and for the year ended 
31 December 2022. The information in this report, including the information that is referred to below, 
shall be deemed to comply with the UK Companies Act 2006 requirements for the UK Statutory 
Directors’ Report. Some disclosures which would typically be included in the UK Statutory Directors’ 
Report have instead been included in the UK Statutory Strategic Report. 
General Information 
Description of the principal activities and likely future developments of the Group’s business  
The principal activities and likely future developments of the Group are outlined in the UK Statutory 
Strategic Report, beginning on page 17 of this Annual Report. 
Research and development activities 
A fulsome view of the Company’s research and development activities is outlined for the Company’s 
key programs in the UK Statutory Strategic Report. Total consolidated research and development 
expense during the year was $104.8 million (2021: $153.6 million). 
Results and dividends 
The Company’s consolidated ﬁnancial results for the year are set out on page 102 of this 
Annual Report. For the year ended 2022 the Directors do not recommend the payment of a dividend 
(2021: nil). 
Directors 
The Directors of the Parent Company who held ofﬁce during the year and up to the date of signing 
the consolidated ﬁnancial statements, unless otherwise stated, are outlined in the “Company 
Information” section on page 2 of this Annual Report. 
Capital Structure 
Details of the issued share capital, together with details of shares issued during the year, are set out 
in note 23 to the consolidated ﬁnancial statements. Share capital activity for the 2022 ﬁnancial year 
is outlined on page 105 of the consolidated ﬁnancial statements in the Consolidated statement of 
changes in equity. 
Political Contributions 
No political donations were made, and no political expenditure was incurred, by the Company, during 
2022 (2021: nil). 
Post Balance Sheet Events 
Ratio change 
On 10 February 2023, the Company announced that the Company's Board of Directors approved a 
change to the ratio of the Company's ADSs to ordinary shares (the "ADS Ratio") from the previous 
ADS Ratio of one ADS to one ordinary share to a new ADS Ratio of one ADS to ten ordinary shares. 
The ratio change became effective on 10 March 2023. The change in the ADS Ratio had the same 
effect as a one-for-ten reverse ADS split and is intended to enable the Company to regain compliance 
with the Nasdaq minimum bid price requirement. As all ﬁnancial statement and disclosure information 
is presented in ordinary share amounts, not ADSs, there was no impact to the consolidated ﬁnancial 
statements and footnote disclosures.  
Issuance of  shares through 2023 Private Placement 
On 6 March 2023, the Company entered into a Securities Purchase Agreement (the “Purchase 
Agreement”) pursuant to which the Company agreed to sell, in an unregistered offering, up to an 
 
66 Orchard Therapeutics plc 
UK STATUTORY DIRECTORS’ REPORT

aggregate of (i) 99,166,900 shares, consisting of a combination of Ordinary Shares, nominal value 
£0.10 per share (“Ordinary Shares”) and Non-Voting Ordinary Shares, nominal value £0.10 per share 
(“Non-Voting Ordinary Shares” and together with the Ordinary Shares, “Shares”) and (ii) warrants to 
purchase an aggregate of 109,083,590 Ordinary Shares or Non-Voting Ordinary Shares (the 
“Warrants”). 
The 2023 Private Placement consists of two closings. The Company agreed to sell and issue in the 
initial closing of the 2023 Private Placement (i) 56,666,900 Shares and (ii) Warrants to purchase an 
aggregate of 62,333,590 Shares, at a purchase price of $6.00 per unit, where each unit consists of 
ten (10) Shares and an accompanying Warrant to purchase eleven (11) Shares. The initial closing of 
the 2023 Private Placement occurred on 10 March 2023. The Company received gross proceeds of 
approximately $34.0 million from the initial closing of the 2023 Private Placement, before deducting 
fees to the placement agent and other offering expenses payable by the Company. 
In addition, the Company agreed to sell and issue in the second closing of the 2023 Private 
Placement (i) 42,500,000 Shares and (ii) Warrants to purchase an aggregate of 46,750,000 Shares, 
at a purchase price of $8.00 per unit, where each unit consists of ten (10) Shares and an 
accompanying Warrant to purchase eleven (11) Shares. The second closing is conditioned upon (x) 
the Company’s announcement of its intention to ﬁle a biologics license application (“BLA”) submission 
following receipt of the minutes from the U.S. Food and Drug Administration (“FDA”) in connection 
with the Company’s pre-BLA (Type B) meeting for OTL-200, provided such minutes do not expressly 
advise the Company not to proceed with a BLA submission, and (y) receipt of Shareholder Approval 
(as deﬁned below) (collectively, the “Second Closing Trigger”). 
In connection with the Private Placement, the Company has agreed to hold a meeting of its 
shareholders no later than 120 days following the initial closing of the Private Placement to seek 
approval to give the Company’s directors authority under s551 of the Companies Act 2006 to issue 
the securities to be issued and sold in the second closing of the Private Placement and the Shares 
issuable upon exercise of the Warrants to be issued and sold in the Private Placement, and to 
disapply pre-emption rights in respect of such authority under s570 of the Companies Act 2006 
(collectively, “Shareholder Approval”). 
The second closing is expected to occur on the ﬁfth trading day after the Company notiﬁes the 
purchasing parties that the Second Closing Trigger has occurred and is subject to additional, 
customary closing conditions. If the Second Closing Trigger occurs, the Company anticipates 
receiving gross proceeds of approximately $34.0 million from the second closing of the 2023 Private 
Placement, before deducting fees to the placement agent and other offering expenses payable by 
the Company. 
Each Warrant will have an exercise price equal to $1.10 per Share in the event the Vesting Event 
(as deﬁned below) occurs on or prior to 31 December 2024, and $0.95 per Share in the event the 
Vesting Event occurs after 31 December 2024. The Warrants will be exercisable during the 30 days 
following the Company’s announcement of receipt of marketing approval of its BLA with respect to 
OTL-200 (the “Vesting Event”); provided that exercise of any Warrant is conditioned upon the receipt 
of Shareholder Approval. Commencement of the 30-day exercise period may be delayed as set forth 
in the Warrants in the event the Vesting Event occurs prior to Shareholder Approval. The Warrants 
will expire at the conclusion of the 30- day exercise period or, if the Vesting Event does not occur, 
10 March 2026. 
UK STATUTORY DIRECTORS’ REPORT 
continued 
 
Orchard Therapeutics plc 67

Going Concern 
The Group expects that its cash, cash equivalents, and short-term investments as of 31 December 2022, 
of $143.8 million, together with expected proceeds from sales of Libmeldy and the $34 million received 
in March 2023 from the 2023 Private Placement, will be sufﬁcient to fund its operations and capital 
expenditure requirements for at least twelve months from the date of signing of this Annual Report and 
Financial Statements. Management have prepared a budget to support the going concern assumption 
of the Group which shows the Group has sufﬁcient resources to continue as a going concern into 2025. 
Therefore, the Directors have at the time of approving the ﬁnancial statements, a reasonable expectation 
that the Group and Company have adequate resources to continue in operational existence for the 
foreseeable future and for a period of at least 12 months from the date of signing these ﬁnancial 
statements. Accordingly, the Group and Company continues to adopt the going concern basis of 
accounting in preparing these ﬁnancial statements. 
Employee Involvement 
The Company has outlined key human capital disclosures in our Strategic Report on page 62 of this 
Annual Report. 
Greenhouse gas emissions 
The Company has outlined its greenhouse gas emissions estimate in the “Environmental Matters” 
section of the Strategic Report beginning on page 63 of this Annual Report. 
Financial Risk Management 
Credit and Interest Rate Risk 
As of 31 December 2022, we had cash, cash equivalents, short-term investments, and restricted 
cash of $148.0 million. Our exposure to interest rate sensitivity is impacted by changes in the 
underlying UK and U.S. bank interest rates. Our surplus cash has been invested in corporate bonds, 
commercial paper, U.S. treasuries, and money market accounts. We have not entered into investments 
for trading or speculative purposes. Due to the conservative nature of our investment portfolio, which 
is predicated on capital preservation of investments with short-term maturities, we do not believe an 
immediate one percentage point change in interest rates would have a material effect on the fair 
market value of our portfolio, and therefore we do not expect our operating results or cash ﬂows to 
be signiﬁcantly affected by changes in market interest rates. 
We have borrowed $33.0 million under our credit facility. Amounts outstanding under the credit facility 
bear interest at a variable interest rate of 5.95% plus LIBOR. As of 31 December 2022, the carrying 
value of the term loans under the credit facility was $32.4 million. 
In 2017, the United Kingdom’s Financial Conduct Authority announced that after 2021 it would no 
longer compel banks to submit the rates required to calculate the London Interbank Offered Rate 
(LIBOR) and other interbank offered rates, which have been widely used as reference rates for various 
securities and ﬁnancial contracts, including loans, debt and derivatives. Regulators in the U.S. and 
other jurisdictions have been working to replace these rates with alternative reference interest rates 
that are supported by transactions in liquid and observable markets, such as the Secured Overnight 
Financing Rate (SOFR). As at 31 December 2022, our credit facilities reference LIBOR-based rates. 
In January 2023, we amended and restated our credit facility to change from LIBOR to SOFR. The 
newly amended facility bears a variable interest rate of 5.95% above SOFR plus 0.10% per annum, 
plus a ﬁnal payment equal to 3.5% of the principal borrowed under the Amended Credit Facility. 
Liquidity Risk 
From our inception through 31 December 2022, we have not generated signiﬁcant revenue from 
product sales and incurred signiﬁcant operating losses and negative cash ﬂows from our operations. 
UK STATUTORY DIRECTORS’ REPORT 
continued 
 
68 Orchard Therapeutics plc 

We acquired our commercial product Strimvelis and the program that is now Libmeldy from GSK in 
April 2018, and our product candidates are in various phases of preclinical and clinical development. 
In December 2020, the European Commission granted standard marketing authorization for Libmeldy. 
We launched Libmeldy in Europe and generated product revenue during the year ended 
31 December 2022. To date, we have ﬁnanced our operations primarily with proceeds from the sale 
of ADSs in our IPO and follow-on offering, proceeds from the sale of ordinary shares in our private 
placement, proceeds from the sale of convertible preferred shares, reimbursements associated with 
two UK research and development tax relief programs, the Small and Medium-sized Enterprises 
research and development tax credit (“SME”) program and the Research and Development 
Expenditure (“RDEC”) program, reimbursements from our research agreement with UCLA and, 
following transfer of the ADA-SCID research program sponsorship from UCLA to us in July 2018, 
a grant from the California Institute of Regenerative Medicine (“CIRM”), upfront payments from our 
collaboration agreement with Pharming Group N.V., our Original Credit Facility and our Amended 
Credit Facility with MidCap, and through proceeds from sales of Libmeldy in Europe beginning 
in 2022.  
On 27 February 2020, we entered into a Sales Agreement with Cowen and Company, LLC (“Cowen”), 
as agent, relating to an “at the market offering,” pursuant to which we may issue and sell ADSs 
representing our ordinary shares, having an aggregate offering price of up to $100.0 million. 
On 24 March 2022, we delivered written notice to Cowen to terminate the Sales Agreement, effective 
as of 30 March 2022, pursuant to Section 11(b) thereof. Prior to termination, we had not sold any 
ADSs pursuant to the Sales Agreement. As a result of the termination of the Sales Agreement, we will 
not offer or sell any ADSs under the Sales Agreement. On 6 October 2022 we entered into a Sales 
Agreement with Guggenheim Securities, LLC, as agent, relating to an “at the market offering,” 
pursuant to which we may issue and sell ADSs representing our ordinary shares, having an aggregate 
offering price of up to $30.0 million. As of 31 December 2022, we have not sold any shares under 
the Guggenheim Sales Agreement. 
We currently have no ongoing material ﬁnancing commitments, such as lines of credit or guarantees, 
that are expected to affect our liquidity over the next ﬁve years, other than our manufacturing, lease, 
and debt obligations described in the Notes to the Consolidated ﬁnancial statements.  
Foreign exchange risk 
The Company is exposed to foreign currency exchange risk because it currently operates in the 
United Kingdom and the United States. The reporting currency of the Company is the U.S. dollar. 
The Company has determined the functional currency of the ultimate parent company, Orchard 
Therapeutics plc, is U.S. dollars because it predominantly raises ﬁnance and expends cash in 
U.S. dollars, and expects to continue to do so in the future. We recorded realized and unrealized 
foreign currency losses of $24.3million in the year to 31 December 2022 (2021: $1.1million loss). 
2022 saw a signiﬁcant change in the U.S. dollar to GB pound exchange rate, with the rate changing 
by 12%. There are signiﬁcant intercompany loans between Group companies that are denominated 
in U.S. dollars where the functional currency of the counterparty company is in GB pounds. The 
change in exchange rate resulted in large foreign currency losses on these balances. These foreign 
currency transaction gains and losses are included in the Consolidated statement of proﬁt and loss. 
UK STATUTORY DIRECTORS’ REPORT 
continued 
 
Orchard Therapeutics plc 69

We do not currently engage in currency hedging activities in order to reduce our currency exposure, 
but we may begin to do so in the future. Instruments that may be used to hedge future risks include 
foreign currency forward and swap contracts. These instruments may be used to selectively manage 
risks, but there can be no assurance that we will be fully protected against material foreign currency 
ﬂuctuations. 
Branches outside of the UK 
The following table outlines all subsidiaries of the Parent Company: 
Name of Subsidiary                                                                          Jurisdiction of Incorporation or Organization 
Orchard Therapeutics (Europe) Limited                             England and Wales 
Orchard Therapeutics North America                                California (United States) 
Orchard Therapeutics (Netherlands) B.V.                           Netherlands 
Orchard Therapeutics (France) SAS                                  France 
Orchard Therapeutics (Italy) S.r.l                                        Italy 
Orchard Therapeutics (Germany) GmbH                           Germany 
Orchard Therapeutics (Switzerland) GmbH                       Switzerland 
Orchard Therapeutics (Sweden) AB                                  Sweden 
Qualifying third party indemnity provisions 
The Company has granted a qualifying third-party indemnity to each of its Directors against liability 
in respect of proceedings brought by third parties, which was in force throughout the ﬁnancial year, 
and remains in force as at the date of approving the UK Statutory Directors’ Report. 
Independent Auditors 
PricewaterhouseCoopers LLP have expressed their willingness to continue in ofﬁce as auditors for 
another year. In accordance with Section 418 of the UK Companies Act 2006, a resolution proposing 
that PricewaterhouseCoopers LLP be re-appointed as auditors of the Group and Company will be 
proposed at the Annual General Meeting.  
On behalf of the Board of Directors: 
 
Hubert Gaspar  
Director 
27 April 2023  
 
 
70 Orchard Therapeutics plc 
UK STATUTORY DIRECTORS’ REPORT 
continued 

 
Orchard Therapeutics plc 71
Annual Statement from the Chair of the Compensation Committee  
Dear Shareholder,  
As the Chair of the Compensation Committee (the “Committee”), I am pleased to present, on behalf 
of the Board of Directors (the “Board”) of Orchard Therapeutics plc (the “Company” or “Orchard”), 
the Directors’ Remuneration Report for the year ended 31 December 2022 (the “Remuneration 
Report”). 
The Company’s Remuneration Report will be subject to an advisory vote at the forthcoming Annual   
General Meeting on 14 June 2023 (the “AGM”). 
Introduction  
Our executive compensation program seeks to incentivize and reward strong corporate performance. 
All compensation decisions at Orchard remain aligned to our key principle of paying for performance. 
Further, as a global biopharmaceutical company with major operations in the United States and 
Europe we operate within a global marketplace for talent. Given that the market for experienced 
directors and biopharmaceutical executive talent is very competitive, particularly in the United States, 
the Committee references the U.S. market as the leading indicator for remuneration levels and 
practices. This helps attract and retain directors and motivate the superior executive talent needed 
to successfully manage the Company’s complex global operations. Being consistent in this market 
view of the United States as the primary benchmark for remuneration practices for our Executive and 
Non-Executive Directors is key for the Company as it builds its global operations in a manner 
designed to deliver sustainable, long-term growth and shareholder value. 
As a Committee, we are also mindful of general UK compensation frameworks and investor guidance 
in that regard when making decisions on Orchard’s executive compensation. 
With these various factors in mind, we were pleased to receive shareholder support adopting our 
2022 Remuneration Policy at the 2022 AGM. Gratefully supported by our shareholders, myself and 
the Compensation Committee believe that the overall structure of our Directors’ Remuneration Policy 
remains appropriate to attract, retain and motivate directors to execute the Company’s strategy. 
Key remuneration decisions for 2022 
The Committee and I were mindful of the prevailing economic environment, ﬁscal position and 
available cash resources of the Company at year-end 2022 and the Company’s share price 
performance during the year. We acknowledge and celebrate the many achievements made by all 
our colleagues at Orchard while ensuring the broader context of the Company and the 
macro-economic environment are considered when making remuneration decisions. 
In the ﬁrst quarter of 2022, all employees’ salaries at Orchard were increased by 5%. This decision 
was made in response to the competitive landscape of the biotechnology sector and a fast-paced 
compensation market for talent and skills we require as well as the inﬂationary environment in which 
we are operating. The CEO’s salary was treated in the same manner as all other employees. 
Two key decisions during 2022 related to equity-based compensation. Firstly, to reinforce the 
performance focus of our executive compensation program, the CEO’s annual equity award, half of 
the award was granted as performance-based share options with an exercise price set at a 
25% premium above the share price on the date of grant.  
DIRECTORS’ REMUNERATION REPORT 

 
72 Orchard Therapeutics plc 
Secondly, in October 2022 and under the terms of the Company’s Share Option Incentive Plan 2018, 
the Board of Directors approved a repricing of previously awarded share options which were 
signiﬁcantly ‘underwater’. In the situation where substantial portions of employees’ equity holding 
had little or no value, the Board took the decision to reprice these awards. This was done in order to 
reengage staff with the future success of Orchard and provide additional retentive value to the 
investment previously made in our equity program. The Company has, and continues to grant, 
equity-based compensation to all employees – aligning the entire workforce with the future value of 
the Company. The CEO’s equity was treated in the same manner as all other employees, with details 
shown in the Annual Report on Remuneration. In making this decision, the Board of Directors 
considered several factors in determining which grants would be eligible for repricing and which 
grants would remain on the original terms, including (i) none of the non-executive director grants 
were repriced; (ii) only grants with an original exercise price above $1.251 were repriced, representing 
a 150% premium to the share price on the date of repricing; (iii) none of the grants from 2022 were 
repriced; and (iv) the exercise price of the repriced options was set at a 16% premium to the closing 
market price on the date of repricing. 
2022 Annual Bonus 
Orchard’s annual bonus is based on stated corporate objectives set by the Board and the 
Compensation Committee at the beginning of the year. For 2022 this was made up of a combination 
of objectives contributing to the foundation of a sustainable commercial business, advancing our 
portfolio towards key clinical and regulatory milestones, and maintaining a performance-driven culture 
both internally and with our partners. 
For the CEO and consistent for all employees, the Committee determined a corporate score of 85% 
of target. This is reﬂective of the Company as a whole making considerable strides towards all of 
our stated objectives while also acknowledging that some key objectives were not achieved during 
the year due to either internal or external factors. The Committee does however recognize that the 
progress and achievements during 2022 puts the Company in a favorable position with considerable 
momentum going into 2023 and beyond. 
The Committee’s decision is taken in the context of the broader ﬁnancial position of the Company, 
the share price performance during the year, and the competition for talent in the global 
biotechnology sector. 
Remuneration for 2023 
There are no substantial changes to our approach to executive compensation for 2023. At his own 
request and recommendation, the CEO will not receive a salary increase for 2023. The Committee 
commends Dr. Gaspar for this proposal.  
Consistent with our pay for performance philosophy, we continue to make an annual award of share 
options to Dr. Gaspar for 2023. Consistent with 2022, we have granted half of the 2023 award in 
performance-based, premium-priced options – options with an exercise price above the stock price 
on the date of grant. This instills a further hurdle before a portion of Dr. Gaspar’s long-term incentive 
has any intrinsic value and further aligns our compensation approach with the shareholder 
experience. Similarly, a portion of the 2023 options granted to the entire executive team were also 
issued with an exercise price at a premium above the stock price on the date of grant. 
DIRECTORS’ REMUNERATION REPORT  
continued 
1
Share price before 1:10 American Deposit Share (ADS) ratio change effective on 10 March 2023.

 
Orchard Therapeutics plc 73
As part of an on-going review of the Board’s remuneration, an adjustment to the fees paid to 
Non-Executive Directors will be implemented for 2023. The principal adjustment is the reduction by 
$5,000 in the base cash compensation provided for Board membership – this removes a supplement 
previously provided for time and commitment to international travel with a corresponding rebalancing 
in equity compensation. Additionally, from 2023 a shareholding guideline of three-times this base fee 
is introduced for Non-Executive Directors with a ﬁve year period allowed for each Board member to 
gain compliance. We believe this is an important step in reinforcing the connection between the 
Board and the long-term value of the Company. 
Conclusion 
The Committee believes that the Directors’ Remuneration Policy has been implemented fairly and 
consistently, as described in this report. We are conﬁdent that remuneration arrangements will 
continue to properly motivate our Directors and executive team to deliver sustainable growth and 
shareholder value over the long term and to do so in a responsible and cost-efﬁcient manner. 
I hope that you ﬁnd the information in this report helpful, and I look forward to your support at the 
Company’s AGM. 
Yours sincerely, 
 
Charles Rowland, Jr.  
Chair of  the Compensation Committee 
27 April 2023
DIRECTORS’ REMUNERATION REPORT  
continued 

 
74 Orchard Therapeutics plc 
Remuneration Policy  
The following section sets out our Directors’ Remuneration Policy (the “Policy”) as approved by 
binding shareholder vote at the annual general meeting on 7 June 2022. The document, as approved, 
can be found in the Company’s 2021 Annual Report. 
The policy received strong shareholder support, as has the implementation of the policy in the 
annual voting.  
Key considerations when determining the Remuneration Policy 
The Policy is designed by the Committee with a number of speciﬁc principles in mind: 
•
attract, retain and motivate high calibre senior management and focus them on the delivery of 
the Company’s strategic and business objectives; 
•
encourage a corporate culture that promotes the highest level of integrity, teamwork and ethical 
standards; 
•
be competitive against appropriate market benchmarks (being predominantly the US biotech 
sector) and have a strong link to performance, providing the ability to earn above-market rewards 
for strong performance; 
•
be simple and understandable, both internally and externally; 
•
encourage increased equity ownership to motivate executives in the overall interests of 
shareholders, the Company, employees and customers; and 
•
take due account of good governance and promote the long-term success of the Company. 
In seeking to achieve the above objectives, the Committee is mindful of the views of a broad range 
of stakeholders in the business and accordingly takes account of a number of factors when setting 
remuneration including: market conditions; pay and beneﬁts in relevant comparator organisations; 
terms and conditions of employment across the Company; the Company’s risk appetite; the 
expectations of institutional shareholders; and any speciﬁc feedback received from shareholders 
and other stakeholders. 
Key changes to the Remuneration Policy 
The Committee maintains that the overall structure of remuneration is appropriate and no fundamental 
structural changes are proposed. The Committee does acknowledge that there are developments in 
market and best practices which include: 
•
Introduction of share ownership requirements for Executive Directors – intends to ensure 
long- term alignment between our Executive Directors and shareholders. 
•
Introduction of recovery provisions (malus and clawback) – provides mitigation against payment 
for failure and ensures that all future incentive-based compensation in subject to recovery. 
•
The retainer arrangements for Non-Executive Directors will include the ﬂexibility for Directors to 
elect a portion, or all, of their fees as either cash or in equity equivalents. This is common practice 
in the US and is included to ensure our Director compensation arrangements are competitive 
within our sector landscape.
DIRECTORS’ REMUNERATION REPORT  
continued 

 
Orchard Therapeutics plc 75
Remuneration Policy table  
The table in the following pages sets out, for each element of pay, a summary of how remuneration 
is structured and how it supports the Company’s strategy. 
Executive Directors 
Purpose and link to  
strategy
Operation                                Maximum opportunity            Performance metrics 
 
Base salary 
To 
recruit 
and 
retain 
Executive Directors of the 
highest calibre who are 
capable 
of 
delivering 
the  Company’s strategic 
objectives, reﬂecting the 
individual’s experience and 
role within the Company. 
Base salary is designed to 
provide an appropriate level 
of ﬁxed income to avoid any 
over-reliance on variable pay 
elements 
that 
could 
encourage excessive risk 
taking. 
 
Salaries 
are 
normally 
reviewed annually. 
The annual salary review for 
Executive Directors takes a 
number of factors into 
consideration, including: 
•
business performance; 
•
salary 
increases 
awarded to the overall 
employee population; 
•
skills and experience 
of the individual over 
time; 
•
scope of the individual’s 
responsibilities; 
•
changes in the size 
and complexity of the 
Company; 
•
market competitiveness 
assessed by periodic 
benchmarking; and 
•
the underlying rate of 
inﬂation. 
 
Whilst there is no prescribed 
formulaic maximum, any 
increases will take into 
account prevailing market 
and economic conditions 
and 
the 
approach 
to 
employee pay throughout 
the organisation. 
Base salary increases are 
awarded at the discretion of 
the Committee; however, 
salary 
increases 
will 
normally be no greater than 
the 
general 
increase 
awarded 
to 
the 
wider 
workforce, in percentage of 
salary 
terms. 
However, 
a  higher increase may be 
made where an individual 
had been appointed to a 
new role at below- market 
salary 
while 
gaining 
experience. 
Subsequent 
demonstration of strong 
performance may result in a 
salary increase that is higher 
than that awarded to the 
wider workforce.
 
 
Executive 
Directors’ 
performance is a factor 
considered 
when 
determining 
any 
salary 
increases. 
DIRECTORS’ REMUNERATION REPORT  
continued 

Executive Directors 
Purpose and link to  
strategy
Operation                                Maximum opportunity            Performance metrics 
 
 
Benefits 
Reasonable beneﬁts-in- kind 
are provided to support 
Executive 
Directors 
in 
carrying out their duties and 
assist with retention and 
recruitment. 
 
The Company aims to offer 
beneﬁts that are in line with 
market practice. 
The main beneﬁts currently 
provided include private 
health insurance, long-term 
disability, critical illness and 
death in service. 
Under 
certain 
circumstances the Company 
may 
offer 
relocation 
allowances or assistance. 
Expatriate beneﬁts may be 
offered where required. 
Travel and any reasonable 
business- related expenses 
(including tax thereon) may 
be reimbursed. 
Executive 
Directors 
may 
become eligible for other 
beneﬁts in future where the 
Committee 
deems 
it 
appropriate. Where additional 
beneﬁts 
are 
introduced 
for  the wider workforce, 
Executive 
Directors 
may 
participate on broadly similar 
terms. 
Beneﬁts may also include 
payment by the Company of 
any stamp duty arising in 
respect of the settlement of 
equity incentives.
 
The value of each beneﬁt is 
not predetermined and is 
typically based upon the 
cost to the Company of 
providing said beneﬁt. 
Not performance related. 
Retirement benefits 
The 
Company 
aims 
to 
provide 
a 
contribution 
towards life in retirement. 
 
Executive 
Directors 
are 
eligible to receive employer 
contributions 
to 
the 
Company’s Group Personal 
Pension Scheme or to a 
401k plan or a salary 
supplement 
in 
lieu 
of 
pension 
beneﬁts, 
or 
a 
mixture of both. 
 
Up to 6% of salary per 
annum 
for 
Executive 
Directors. 
6% is the contribution rate 
provided 
to 
all 
UK 
employees.
 
Not performance related. 
 
76 Orchard Therapeutics plc 
DIRECTORS’ REMUNERATION REPORT  
continued 

Executive Directors 
Purpose and link to  
strategy
Operation                                Maximum opportunity            Performance metrics 
 
Annual bonus 
The annual bonus scheme 
rewards the achievement of 
stretching objectives that 
support 
the 
Company’s 
corporate goals and delivery 
of the business strategy. 
 
Bonuses are determined 
based on measures and 
targets that are agreed by 
the Committee at the start of 
each ﬁnancial year. 
In exceptional circumstances, 
the 
Committee 
may 
add  further performance 
measures and milestones 
during the year. 
 
The 
target 
bonus 
opportunity for Executive 
Directors is up to 80% of 
salary, with a maximum 
bonus opportunity of up to 
two 
times 
the 
target 
opportunity. 
For threshold performance, 
no more than 50% of target 
bonus may be payable. 
For 2023, the target bonus 
opportunity for Executive 
Directors will be no more 
than 60% of salary, with a 
maximum bonus opportunity 
of up to 150% of the target 
opportunity. 
Any exceptional bonuses 
would operate within the 
overall annual maximum 
opportunity.
 
Performance measures are 
determined 
by 
the 
Committee each year and 
may vary to ensure that they 
promote the Company’s 
business 
strategy 
and 
shareholder value. 
The annual bonus will be 
based on strategic goals, 
which may include ﬁnancial, 
strategic 
and 
personal 
objectives. 
The Committee may alter the 
bonus 
outcome 
if 
it 
considers that the pay-out is 
inconsistent 
with 
the 
Company’s 
overall 
performance, 
taking 
account of any factors it 
considers relevant. This will 
help ensure that pay-outs 
reﬂect 
overall 
Company 
performance during the year. 
 
Orchard Therapeutics plc 77
DIRECTORS’ REMUNERATION REPORT  
continued 

Executive Directors 
Purpose and link to  
strategy
Operation                                Maximum opportunity            Performance metrics 
 
Long-term incentives 
At the date of this Policy, 
long-term incentives are 
normally granted under the 
2018 Share Option and 
Incentive Plan ( “SOIP”). The 
SOIP 
is 
designed 
to 
incentivise the successful 
execution 
of 
business 
strategy over the longer term 
and 
provide 
long-term 
retention. 
Facilitates share ownership 
to provide further alignment 
with shareholders. 
 
The Committee will select 
the most appropriate form of 
SOIP award(s) each year. 
Awards will typically be 
granted annually, in the form 
of options and restricted 
share 
units 
(“RSUs”) 
although 
may 
also 
be 
granted in the form of share 
appreciation 
rights, 
restricted 
shares, 
unrestricted 
shares, 
performance share units, 
cash or dividend equivalent 
rights. 
Currently, options normally 
vest over a period of four 
years on a monthly basis. 
Initial grants made in relation 
to appointment generally 
vest 25% after one year, and 
monthly 
thereafter 
for 
36 
months. 
Currently, 
time-based RSUs normally 
vest in equal installments 
annually over a total period 
of no less than three years. 
Performance Share Units 
(“PSUs”) normally vest in 
three equal tranches on the 
meeting of agreed milestone 
events within a period of 
three years. The Committee 
may 
vary 
the 
vesting 
schedule of future grants of 
options and PSUs as it 
considers appropriate. 
At the discretion of the 
Committee, participants may 
also be entitled to receive 
the value of dividends paid 
between grant and vesting 
on 
vested 
shares. 
The 
payment may be in cash or 
shares and may assume 
dividend reinvestment. 
 
There 
is 
no 
deﬁned 
maximum opportunity under 
the 
SOIP. 
However, 
the 
Committee 
will 
generally 
work within the guidelines 
provided 
by 
our 
compensation consultants. 
We 
seek 
to 
establish 
equity-based remuneration 
competitive to that offered by 
a 
set 
of 
comparable 
companies with whom we 
may compete for talent.
 
Performance conditions may 
apply to awards. Such 
conditions may be strategic 
objectives 
which 
may 
include milestone events, 
ﬁnancial, strategic and/or 
personal objectives. 
Share options are granted 
with an exercise price no 
less than the fair market 
value of the shares on the 
date of grant. 
Accordingly, share options 
will only have value to the 
extent the Company’s share 
price appreciates following 
the date of grant. 
Any performance conditions 
set will be designed to 
incentivise performance in 
support of the Company’s 
strategy 
and 
business 
objectives. 
The Committee has ﬂexibility 
to vary the mix of measures 
or introduce new measures 
for each subsequent award 
taking into account business 
priorities at the time of grant. 
The Committee may alter the 
vesting 
outcome 
if 
it 
considers that the level of 
vesting is inconsistent with 
the underlying performance 
of the business, taking 
account of any factors it 
considers relevant. This will 
help ensure that vesting 
reﬂects overall Company 
performance during the year. 
 
 
78 Orchard Therapeutics plc 
DIRECTORS’ REMUNERATION REPORT  
continued 

Executive Directors 
Purpose and link to  
strategy
Operation                                Maximum opportunity            Performance metrics 
All employee share schemes 
 
Encourages employee share 
ownership and therefore 
increases alignment with 
shareholders. 
Executive 
Directors will be eligible to 
participate 
in 
any 
all-employee share scheme. 
The 
Company 
currently 
operates 
an 
Employee 
Share 
Purchase 
Plan 
(“ESPP”) 
that 
offers 
employees the opportunity 
to purchase shares in the 
Company through payroll 
deductions at a price equal 
to 85% of the lower of fair 
market value of the shares 
on the ﬁrst business day or 
the last business day of the 
offering period. The ESPP is 
available to all employees 
whose 
customary 
employment is for more than 
20 hours per week and have 
completed at least 30 days 
of employment. 
The Company may adopt 
equivalent arrangements in 
any jurisdiction in order to 
comply 
with 
local 
requirements. 
Employees may contribute 
up to 15% of their base 
compensation to purchase 
shares under the ESPP. 
However, 
the 
right 
to 
purchase shares under the 
ESPP may not accrue at a 
rate that exceeds $25,000 
worth of ordinary shares, 
valued at the start of the 
purchase period, under the 
ESPP, for each calendar year 
in the purchase period.
Not performance related.
 
Orchard Therapeutics plc 79
DIRECTORS’ REMUNERATION REPORT  
continued 

Non-Executive Directors 
Purpose and link to  
strategy
Operation                                Maximum opportunity            Performance metrics 
 
Fees 
To attract Non-Executive 
Directors who have a broad 
range of experience and 
skills to provide independent 
judgement on issues of 
strategy, 
performance, 
resources and standards of 
conduct. 
 
Non-Executive 
Directors 
receive an annual retainer 
paid in cash, comprising a 
base fee plus additional fees 
for additional responsibilities, 
such 
as 
a 
Committee 
Chairpersonship 
or 
membership and the role of 
Chairperson. 
At a Directors’ election, cash 
retainers may be delivered 
as an equivalent number of 
share options – calculated at 
fair value on the date of 
grant - vesting quarterly over 
a one-year period. 
The Chair’s fee is reviewed 
annually by the Committee 
(without the Chair present). 
Fee 
levels 
for 
the 
Non-Executive Directors are 
determined by the Company 
Chair 
and 
Executive 
Directors. 
When reviewing fee levels, 
account is taken of market 
movements in fee levels, 
Board 
committee 
responsibilities, 
ongoing 
time commitments and the 
general 
economic 
environment. 
In exceptional circumstances, 
if there is a temporary yet 
material increase in the time 
commitments 
for 
Non-Executive Directors, the 
Board may pay additional 
fees 
to 
recognise 
that 
additional workload. 
Non-Executive 
Directors 
ordinarily do not participate 
in any pension, bonus or 
performance-based share 
incentive 
plans. 
Travel, 
accommodation and other 
business- related expenses 
incurred in carrying out the 
role will be paid by the 
Company 
including, 
if relevant, any gross-up for 
tax.
 
When reviewing fee levels, 
account is taken of market 
movements in the fees of 
Non-Executive 
Directors, 
Board 
Committee 
responsibilities and ongoing 
time commitments, as well as 
the 
underlying 
rate 
of 
inﬂation. 
Actual 
fee 
levels 
are 
disclosed in the annual 
Directors’ 
Remuneration 
Report 
for 
the 
relevant 
ﬁnancial year. 
 
 
Not performance related.
 
80 Orchard Therapeutics plc 
DIRECTORS’ REMUNERATION REPORT  
continued 

Non-Executive Directors 
Purpose and link to  
strategy
Operation                                Maximum opportunity            Performance metrics 
 
An illustration of the application of the Remuneration Policy can be found in the Company’s 2021 
Annual Report. 
Notes to the policy table  
Legacy arrangements  
For the duration of this Policy, the Company will honour any commitments made in respect of current 
or former Directors before the date on which either: (i) the Policy becomes effective; or (ii) an 
individual becomes a Director, even where not consistent with the Policy set out in this report or 
prevailing at the time such commitment is fulﬁlled. For the avoidance of doubt, all outstanding historic 
awards that were granted in connection with, or prior to, listing remain eligible to vest based on their 
original or modiﬁed terms. 
Performance conditions  
The choice of annual bonus performance metrics reﬂects the Committee’s belief that any incentive 
remuneration should be appropriately challenging and tied to the delivery of key strategic objectives 
intended to ensure that Executive Directors are incentivised to deliver across a range of objectives 
for which they are accountable. The Committee has retained ﬂexibility on the speciﬁc measures which 
will be used to ensure that any measures are fully aligned with the strategic imperatives prevailing at 
the time they are set. 
Equity Awards 
To facilitate share ownership 
and provide alignment with 
shareholders. 
 
Non-Executive 
Directors 
may receive an equity award 
in the form of options, share 
appreciation 
rights, 
restricted shares, restricted 
share units or such other 
form permitted under the 
SOIP. 
New 
Non-Executive 
Directors receive an initial 
equity 
award 
upon 
appointment or election. In 
addition, 
Non-Executive 
Directors receive annual 
equity awards at the time of 
the annual meeting. 
Currently any initial equity 
awards normally vest in 
equal monthly installments 
for 36 months, and any 
annual awards normally are 
awarded at the AGM and 
vest at the earlier of the next 
AGM or one year after the 
grant date. 
 
There is no maximum award 
level for equity awards to 
Non- Executive Directors. 
The size of the equity awards 
is determined by the full 
Board of Directors, upon 
recommendation 
of 
the 
Compensation Committee. 
When reviewing award levels, 
account is taken of market 
movements in equity awards, 
Board 
committee 
responsibilities, ongoing time 
commitments 
and 
the 
general 
economic 
conditions. 
 
 
Not performance related.
 
Orchard Therapeutics plc 81
DIRECTORS’ REMUNERATION REPORT  
continued 

The targets for the bonus scheme for the forthcoming year will be set out in general terms, subject to 
limitations with regards to commercial sensitivity. The full details of the targets will be disclosed when 
they are in the public domain and are no longer considered commercially sensitive. 
Where used, performance conditions applicable to SOIP awards will be aligned with the Company’s 
objective of delivering superior levels of long-term value to shareholders. The full details of 
performance conditions will be disclosed when they are in the public domain and are no longer 
commercially sensitive. Prior to each award, the Committee has ﬂexibility to select measures that are 
fully aligned with the strategy prevailing at the time awards are granted. 
The Committee will review the calibration of targets applicable to the annual bonus, and the SOIP in 
years where performance measures apply, annually to ensure they remain appropriate and sufﬁciently 
challenging, taking into account the Company’s strategic objectives and the interests of shareholders. 
Shareholding guidelines 
Executive Directors are expected to build up and maintain, a shareholding equivalent to a multiple 
of their respective base salary. For the Chief Executive Ofﬁcer, this multiple is equal to two-times their 
base salary and for any other Executive Director, one-times base salary. Executive Directors will have 
ﬁve years from either the adoption of the policy or their appointment to the Board, whichever is later, 
to achieve the target level of share ownership. 
Differences in remuneration policy between Executive Directors and other 
employees 
The overall approach to reward for employees across the workforce is a key reference point when 
setting the remuneration of the Executive Directors. When reviewing the salaries of the Executive 
Directors, the Committee pays close attention to pay and employment conditions across the wider 
workforce and in normal circumstances the increase for Executive Directors will be no higher than 
the average increase for the general workforce. 
The key difference between the remuneration of Executive Directors and that of our other employees 
is that, overall, at senior levels, remuneration is increasingly long-term, and ‘at risk’ with an emphasis 
on performance-related pay linked to business performance and share-based remuneration. This 
ensures that remuneration at senior levels will increase or decrease in line with business performance 
and provides alignment between the interests of Executive Directors and shareholders. 
Committee discretion in operation of variable pay schemes 
The Committee operates under the powers it has been delegated by the Board. In addition, 
it complies with rules that are either subject to shareholder approval or by approval from the Board. 
These rules provide the Committee with certain discretions which serve to ensure that the 
implementation of the remuneration policy is fair, both to the individual Director and to the 
shareholders. The Committee also has discretions to set components of remuneration within a range, 
from time to time. The extent of such discretions is set out in the relevant rules, the maximum 
opportunity or the performance metrics section of the policy table above. To ensure the efﬁcient 
administration of the variable incentive plans outlined above, the Committee will apply certain 
operational discretions. 
 
82 Orchard Therapeutics plc 
DIRECTORS’ REMUNERATION REPORT  
continued 

These include the following:  
•
selecting the participants in the plans on an annual basis; 
•
determining the timing of grants of awards and/or payments; 
•
determining the quantum of awards and/or payments (within the limits set out in the policy table 
above); 
•
determining the choice (and adjustment) of performance measures and targets for each incentive 
plan in accordance with the policy set out above and the rules of each plan; 
•
determining the extent of vesting based on the assessment of performance and discretion 
relating to measurement of performance in certain events such as a change of control or 
reconstruction; 
•
making the appropriate adjustments required in certain circumstances, for instance for changes 
in capital structure; 
•
determining “good leaver” status, if applicable, for incentive plan purposes and applying the 
appropriate treatment; and 
•
undertaking the annual review of weighting of performance measures and setting targets for the 
annual bonus plan and other incentive schemes, where applicable, from year to year. 
If an event occurs which results in the annual bonus plan or SOIP performance conditions and/or targets 
being deemed no longer appropriate (e.g. material acquisition or divestment), the Committee will have 
the ability to make appropriate adjustments to the measures and/or targets and alter weightings, 
provided that the revised conditions are not materially less challenging than the original conditions. Any 
use of the above discretion would, where relevant, be explained in the Annual Report on Remuneration 
and may, as appropriate, be the subject of consultation with the Company’s major shareholders. 
Recovery Provisions (malus and clawback) 
Prior to vesting, the Compensation Committee may reduce or cancel any awards granted under the 
Company’s 2018 SOIP, or impose additional conditions on awards in circumstances the Compensation 
Committees deems appropriate (‘malus’). Such circumstances may include: a serious misstatement 
of the Group’s audited ﬁnancial results; a serious miscalculation of any relevant performance measure; 
a serious failure of risk management or regulatory compliance by a relevant entity; serious reputational 
damage to the Group; the participant’s material misconduct, or a material corporate failure. 
In addition, for cash bonus and SOIP awards the Compensation Committee may also apply malus 
and/or clawback in certain extreme circumstances (including those listed above) for up to two years 
following the determination of the relevant performance outcome of vesting of the award. 
Prior to applying malus or clawback, the Compensation Committee will take into account all relevant 
factors (including, where a serious failure of risk management or regulatory compliance or serious 
reputational damage has occurred, the degree of involvement of the employee in that failure or 
damage in question and the employee’s level of responsibility) in deciding whether, and to what extent, 
it is reasonable to operate malus and/or clawback. The Compensation Committee is satisﬁed that the 
above provisions provide robust safeguards against inappropriate payment of incentive awards. 
 
Orchard Therapeutics plc 83
DIRECTORS’ REMUNERATION REPORT  
continued 

 
84 Orchard Therapeutics plc 
Shareholder views  
The Board is committed to dialogue with shareholders and intends to engage directly with them and 
their representative bodies when considering any signiﬁcant changes to our remuneration 
arrangements. The Compensation Committee will consider shareholder feedback received following 
the AGM, as well as any additional feedback and guidance received from time to time. This feedback 
will be considered by the Committee as it develops the Company’s remuneration framework and 
practices going forward. Assisted by its independent adviser, the Compensation Committee also 
actively monitors developments in the expectations of institutional investors and their representative 
bodies. 
Employment conditions  
The Committee is regularly updated throughout the year on pay and conditions applying to Company 
employees and has formal responsibility for human capital measures across the Company with a 
particular focus on diversity and inclusion activities. Where signiﬁcant changes are proposed to 
employment conditions elsewhere in the Company these are highlighted for the attention of the 
Committee at an early stage. 
Other remuneration policies  
Remuneration for new appointments  
Where it is necessary to appoint or replace an Executive Director or to promote an existing Executive 
Director, the Committee’s approach when considering the overall remuneration arrangements in the 
recruitment of a new Executive Director is to take account of the calibre, expertise and responsibilities 
of the individual, his or her remuneration package in their prior role and market rates. Remuneration 
will be in line with our policy and the Committee will not pay more than is necessary to facilitate their 
recruitment. 
The remuneration package for a new Executive Director will be set in accordance with the terms of 
the Company’s approved remuneration policy in force at the time of appointment. Further details are 
provided below: 
Salary
The Committee will set a base salary appropriate to the calibre, experience and 
responsibilities of the new appointee. In arriving at a salary, the Committee may take 
into account, amongst other things, the market rate for the role and internal relativities. 
The Committee has the ﬂexibility to set the salary of a new Executive Director at a 
lower level initially, with a series of planned increases implemented over the following 
few years to bring the salary to the desired positioning, subject to individual 
performance. 
In exceptional circumstances, the Committee has the ability to set the salary of a new 
Executive Director at a rate higher than the market level to reﬂect the criticality of the 
role and the experience and performance of the individual. 
DIRECTORS’ REMUNERATION REPORT  
continued 

Benefits
Beneﬁts will be consistent with the principles of the policy. The Company may award 
certain additional beneﬁts and other allowances including, but not limited to, those to 
assist with relocation support, temporary living and transportation expenses, 
educational costs for children and tax equalisation to allow ﬂexibility in employing an 
overseas national. 
Pension 
A maximum pension contribution of 6% of salary may be payable for external  
Benefits
appointments. For an internal appointment, his or her existing pension arrangements 
may continue to operate. Any new Executive Director based outside the UK will be 
eligible to participate in pension or pension allowance, insurance and other beneﬁt 
programmes in line with local practice. 
Annual bonus The maximum bonus opportunity for new appointments is 150% of their target bonus. 
Other cash or Executive Directors may receive awards under the SOIP on appointment. The  
equity-based Committee will assess and determine the award level, award vehicle, performance 
awards
conditions and vesting schedule for each individual on a case-by-case basis. 
In addition, Executive Directors are eligible to participate in any all employee share 
scheme (for example, ESPP) subject to the conditions set forth therein.  
In addition, the Committee may offer additional cash and/or equity-based elements 
in order to “buy-out” remuneration relinquished on leaving a former employer. Any 
awards made in this regard may have no performance conditions, or different 
performance conditions, or a different vesting schedule compared to the Company’s 
existing plans, as the Committee considers appropriate. Depending on the timing and 
responsibilities of the appointment, it may be necessary to set different annual bonus 
or SOIP performance measures and targets as applicable to other Executive Directors. 
The terms of appointment for a Non-Executive Director would be in accordance with the remuneration 
policy for Non-Executive Directors as set out in the policy table. 
Service contracts and termination policy 
Executive Directors have rolling service agreements which may be terminated in accordance with 
the terms of these agreements. The period of notice for Executive Directors will not normally exceed 
12 months. Executive Directors’ service agreements are available for inspection at the Company’s 
registered ofﬁce during normal business hours. 
Name
Position
Date of service contract
Notice period 
Bobby Gaspar1
Chief Executive Ofﬁcer
2 January 2018
6 months either party 
1
Hubert (Bobby) Gaspar. 
The Company’s policy on remuneration for Executive Directors who leave the Company is set out 
below. The Committee will exercise its discretion when determining amounts that should be paid to 
leavers, taking into account the facts and circumstances of each case. Generally, in the event of 
termination, the Directors’ service contracts may provide for payment of basic salary over the notice 
period. Where applicable, the Company may elect to make a payment in lieu of notice (PILON) 
equivalent in value to basic salary for any unexpired portion of the notice period. PILON payments 
 
Orchard Therapeutics plc 85
DIRECTORS’ REMUNERATION REPORT  
continued 

may be made in monthly instalments or as a lump sum, and the individual is expected to take 
reasonable steps to seek alternative income to mitigate the payments. The Company may also pay 
for outplacement services for Executive Directors on termination or the Company may elect to make 
a payment in lieu of outplacement services. The Company may continue to pay the employer health 
plan premium for the Executive Director on termination for a period of up to 12 months (up to 
18 months in connection with a change in control).  
Any outstanding incentive awards will be treated in accordance with the plan rules, as follows:  
 
Termination without cause 
or for cause by participant 
Termination without cause
in connection with change 
or for cause by participant
Termination for cause
of control 
 
 
Salary 
A payment equal to up to 
12 months’ salary payable 
as a lump sum or on a 
monthly basis, less any 
amounts payable pursuant 
to any restrictive covenant 
agreements (if applicable) 
(“Restrictive 
Covenants 
Agreement Setoff”) paid or 
to be paid in the same 
calendar year.
No payment.
A 
payment 
of 
up 
to 
18 months’ salary payable 
as a lump sum or on a 
monthly 
basis 
for 
termination without cause, 
less 
any 
Restrictive 
Covenants 
Agreement 
Setoff (if applicable) paid 
or to be paid in the same 
calendar year.
Annual Bonus 
Unpaid annual cash bonus 
in respect of prior year 
performance, 
which 
otherwise would have been 
earned if participant had 
remained 
employed 
through the payment date, 
should be paid in full. 
A  pro-rata amount of the 
participant’s target bonus 
for the current year should 
be paid, subject to the 
participant’s 
actual 
performance.
Unpaid 
annual 
cash 
bonuses lapse in full.
Up 
to 
1.5 
times 
the 
participant’s target bonus 
may be payable less any 
Restrictive 
Covenants 
Agreement 
Setoff 
(if applicable) paid or to be 
paid in the same calendar 
year.
 
86 Orchard Therapeutics plc 
DIRECTORS’ REMUNERATION REPORT  
continued 

 
Termination without cause 
or for cause by participant 
Termination without cause
in connection with change 
or for cause by participant
Termination for cause
of control 
 
The Company is unequivocally against rewards for failure; the circumstances of any departure, 
including the individual’s performance, would be taken into account in every case. Statutory 
redundancy payments may be made, as appropriate. Service agreements may be terminated 
summarily without notice (or on shorter notice periods) and without payment in lieu of notice in certain 
circumstances, such as gross misconduct or any other material breach of the obligations under their 
employment contract. The Company may require the individual to work during their notice period or 
may place them on garden leave during which they would be entitled to salary, beneﬁts and 
pension only. 
Except in the case of gross misconduct or resignation, the Company may at its absolute discretion 
reimburse for reasonable professional fees relating to the termination of employment and, where an 
Executive Director has been required to re-locate, to pay reasonable repatriation costs, including 
possible tax exposure costs. This includes any statutory entitlements or sums to settle or compromise 
claims in connection with a termination (including, at the discretion of the Committee, reimbursement 
for legal advice and provision of outplacement services). 
Share Option 
Incentive Plan 
Unvested awards lapse in 
full, 
except 
where 
the 
participant 
leaves 
in 
circumstances where they 
retain a statutory right to 
return to work (in which 
case, awards will continue 
to vest on normal terms).
Unvested awards lapse in 
full. 
On a change of control, 
merger, reorganization or 
other corporate event, the 
Company may seek to 
replace awards with new 
awards in the successor 
company (to the extent 
agreed with the successor 
company). In the case of a 
termination without cause 
or 
for 
cause 
by 
the 
participant in connection 
with a change of control, 
such awards will accelerate 
and vest in full. 
Where there is no agreement 
to replace awards, on a 
corporate 
event 
awards 
with 
time-based 
vesting 
conditions shall vest on 
the  date of that event 
and 
awards 
with 
performance-based vesting 
conditions shall vest on the 
date of that event to the 
extent determined by the 
Company (regardless of 
the  extent to which any 
performance 
conditions 
attached to awards have 
been satisﬁed).
 
Orchard Therapeutics plc 87
DIRECTORS’ REMUNERATION REPORT  
continued 

 
88 Orchard Therapeutics plc 
Policy on external appointments 
The Board believes that it may be beneﬁcial to the Company for executives to hold non-executive 
directorships outside the Company. Any such appointments are subject to approval by the Board, 
and the director may retain any fees received at the discretion of the Board. Dr Gaspar does not 
currently hold any outside directorships. 
Non-Executive Directors’ terms of engagement 
Each of the Non-Executive Directors is engaged under a Non-Executive Director appointment letter. 
In any event, each appointment is terminable by either party on not less than three months’ written 
notice. Our board of directors is classiﬁed, meaning that each of our directors is designated to one 
of three classes and is elected to serve a term of between one and three years. The Chair and 
Non-Executive Directors are only entitled to fees accrued to the date of termination. 
The dates of appointment of each of the Non-Executive Directors serving at 31 December 2022 are 
summarised in the table below. Dates prior to our incorporation in August 2018 as Orchard Rx Limited 
(now known as Orchard Therapeutics plc) are for Non-Executive Directors who served on the board 
of our predecessor company, Orchard Therapeutics Limited (now known as Orchard Therapeutics 
(Europe) Limited). 
Non-Executive Directors 
Date of contract or date of appointment 
Service at 31.12.22 
Joanne Beck
1 July 2018
4 years 6 months 
Marc Dunoyer
6 June 2018
4 years 7 months 
James Geraghty
4 June 2018
4 years 7 months 
Charles Rowland
1 June 2018
4 years 7 months 
Alicia Secor
7 December 2018
4 years 1 month 
John Curnutte
30 August 2019
3 years 4 months 
Steven Altschuler
3 February 2020
2 year 11 months 
Directors’ letters of appointment are available for inspection at the Company’s registered ofﬁce during 
normal business hours and will be available for inspection at the AGM. 
DIRECTORS’ REMUNERATION REPORT  
continued 

 
Orchard Therapeutics plc 89
Annual Report on Remuneration 
This part of the report has been prepared in accordance with Part 3 of The Large and Medium-sized 
Companies and Groups (Accounts and Reports) (Amendment) Regulations 2013 as amended, The 
Companies (Directors’ Remuneration Policy and Directors’ Remuneration Report) Regulations 2019 
(“the 2019 regulations”). Since the Company is not FTSE-listed, it is under no obligation to comply 
with the UK Corporate Governance Code, but best practice and good governance have been 
considered when preparing this report. The Annual Report on Remuneration and the Annual 
Statement by the Chair of the Compensation Committee will be put to a single advisory shareholder 
vote at the AGM on 14 June 2023. 
Compensation Committee (the “Committee”)  
The current members of the Committee, who are all independent, are Charles Rowland (Chair), 
Joanne Beck, Ph.D. and Alicia Secor. 
The Chairman of the Board and members of management are invited to attend meetings where 
appropriate. The Company Secretary is the secretary to the Committee. Attendees are not involved 
in any decisions and are not present for any discussions regarding their own remuneration. 
No conﬂicts of interest have arisen during the period and none of the members of the Committee 
has any personal ﬁnancial interest in the matters discussed, other than as shareholders. The fees of 
the Non-Executive Directors are approved by the Board on the joint recommendation of the 
Committee in consultation with our independent compensation consultant. 
Meetings attendance during 2022 
Attendance 
Charles Rowland
5 of 5 
Joanne Beck, Ph.D.
5 of 5 
Alicia Secor
5 of 5 
Independent advisors 
Each year the Committee appoints a wholly independent advisor to provide advise on executive and 
board remuneration. For 2022, the Committee reappointed the Executive Compensation practice of 
Aon plc. Aon advises on remuneration arrangements and all aspects of senior executive and board 
remuneration. In 2022, Aon assisted the Committee and kept the Committee up to date on 
remuneration trends and regulations. During the 2022 ﬁnancial year, fees charged by Aon for advice 
provided to the Committee amounted to $115,943 (2021: $131,226) (excluding VAT) on a time and 
materials basis. In addition, Aon provided advice to the Company’s Human Resources function on 
implementation of HR initiatives. The Company’s retained external legal counsel, Goodwin Procter 
LLP have also advised the Committee and the Company’s Human Resources function on 
compensation. The Committee reviews the independence of all external advisors on an annual basis 
and considers that additional services by Aon and Goodwin in no way prejudices their position as 
independent advisors to the Committee. 
Activity in the period 
The Committee’s principal function is to support Orchard’s strategy by ensuring that those individuals 
responsible for delivering the strategy are appropriately incentivized and rewarded through the 
operation of Orchard’s remuneration policy. In implementing the remuneration policy, and in 
DIRECTORS’ REMUNERATION REPORT  
continued 

 
90 Orchard Therapeutics plc 
constructing the remuneration arrangements for executive directors and senior employees, the Board, 
advised by the Committee, aims to provide remuneration packages that are competitive and designed 
to attract, retain and motivate Executive Directors and senior employees of the highest calibre. 
The Committee is responsible for and considered, where applicable, during the period: 
•
evaluating the efﬁcacy of the Company’s remuneration policy and strategy; 
•
reviewing and determining remuneration to be paid to the Company’s executive ofﬁcers and 
directors; 
•
reviewing and making recommendations to the Board regarding remuneration for non-executive 
members of the Board; 
•
agreeing the design of all share incentive plans; 
•
preparing any report on executive remuneration required by the rules and regulations of the 
U.S. Securities and Exchange Commission, The Nasdaq Stock Market LLC and as required under 
UK law or other countries in which the Company operates; 
•
reviewing, evaluating, and approving employment agreements, severance agreements, 
change-of-control protections, equity grants, corporate performance goals and objectives, and 
other compensatory arrangements of the executive ofﬁcers and other senior management and 
adjusting remuneration, as appropriate; 
•
evaluating and approving remuneration plans and programs and establishing equity remuneration 
policies; 
•
reviewing remuneration practices and trends to assess the adequacy and competitiveness of 
the executive remuneration programs as compared to industry peers, and determining the 
appropriate levels and types of remuneration to be paid; 
•
approving any loans by the Company to employees; 
•
reviewing and approving remuneration arrangements for any executive ofﬁcer involving any 
subsidiary, special purpose or similar entity, with consideration of the potential for conﬂicts of 
interest; and 
•
reviewing the Company’s practices and policies of employee remuneration as they relate to risk 
management and risk-taking incentives. 
The Committee is formally constituted and operates on written terms of reference, which are available 
on Orchard’s website, www.orchard-tx.com.  
Statement of shareholder voting at 2022 AGM 
At last year’s AGM held on 7 June 2022, votes cast by proxy and at the meeting in respect of the 
Directors’ remuneration were as follows: 
                                                    Votes For                   Votes Against               Votes Withheld 
                                              % of      Number            % of      Number            % of      Number 
                                            votes                of          votes                of           votes                of 
                                              cast          votes             cast          votes             cast          votes 
To approve the Directors’ 
Remuneration Report               93.4%  48,023,460            6.3%    3,247,147            0.3%       150,066 
To approve the Directors’  
Remuneration Policy                 93.3%  47,965,263            6.5%    3,334,672            0.2%       120,738 
DIRECTORS’ REMUNERATION REPORT  
continued 

 
Orchard Therapeutics plc 91
Single total figure of Directors’ remuneration – year ended 31 December 2022 (audited)  
The total remuneration of the individual Directors who served in the year ended 31 December 2022, 
is shown below. Total remuneration is the sum of emoluments plus Company pension contributions. 
The below table has been presented in US dollars ($) which is the functional currency of the 
reporting entity: 
                                                                       Base                                                                           Total                                  
                                                                     salary                                                                       remun-        Total        Total 
                                                                        /fees  Benefits2 Pension3     Bonus       SOIP4     eration        fixed   variable 
                                                                        $000         $000         $000         $000         $000         $000 
Executive Directors 
Bobby Gaspar1                                       2022        572.7            4.0          37.8        294.4               –        908.9        614.5        294.4 
                                                       2021        605.1            3.2          27.2        217.8               –        853.3        635.5        217.8 
                                                                       Base                                                                           Total                                  
                                                                     salary                                                                       remun-        Total        Total 
                                                                        /fees  Benefits2   Pension     Bonus       SOIP3     eration        fixed   variable 
                                                                        $000         $000         $000         $000         $000         $000 
Non-Executive Directors 
Steven Altschuler                                    2022          52.7               –               –               –               –          52.7          52.7               –  
                                                       2021          51.9               –               –               –               –          51.9          51.9               –  
Joanne Beck                                           2022          60.2                                                                            60.2          60.2               –  
                                                       2021          59.4               –               –               –               –          59.4          59.4               –  
John Curnutte                                         2022          60.2                                                                            60.2          60.2               –  
                                                       2021          63.7               –               –               –               –          63.7          63.7               –  
Marc Dunoyer                                         2022          59.2                                                                            59.2          59.2               –  
                                                       2021          59.1               –               –               –               –          59.1          59.1               –  
James Geraghty                                     2022          95.4                                                                            95.4          95.4               –  
                                                       2021          95.1               –               –               –               –          95.1          95.1               –  
Charles Rowland                                    2022          82.8                                                                            82.8          82.8               –  
                                                       2021          78.1               –               –               –               –          78.1          78.1               –  
Alicia Secor5                                           2022          66.8                                                                            66.8          66.8               –  
                                                       2021          72.1               –               –               –               –          72.1          72.1               –  
Total                                                       2022      1050.0            4.0          37.8        294.4            0.0      1386.2      1091.8        294.4 
                                                       2021      1084.6            3.2          27.2        217.8            0.0      1332.7      1114.9        217.8 
1.
Dr. Gaspar’s salary is £462,000 per annum, which increased by 5% from £440,000 effective 1 March 2022. 2022 
ﬁgures are converted at a 12-month average rate for 2022 of GBP 1 = USD 1.2495. 2021 ﬁgures are converted at a 
12-month average rate for 2021 of GBP 1 = USD 1.3753. Due to exchange rate ﬂuctuation, the 2022 salary increase 
does not correspond to an increased reporting amount in USD. 
2.
For Executive Directors, beneﬁts include private health insurance, long term disability, critical illness and death in 
service beneﬁts. 
3.
Effective 1 April 2021, Dr. Gaspar began receiving a cash allowance in lieu of the Company’s pension contribution 
equal to 6% of his salary. Dr. Gaspar received no pension beneﬁts from the Company before this date. 
4.
The ﬁgures for the Share Option Incentive Plan (SOIP) represent the intrinsic value of the share options on the date 
of grant. All share options granted to Directors are awarded at the market value and therefore the intrinsic value at 
the time of grant is zero. Details of all options awarded to individual Directors during the year, including the number 
of options under award, the exercise price, vesting schedule and the grant date fair value can be found in the tables 
below. All awards in the column are subject to continued service only and are not subject to any further performance 
conditions. 
5.
Alicia Secor received a one-time retrospective payment of $11,250 in April 2021 for prior services to the Nomination 
and Governance Committee which had previously not been paid. 
2022 Annual bonus 
During a series of meetings between December 2022 and February 2023, the Compensation 
Committee evaluated the achievement of the 2022 corporate objectives and the Chief Executive’s 
individual performance. 
The Compensation Committee reviewed the corporate goals, below, and based on the results, 
approved an 85% achievement level of the 2022 corporate objectives.
DIRECTORS’ REMUNERATION REPORT  
continued 

 
92 Orchard Therapeutics plc 
Successes during 2022 spanned across all areas of the Company’s activity, each individually and 
collectively critical for the long-term success of the Company. Overcoming a number of challenges 
in the year, the achievements assessed by the Committee have built considerable momentum for the 
Company across our portfolio and business operations. 
Key achievements against agreed goals include those from commercial, regulatory, clinical- & 
pre-clinical research as well as ﬁnancial. These are: 
i.
extending the Company’s cash runway through portfolio prioritization, expense management, 
new capital and business development; 
ii.
driving net revenue from Libmeldy sales; 
iii. advancing our portfolio to key clinical and regulatory milestones; 
iv.
strategic decisions in pre-clinical research activities, notably relating to Crohn’s disease. 
A series of scientiﬁc and business-related achievements during the year were also noted by the 
Committee in approving the achievement for the year. 
Annual Bonus (audited) 
As CEO, Dr Gaspar’s annual bonus is directly linked to the performance of the Company. A Corporate 
Performance Score of 85% therefore corresponds to a bonus outcome equivalent to 85% of target 
for the CEO. This equates to a 2022 bonus payment equal to 51% of his base salary.  
The Committee notes that the same corporate performance score has been applied to all employees 
across the Company. 
                                                                           Target Annual 
                                                                             Cash Bonus                Corporate       Cash payment       Cash outcome 
Executive Director                     Base salary ($)         (% of salary)           performance                 % salary                           ($) 
Bobby Gaspar                     $577,250                60%                   85%                  51%         $294,397 
1
Dr. Gaspar’s base salary and bonus are paid in GBP (£) and awards have been translated into USD at a rate of 
GBP 1 = USD 1.2495, which was the average rate during 2022. The salary basis for the bonus was Dr Gaspar’s 
salary as CEO, £462,000. 
DIRECTORS’ REMUNERATION REPORT  
continued 

 
Orchard Therapeutics plc 93
Share Option Incentive Plan  
Awards granted to Executive Directors in 2022 (audited)  
During 2022, Dr Gaspar was granted an annual equity award. This award was made as an award of 
share options, split into two tranches: 
–
options with an exercise price set at the Company’s closing share price on the date of grant 
(‘market-priced’ options); and 
–
options with an exercise price set at a 25% premium to the Company’s closing share price on 
the date of grant (‘premium-priced’ options). 
The Committee believes that granting share options to the CEO remains the most effective alignment 
between executive compensation and long-term shareholder interest. The addition of premium-priced 
options during 2022 reinforces this alignment and ensures that a substantial portion of Dr Gaspar’s 
compensation package is contingent on long-term and sustainable value growth of the Company. 
                                                                                                                                                                                                                                           Value 
                                                                                                                                                                                                                                       realized 
                                                                                                                                           Face              Fair                                                                         at 
                                                                                                                                          Value           Value                                                              exercise 
                                                      Form of           Date of      Shares    Exercise        at Date        at Date             Expiry Vested in                                or           Un- 
Executive Director                                    Award             Grant   Covered1        Price1     of Grant2     of Grant2                Date       20223   Exercised   vesting      vested 
Bobby Gaspar                   Market-priced Options   1 June 2022     422,631     $0.4591     $194,030     $126,844   31 May 2032     88,048                nil           n/a    334,583 
Bobby Gaspar               Premium-priced Options   1 June 2022     427,369   $0.57388     $196,205     $120,094   31 May 2032     89,035                nil           n/a    338,334 
1
The numbers of share and share prices are before the 1:10 American Deposit Share (ADS) ratio change which 
became effective on 10 March 2023.  
2
Market-priced options are granted at the market price which is the exercise price. The face value at date of grant is 
calculated as the number of shares multiplied by the exercise price. The fair value at the date of grant is calculated 
as the Black Scholes value. The face value of the premium-priced options is the number of shares covered multiplied 
by the share price on the date of grant. 
3
The options vest, and become exercisable, over a four-year period on a monthly basis commencing upon the 
one-month anniversary of the vesting commencement date of 1 February 2022. 
In October 2022 under the terms of Orchard’s Share Option Incentive Plan 2018 the Board of Directors 
approved a repricing of previously awarded share options to employees which were signiﬁcantly 
‘underwater’ i.e., where the exercise prices were signiﬁcantly above the Company’s recent trading 
price. This repricing took effect on October 4, 2022.  
All employees at the Company hold share options and in the situation where substantial portions of 
employees’ equity holding had little or no value, the Board took the decision to reprice these awards. 
This was done in order to reengage staff with the future success of Orchard and provide additional 
retentive value to the investment previously made in our equity program. The Company has, and 
continues to grant, equity-based compensation to all employees – aligning the entire workforce with 
the future value of the Company. 
The Board of Directors considered several factors in determining which grants would be eligible for 
repricing and which grants would remain on the original terms: 
•
None of the non-executive director grants were repriced; 
•
Only grants with an original exercise price above $1.25 were repriced, representing a 
150% premium to the price on the date of repricing; 
•
None of the grants from 2022 were repriced; and 
•
The exercise price of the repriced options ($0.58) was set at a 16% premium to the closing market 
price on the date of repricing ($0.50). 
DIRECTORS’ REMUNERATION REPORT  
continued 

 
94 Orchard Therapeutics plc 
As CEO, Dr Gaspar’s awards were treated in the same manner as all other employees. Awards 
granted to Dr Gaspar during 2019, 2020 and 2021 were therefore impacted by this action, with a 
repriced exercise price for the awards listed below set at a premium of 16% above the Company’s 
closing share price of $0.50 on 4 October 2022. 
                                                                                                      Exercise                               Face            Face                                                                      
                                                                                                       Price on                              Value     Value on                                                                      
                                         Form of                Date of     Shares     Date of   Exercise         at Date   4 October                  Expiry     Vested at                            Un- 
Executive Director                      Award                   Grant  Covered1        Grant        Price1       of Grant            2022                      Date      31.12.22   Exercised   vested 
Bobby Gaspar        Market-price options  16 January 2019      50,000      $12.54         $0.58      $627,000       $29,000   15 January 2029        48,9582                nil      1,042 
                     Market-price options    2 January 2020    200,000      $13.58         $0.58   $2,716,000     $116,000     1 January 2030      145,8332                nil    54,167 
                     Market-price options         1 April 2020    300,000        $7.05         $0.58   $2,115,000     $174,000      31 March 2030      200,0002                nil  100,000 
                     Market-price options  1 February 2021    850,000        $5.98         $0.58   $5,083,000     $493,000   31 January 2031      389,5832                nil  460,417 
                     Market-price options  1 February 2021      55,006        $5.98         $0.58      $328,936       $31,903   31 January 2031        55,0063                nil          n/a 
 
1
The numbers of shares and share prices are before the ADS ratio change which became effective on 10 March 2023.  
2
The options vest, and become exercisable, over a four-year period on a monthly basis commencing upon the 
one-month anniversary of the date of grant. 
3
These options vested in equal monthly tranches over 12 months. 
Awards granted to Non-Executive directors between 1 January 2022 and 
31 December 2022 (audited) 
Non-executive directors received the following option awards during the year, each vesting based 
on continued service only. 
                                                                                                                                              Face             Fair                                                                 Value 
                                                                                                                                            Value           Value                                                             realized 
                                                            Form of        Date of       Shares    Exercise       at Date        at Date         Expiry                                                   at    Un-exe- 
Non-Executive Directors                               Award           Grant   Covered1        Price1    of Grant1     of Grant1            Date    Vested1   Exercised   exercise      rcised 
Steven Altschuler                                  FMV Options*      7-Jun-22        46,000         $0.47      $21,836       $13,880      6-Jun-32              nil                 nil             nil      46,000 
Joanne Beck                                         FMV Options*      7-Jun-22        46,000         $0.47      $21,836       $13,880      6-Jun-32              nil                 nil             nil      46,000 
Marc Dunoyer                                       FMV Options*      7-Jun-22        46,000         $0.47     $21,836       $13,880      6-Jun-32              nil                 nil             nil      46,000 
James Geraghty                                   FMV Options*      7-Jun-22        46,000         $0.47      $21,836       $13,880      6-Jun-32              nil                 nil             nil      46,000 
Charles Rowland                                  FMV Options*      7-Jun-22        46,000         $0.47     $21,836       $13,880      6-Jun-32              nil                 nil             nil      46,000 
Alicia Secor                                           FMV Options*      7-Jun-22        46,000         $0.47      $21,836       $13,880      6-Jun-32              nil                 nil             nil      46,000 
John Curnutte                                       FMV Options*      7-Jun-22        46,000         $0.47     $21,836       $13,880      6-Jun-32              nil                 nil             nil      46,000 
1 
The numbers of shares and share prices are before the ADS ratio change which became effective on 10 March 2023. 
2 
The fair market value options are granted at the market price which is the exercise price. The face value at date of 
grant is calculated as the number of shares multiplied by the exercise price. The fair value at date of grant is 
calculated as the Black Scholes value. 
3 
The options vest and become exercisable at the earlier of one year from the date of grant or the next AGM. 
Payments for loss of ofﬁce (audited) 
No payments were made for loss of ofﬁce to Directors during the year. 
Payments to former Directors (audited) 
No payments were made to former Directors of the Company during the year. 
External directorships 
The Executive Directors do not currently hold any outside directorships. 
DIRECTORS’ REMUNERATION REPORT  
continued 

Statement of Directors’ shareholding and share interests (audited)  
The share interests of each Director as of 31 December 2022 (together with interests held by his or 
her connected persons) are set out in the table below. 
During 2022 the Compensation Committee implemented formal shareholding requirements for 
Executive Directors. From 2022 onwards, Executive Directors will be expected to build up and 
maintain a shareholding with a value relative to their salaries. For the CEO, this guideline is 200% of 
salary and for other Executive Directors, 100% salary. Executive Directors will be expected to meet 
or exceed this guideline within 5 years of appointment or 5 years from the implementation of this 
requirement. 
From 2023, a shareholding requirement will be extended to the full Board of Directors and the other 
Executive Ofﬁcers of the Company. 
                                                                                                                        Restricted Shares                                Share Options 
                                                                                                           Unvested          Unvested                                  Unvested        Unvested 
                                                        Beneficially                                  without                   with                                     without                 with 
                                                    owned shares     % Salary     performance    performance      Vested but   performance   performance 
                                                    as at 31/12/22             held         conditions        conditions   unexercised       conditions      conditions 
Executive Directors 
Bobby Gaspar                                                370,158            24%1                          –            195,0002        1,750,765            950,209          338,3343 
Non-Executive Directors 
Steven Altschuler                                                       –               n/a                          –                        –           122,222              48,778                       – 
Joanne Beck                                                       9,292               n/a                          –                        –           190,030              46,000                       – 
John Curnutte                                                            –               n/a                          –                        –           125,000              46,000                       – 
Marc Dunoyer                                                   37,179               n/a                          –                        –           190,030              46,000                       – 
James Geraghty                                               44,391               n/a                          –                        –           430,120              46,000                       – 
Charles Rowland                                              12,294               n/a                          –                        –           190,030              46,000                       – 
Alicia Secor                                                                –               n/a                          –                        –           160,000              46,000                       – 
1 
The value of Dr. Gaspar’s beneﬁcially owned shares is calculated using the closing price of Orchard’s shares on 
31 December 2022. As the CEO, Dr. Gaspar has a shareholding requirement of 5x base salary and has until 2027 to 
achieve this following the implementation of this requirement in 2022. The Committee notes Dr. Gaspar’s vested and 
unvested holdings. 
2
Refers to a one-time grant of Performance Share Units (PSUs) awarded to Dr. Gaspar on 1 April 2020. This PSU 
award vests as follows: 1/3 of the PSUs will vest on each of the ﬁrst three of speciﬁc clinical and regulatory milestones 
achieved, subject to Bobby Gaspar remaining an employee of the Company on the date of achievement and provided 
that in each case the milestone is achieved on or before 2 January 2024. None of these awards have vested. The 
speciﬁc milestones are considered commercially sensitive. Details of the milestones and performance against them 
will be disclosed at the appropriate time.  
3
In 2022 Dr. Gaspar was awarded share options with an exercise price set at a 25% premium to the market price on 
the date of grant.  
Performance graph and table 
The chart below shows the Company’s Total Shareholder Return (TSR) performance compared with 
that of the SPDR S&P Biotech Index (XBI) over the period from the date of the Company’s admission 
to 31 December 2022. The XBI Index has been chosen as an appropriate comparator as a broad index 
comprising of small and mid-cap biotechnology companies. TSR is deﬁned as the return on investment 
obtained from holding a company’s shares over a period. It includes dividends paid, the change in the 
capital value of the shares and any other payments made to or by shareholders within the period. 
This graph shows the value, by 31 December 2022, of $100 invested in Orchard Therapeutics on 
31 October 2018 at the IPO price of $14, compared with the value of $100 invested in the XBI on the 
same date. 
 
Orchard Therapeutics plc 95
DIRECTORS’ REMUNERATION REPORT  
continued 

 
96 Orchard Therapeutics plc 
 
Aligning pay with performance 
The total remuneration ﬁgure for the CEO is shown in the table below, along with the value of bonuses 
paid, and SOIP vesting, as a percentage of the maximum opportunity: 
Chief Executive Officer                                2018            2019            2020            2021            2022 
Total remuneration ($000)1                             $555         $1,016            $764            $853            $909 
Actual bonus (% of the maximum)2                  N/A          44.0%          37.5%          22.5%          31.8% 
SOIP vesting (% of the maximum)3                  N/A              N/A              N/A              N/A              N/A 
1
For 2018 and 2019, these ﬁgures are for Orchard’s previous CEO Mark Rothera and for 2020 and 2021 the full-year 
remuneration for Dr. Gaspar. These ﬁgures are also impacted by exchange rate ﬂuctuations between the currency in 
which Dr. Gaspar is paid, GBP, and our reporting currency, USD. 
2
Calculated as the bonus earned in the year by Dr. Gaspar expressed as a portion of the maximum available under 
the Company’s Directors’ Remuneration Policy 160% of salary. 
3
There is no maximum grant policy under the SOIP; therefore, this information cannot be disclosed. 
Relative importance of spend on pay  
The table below illustrates the Company’s expenditure on pay by the Group in comparison to total 
operating expenses. Total operating expenses is a combined total of R&D and selling, general & 
administrative expenses before any deduction for any research and development tax credits 
recognized in the year. This is chosen as an appropriate measure of the Company’s major 
year-on-year expenditure. It is considered to be a more complete representation of our operations 
compared to R&D expenses which had been used in prior years. 
                                                                                                         2021            2022   % 
change 
Total operating expenses ($’000)                                                        $206.8         $174.9        -15.4% 
Total employee pay expenditure ($’000)1                                              $71.1           $61.5        -13.5% 
1
Total employee pay expenditure in the table above is inclusive of cash payments for salaries and wages, as well as 
employer beneﬁts and tax costs. It also includes $11,418k and $19,900k in non-cash share-based compensation 
expense for 2022 and 2021 respectively.
DIRECTORS’ REMUNERATION REPORT  
continued 

 
Orchard Therapeutics plc 97
Average percentage change in remuneration of Directors and Employees 
The table below shows a comparison of the annual change of each individual director’s pay to the 
annual change in average employee pay in the year ended 31 December 2022.  
                                                                 Change in pay between                                    Change in pay between                                  Change in pay between 
                                                               31/12/2021 and 31/12/2022                                31/12/2020 and 31/12/2021                              31/12/2019 and 31/12/2020 
                                                     Base                                                                  Base                                                                  Base  
                                             salary/fee              Bonus             Benefit        salary/fee              Bonus             Benefit        salary/fee             Bonus             Benefit 
Executive Directors 
Bobby Gaspar1                                         -5%                  35%                 38%2                 12%                 28%3              361%2                  58%                -54%                    0% 
Non-Executive Directors4 
Steven Altschuler                                        1%                    n/a                    n/a                 10%                    n/a                    n/a                   n/a5                    n/a                   n/a  
Joanne Beck                                              1%                    n/a                    n/a                   2%                    n/a                    n/a                  41%                    n/a                   n/a  
John Curnutte                                            -5%                    n/a                    n/a                   5%                    n/a                    n/a               278%6                    n/a                   n/a  
Marc Dunoyer                                            0%                    n/a                    n/a                  -1%                    n/a                    n/a                  27%                    n/a                   n/a  
James Geraghty                                        0%                    n/a                    n/a                  -1%                    n/a                    n/a                  15%                    n/a                   n/a  
Charles Rowland                                        6%                    n/a                    n/a                  -1%                    n/a                    n/a                  31%                    n/a                   n/a  
Alicia Secor                                              -7%                    n/a                    n/a                36%7                    n/a                    n/a                  23%                    n/a                   n/a  
Average employee8                                   n/a                    n/a                    n/a                    n/a                    n/a                    n/a                    n/a                   n/a                   n/a  
Please note that all ﬁgures are impacted by exchange rate ﬂuctuation between the currency in which the Board is paid, 
GBP, and our reporting currency, USD. 
1
Dr. Gaspar received a 5% salary increase, in GBP, effective1 March 2022. He did not receive a salary increase in 
2021 for his services as CEO. The increases represented here correspond to a salary increase upon promotion to 
CEO during 2020. These ﬁgures are also impacted by exchange rate ﬂuctuations. 
2
Dr. Gaspar’s company-provided beneﬁts are unchanged year-on-year – the reported ﬁgure combines the taxable 
value of private medical insurance and a cash allowance in lieu of pension. The 2021 increase relates to a cash 
allowance in lieu of pension contribution effective 1 April 2021 which he had not received prior to that date. 
3
The 2020 bonus (paid in February 2021) ﬁgure represents the cash amount paid only. Dr. Gaspar received share 
options with a fair value equal to 50% of the 2020 annual bonus in lieu of cash. 
4
None of the Non-Executive Directors are eligible for an annual bonus and none claimed any beneﬁts during the year. 
5
Steven Altschuler joined the Board during 2020 and therefore no comparative information is shown. 
6
John Curnutte joined the Board in 2019 and the remuneration received in 2019 was not a full annual amount. 
7
Alicia Secor received a one-off retrospective payment of $11,250 in April 2021 for prior services to the Nomination 
and Governance Committee which has previously not been paid. Her fees for services to the Board were not 
increased during 2021. 
8
As the parent company Orchard Therapeutics Plc has no direct employees. All employees are employed by the 
relevant legal entities. 
Statement of implementation of remuneration policy in 2023 
Annual base salary 
At his own request, the Committee reviewed and commended a proposal from Dr Gaspar that his 
salary not be adjusted for 2023. Dr Gaspar recognized the prevailing economic environment, ﬁscal 
position and available cash resources of the Company at year-end 2022. Based on the combination 
of these factors he, therefore, did not wish to receive a salary increase. 
                                                                      Base salary                   Base salary                       
                                                                                  2023                               2022       % change 
                                                                                                  (from 1 March 2022) 
Bobby Gaspar, Chief Executive Ofﬁcer                    £462,000                        £462,000                   nil 
Beneﬁts and pension  
In 2022, Executive Directors are eligible for the same beneﬁts (such as health insurance and pension) 
as provided to all employees in the jurisdiction in which they reside. Pension contributions for 
Executive Directors are up to 6% of base salary which may be taken as a cash allowance. 6% is the 
rate provided to all employees in the UK at the Company, and therefore representative of the rate for 
the rest of the workforce. 
DIRECTORS’ REMUNERATION REPORT  
continued 

 
98 Orchard Therapeutics plc 
Annual Bonus 
The CEO will be entitled to a target bonus of 60% of base salary, with the maximum payout up to 
150% of target bonus (90% salary). 
These 2023 targets and maximum have been set within the overall Directors’ Remuneration Policy. 
Unless otherwise determined by the Compensation Committee, the bonus will be paid in cash and 
subject to the achievement of a number of strategic objectives determined by the Committee. 
Speciﬁc targets are commercially sensitive and therefore are not disclosed in advance. However, full 
details of the targets and performance against them will be disclosed when they are no longer 
considered commercially sensitive. 
Within the overall maximum annual bonus provision in the Directors’ Remuneration Policy – currently 
150% of salary per annum - the Committee reserves the right to provide an additional 
milestone-based bonus. This would only be applied in circumstances deemed appropriate to focus 
on and incentivize key fundamental objectives to the Company. The Executive Directors currently 
have no such arrangements in place.  
Share Option Incentive Plan (SOIP) 
Annual award of  share options 
In 2023, as part of the annual compensation package the CEO has been awarded an award of 
market-price and premium-price options in the Company at the same time as all eligible employees. 
These premium priced options will have an exercise price set at 25% higher than the closing price 
of the Company’s ADSs on the Nasdaq National Select Market on the date of grant. Consequently, 
approximately half of the CEO’s 2023 share option award will have no intrinsic value until the share 
price increases by at least 25%. 
The Committee believes that granting share options to the CEO remains the most effective alignment 
between executive compensation and long-term shareholder interest. The addition of premium-priced 
options since 2022 reinforces this alignment and ensures that a substantial portion of Dr Gaspar’s 
compensation package is performance-based and contingent on long-term and sustainable value 
growth of the Company. 
DIRECTORS’ REMUNERATION REPORT  
continued 

                                                                                                                      Maximum 
Executive                                                   Form of                  Date of                   Shares                Exercise                      Vest 
Director                                                         Award                     Grant                Covered                      Price                   Terms 
Bobby Gaspar             Market-priced share options        1 March 2023                  563,410                  $0.4636                          (1) 
                         Premium-priced share options        1 March 2023                  581,590                  $0.5795                          (1) 
(1) The share options will expire 10 years from the date of grant. The share options vest monthly over a 4-year period 
and are not subject to any further performance conditions. 
At the date of this report, there is no intention to make any further awards under the SOIP to any 
Directors. Any awards made during the year, including the full details of the award described for 
Dr. Gaspar, will be disclosed in the relevant Directors’ Remuneration Report. 
Non-Executive Directors’ fees for 2023 
Non-Executive Directors are eligible to receive the following cash compensation annually. Following 
a review of the fees paid to the Board, the Company resolved to reduce by $5,000 the base fee 
provided to the Chair and Members of the Board. This removes a supplement previously provided 
for time and commitment to international travel with a corresponding rebalancing in equity 
compensation. 
Additionally, the fee for the Chair of the Science and Technology Committee has been increased, 
recognizing the crucial role this position holds in the long-term success of the Company. 
In reinforcing the Board’s stewardship of the Company, from 2023, all Non-Executive Directors will 
be required to build up a shareholding equivalent to three times the base fee and they will have ﬁve 
years to gain compliance with this new requirement. 
Collectively, the Compensation Committee believes these are important changes and represent 
incremental improvements to the Company’s Board remuneration structure. The changes ensure that 
this structure matches long-term shareholder interest and remains market competitive. 
                                                                                                            2023 Fee               2022 Fee 
                                                                                                              in $’000                in $’000  
Base fee: 
Board Chair                                                                                                        $80                        $85 
Board Member                                                                                                   $40                        $45 
Additional fees: 
Audit Committee Chair                                                                                       $18                        $18 
Audit Committee Member                                                                                    $9                          $9 
Compensation Committee Chair                                                                        $15                        $15 
Compensation Committee Member                                                                  $7.5                       $7.5 
Nominating and Corporate Governance Committee Chair                                $10                        $10 
Nominating and Corporate Governance Committee Member                             $5                          $5 
Science and Technology Committee Chair                                                        $15                        $10 
Science and Technology Committee Member                                                  $7.5                       $7.5 
 
Orchard Therapeutics plc 99
DIRECTORS’ REMUNERATION REPORT  
continued 

The Company intends to provide an initial, one-time equity award of 180,000 stock options (equivalent 
to 18,000 ADS following the 1:10 ratio change implemented on 10 March 2023) to each new 
Non-Executive Director upon his or her election to our board of directors. Under normal 
circumstances, initial share awards vest monthly over three years. The Company intends to provide 
an annual equity incentive award of 105,000 stock options (equivalent to 10,500 ADS from 10 March 
2023) to each Non-Executive Director at the 2023 AGM. Options awarded annually will usually vest 
upon the earlier to occur of the ﬁrst anniversary of the date of grant or the date of the next annual 
general meeting. 
As approved in our 2022 Directors’ Remuneration Policy Non-Executive Directors may elect to receive 
fees as market value share options with an equivalent value calculated as the fair value on the date 
of grant. 
Non-Executive Directors will not be eligible to participate in any performance-based incentive plans. 
Each Non-Executive Director will also be entitled to reimbursement of reasonable expenses and 
reimbursement of up to $5,000 for tax preparation assistance if Board services requires a 
Non-Executive Director to ﬁle a tax return in a jurisdiction that the director otherwise would not have 
been required to ﬁle on his own. 
 
On behalf of the Board 
Charles Rowland, Jr. 
Chair of  the Compensation Committee 
27 April 2023 
 
 
100 Orchard Therapeutics plc 
DIRECTORS’ REMUNERATION REPORT  
continued 

 
Orchard Therapeutics plc 101
ORCHARD THERAPEUTICS PLC 
ANNUAL REPORT AND FINANCIAL STATEMENTS 
31 DECEMBER 2022 
Registered number 11494381

 
102 Orchard Therapeutics plc 
Consolidated Statement of Proﬁt or Loss 
for the year ended 31 December 2022 
                                                                                                                Note                            2022                            2021 
                                                                                                                                                    $000                            $000 
Product sales                                                                              3                    20,610                        700 
Collaboration revenue                                                                 3                      2,045                        975 
Total revenue                                                                             3                    22,655                     1,675 
Cost of sales                                                                                                     (6,771)                      (226) 
Gross profit                                                                                                     15,884                      1,449 
Research and development expenses                                                          (104,833)               (153,645) 
Selling, general and administrative expenses                                                (45,809)                 (51,847) 
Other operating income and expenses                                      5                         (67)                        (90) 
Net foreign exchange loss                                                          5                  (24,344)                   (1,148) 
Operating loss                                                                                             (159,169)               (205,281) 
Finance income                                                                          9                      2,580                     1,469 
Finance expense                                                                        9                    (5,339)                   (5,799) 
Net finance expense                                                                                       (2,759)                   (4,330) 
Loss before taxation                                                                                   (161,928)               (209,611) 
Taxation                                                                                     10                      8,058                   11,336 
Loss for the year attributable to ordinary shareholders                         (153,870)               (198,275) 
Basic and diluted earnings per share ($)                                6                      (1.20)                     (1.60) 
 

 
Orchard Therapeutics plc 103
Consolidated Statement of Comprehensive Loss 
for the year ended 31 December 2022 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Loss for the year                                                                                         (153,870)               (198,275) 
Items that are or may be reclassiﬁed subsequently to  
statement of  proﬁt or loss: 
Foreign currency translation differences – foreign operations                        17,062                      1,097 
Net change in fair value of debt investments at fair value  
through other comprehensive income                                                                   (66)                      (251) 
Other comprehensive loss for the year, net of income tax                       16,996                         846 
Total comprehensive loss for the year                                                      (136,874)               (197,429) 
 

 
104 Orchard Therapeutics plc 
Consolidated Statement of Financial Position 
As at 31 December 2022 
                                                                                                                Note                            2022                            2021 
                                                                                                                                                             $000                              $000 
Non-current assets 
Property, plant and equipment                                                             12                         8,138                         4,767 
Right-of-use assets                                                                              25                       12,769                       13,873 
Intangible assets                                                                                  13                       48,292                       63,408 
Finance lease receivables                                                                   25                       12,905                       14,200 
Other receivables                                                                                 17                         5,725                         6,363 
Deferred tax assets                                                                              11                         5,483                         3,113 
                                                                                                                                        93,312                     105,724 
Current assets 
Inventories                                                                                            16                         3,398                         2,015 
Finance lease receivables                                                                   25                         1,294                         1,143 
Trade and other receivables                                                                17                       14,948                       22,435 
Research and development tax credit receivable                                                            5,942                       30,723 
Short-term investments                                                                        15                       75,326                     164,195 
Cash and cash equivalents                                                                  18                       68,424                       55,912 
                                                                                                                                      169,332                     276,423 
Total assets                                                                                                                 262,644                     382,147 
Current liabilities 
Trade and other payables                                                                    20                       40,331                       33,655 
Loans and borrowings                                                                         19                         9,429                            786 
Lease liabilities                                                                                     19                         6,424                         7,335 
Deferred income                                                                                    3                            959                            346 
Provisions                                                                                             22                            605                            671 
                                                                                                                                        57,748                       42,793 
Non-current liabilities 
Loans and borrowings                                                                         19                       22,991                       32,086 
Lease liabilities                                                                                     19                       19,246                       19,278 
Other payables                                                                                     20                         6,616                         2,607 
Deferred income                                                                                    3                       10,315                       12,519 
Provisions                                                                                             22                            908                         3,176 
                                                                                                                                        60,076                       69,666 
Total liabilities                                                                                                              117,824                     112,459 
Net assets                                                                                                                   144,820                     269,688 
Equity                                                                                                       
Share capital                                                                                        23                       16,409                       16,243 
Share premium                                                                                     23                     486,405                     486,382 
Translation reserve                                                                               23                       18,451                         1,389 
Share-based payment reserve                                                            23                     100,126                       88,309 
Fair value reserve                                                                                 23                           (237)                          (171) 
Retained earnings                                                                                                       (476,334)                   (322,464) 
Total Equity                                                                                                                 144,820                     269,688 
These ﬁnancial statements were approved by the board of directors on 27 April 2023 and were signed 
on its behalf by: 
 
Hubert Gaspar, Director  
27 April 2023
Company registered number: 11494381 

 
Orchard Therapeutics plc 105
Consolidated Statement of Changes in Equity  
for the year ended 31 December 2022 
                                                                                                                           Share-                                     
                                                                                                                            based          Fair                    
                                                                Share         Share   Translation   payment       value    Retained            Total 
                                                               capital    premium         reserve      reserve    reserve    earnings          Equity 
                                                                  $000           $000              $000           $000         $000           $000             $000 
Balance at 1 January 2022         16,243   486,382          1,389     88,309       (171) (322,464)   269,688 
Total comprehensive  
loss for the year 
Loss for the year                                  –              –                 –              –            –  (153,870)  (153,870) 
Other comprehensive income             –              –        17,062              –         (66)             –       16,996 
Total comprehensive  
loss for the year                                    –              –        17,062              –         (66) (153,870)  (136,874) 
Transactions with owners,  
recorded directly in equity 
Issue of shares under  
employee equity plans                     166            24                 –              –            –               –            190 
Issue of shares under  
consulting agreements                         –             (1)                –              –            –               –              (1) 
Share-based compensation  
expense                                                –              –                 –     11,418            –               –       11,418 
Deferred tax on share-based  
compensation                                      –              –                 –          399            –               –            399 
Total transactions with owners         166            23                 –     11,817            –               –       12,006 
Balance at 31 December 2022  16,409   486,405        18,451   100,126       (237) (476,334)   144,820 

 
106 Orchard Therapeutics plc 
Consolidated Statement of Changes in Equity  
for the year ended 31 December 2021 
                                                                                                                           Share-                                     
                                                                                                                            based          Fair                    
                                                                Share         Share   Translation   payment       value    Retained            Total 
                                                               capital    premium         reserve      reserve    reserve    earnings          Equity 
                                                                  $000           $000              $000           $000         $000           $000             $000 
Balance at 1 January 2021         12,497   339,435             292     82,714          80  (124,189)   310,829 
Total comprehensive  
loss for the year 
Loss for the year                                  –               –                 –              –            –  (198,275)  (198,275) 
Other comprehensive income              –               –          1,097              –       (251)              –            846 
Total comprehensive  
loss for the year                                    –               –          1,097              –       (251) (198,275)  (197,429) 
Transactions with owners,  
recorded directly in equity 
Issue of shares under  
employee equity plans                     263       2,650                 –              –            –               –         2,913 
Issue of shares under  
collaboration agreements                170       3,965                 –              –            –               –         4,135 
Issue of shares under  
consulting agreements                         3             (3)                –              –            –               –                – 
Issue of shares from  
private placement                         3,310   146,690                 –              –            –               –     150,000 
Share issue costs                                 –      (6,355)                –              –            –               –       (6,355) 
Share-based compensation  
expense                                                –               –                 –     19,900            –               –       19,900 
Deferred tax on share-based  
compensation                                      –               –                 –    (14,305)           –               –     (14,305) 
Total transactions with owners      3,746   146,947                 –       5,595            –               –     156,288 
Balance at 31 December 2021  16,243   486,382          1,389     88,309       (171) (322,464)   269,688 

 
Orchard Therapeutics plc 107
Consolidated Cash Flow Statement 
for the year ended 31 December 2022 
                                                                                                                Note                            2022                            2021 
                                                                                                                                                    $000                            $000 
Cash flows from operating activities 
Loss for the year                                                                                                          (153,870)                   (198,275) 
Adjustments for:  
Depreciation and amortisation                                                              5                       15,989                       24,364 
Impairment loss on intangible assets                                                    5                                –                       40,358 
Share-based compensation                                                                   8                       11,418                       19,900 
Amortization of (discount)/premium on short-term investments                                            (305)                        1,514 
Net ﬁnance expense                                                                              9                         2,759                         4,330 
Taxation                                                                                                10                        (8,058)                     (11,336) 
Unrealised foreign currency gains/losses and other non-cash 
adjustments                                                                                                                          23,208                         9,687 
Changes in working capital: 
Increase in inventories                                                                                                     (1,384)                       (1,351) 
Decrease/(increase) in trade and other receivables                                                      (1,131)                       (2,627) 
Decrease/(increase) in research and development  
tax credit receivable                                                                                                             779                        (1,620) 
Increase/(decrease) in trade and other payables                                                         12,837                      (10,420) 
(Decrease)/increase in deferred income                                                                           (272)                      13,122 
Increase in other non-current liabilities                                                                            2,154                              34 
Decrease in provisions                                                                                                    (2,337)                          (792) 
Cash used in operating activities, before tax                                                           (98,213)                   (113,112) 
Tax paid, net of research and development tax credit received                                   28,629                        (1,651) 
Net cash outflow used in operating activities                                                          (69,584)                   (114,763) 
Cash flows from investing activities 
Interest received on Short-term investments                                                                    2,580                            412 
Proceeds from the sale of other investments                                                               201,389                     234,732 
Receipt of funds from construction deposit                                                                     7,966                            216 
Acquisition of property and equipment                                                                           (6,514)                       (2,348) 
Acquisition of intangible assets                                                                                               –                           (887) 
Acquisition of other investments                                                                                 (112,281)                   (263,878) 
Lease payments received on ﬁnance leases                                                                    1,143                            181 
Net cash from investing activities                                                                               94,283                      (31,572) 
Cash flows from financing activities 
Proceeds from loans and borrowings                                                  19                                –                         7,375 
Proceeds from issue of shares under employee equity plans                                              212                         3,303 
Proceeds from issue of shares under collaboration  
agreements                                                                                                                              –                         4,135 
Proceeds from issue of shares from private placement                                                          –                     150,000 
Costs related to issue of shares                                                                                         (119)                       (6,747) 
Interest paid                                                                                                                    (4,908)                       (5,405) 
Repayment of borrowings                                                                   19                           (786)                               – 
Payment of lease liabilities                                                                  19                        (5,218)                       (5,523) 
Net cash (used in)/from financing activities                                                             (10,819)                    147,138 
Net increase in cash and cash equivalents                                                                    13,880                            803 
Cash and cash equivalents at 1 January                                                                        60,178                       59,401 
Effect of exchange rate ﬂuctuations on cash held                                                          (1,419)                            (26) 
Cash, cash equivalents and restricted cash at  
31 December                                                                                       18                       72,639                       60,178 
Cash and cash equivalents                                                                                             68,424                       55,912 
Restricted cash                                                                                    17                         4,215                         4,266 
Cash, cash equivalents and restricted cash at 31 December        18                       72,639                       60,178  

 
108 Orchard Therapeutics plc 
Notes to the Annual Report and Financial Statements 
1
ACCOUNTING POLICIES  
1.1 NATURE OF BUSINESS AND BASIS OF PREPARATION 
Orchard Therapeutics plc (the “Company”) is a global gene therapy company dedicated to 
transforming the lives of people affected by severe diseases through the development of innovative, 
potentially curative gene therapies. The Company and its subsidiary undertakings are referred to in 
this report as the “Group”. The Group’s ex vivo autologous hematopoietic stem cell (“HSC”) gene 
therapy approach utilizes genetically modiﬁed blood stem cells and seeks to correct the underlying 
cause of disease in a single administration. The Group has a portfolio that includes a 
commercial-stage product and research and development-stage product candidates. 
The Company is a public limited company incorporated pursuant to the laws of England and Wales.  
The Company is domiciled and registered in the UK. The registered number is 11494381 and the 
registered address is 245 Hammersmith Road, 3rd Floor, London, England, W6 8PW, United Kingdom.  
The Company has American Depositary Shares (“ADSs”) registered with the U.S. Securities and 
Exchange Commission (the “SEC”). The ADSs were listed on the Nasdaq Global Select Market on 
31 October 2018 and were transferred to the Nasdaq Capital Market on 13 September 2022. As at 
31 December 2022 each holder of ordinary shares and ADSs is entitled to one vote per ordinary 
share and to receive dividends when and if such dividends are recommended by the board of 
directors and declared by the shareholders. The Company did not declare any dividends in 2022 or 
2021. Following the ratio change on 10 March 2023 (see note 28) each ADS represents 10 ordinary 
shares of the Company. 
On 9 February 2021, the Company issued and sold (i) 20,900,321 ordinary shares, nominal value 
£0.10 per share, at a purchase price of $6.22 per share (the “Purchase Price”), which was the closing 
sale price of the Company’s ADSs on the Nasdaq Global Select Market on 4 February 2021, and 
(ii) 3,215,434 non-voting ordinary shares, nominal value £0.10 per share, at the Purchase Price (together 
(i) and (ii) the “Private Placement”). The Private Placement resulted in net proceeds to the Company of 
$143.6 million after deducting placement agent fees of $6.0 million and other issuance costs of 
$0.4 million. The ordinary shares and non-voting ordinary shares were sold pursuant to a securities 
purchase agreement entered into between the Company and the purchasers named therein on 
4 February 2021. At 31 December 2021, all outstanding non-voting shares have been converted to voting 
ordinary shares. 
The group ﬁnancial statements consolidate those of the Company and its subsidiaries (together 
referred to as the “Group”). The parent company ﬁnancial statements present information about the 
Company as a separate entity and not about its group. 
The Group ﬁnancial statements have been prepared and approved by the directors in accordance 
with international accounting standards in accordance with UK-adopted international accounting 
standards (“UK-adopted IFRS”). The Company has elected to prepare its parent company ﬁnancial 
statements in accordance with FRS 101. 
The accounting policies set out below have, unless otherwise stated, been applied consistently to all 
periods presented in these group ﬁnancial statements and in preparing an opening IFRS 
Consolidated statement of ﬁnancial position at 1 January 2021 for the purposes of the transition from 
accounting principles generally accepted in the United States of America (“US GAAP”) to UK-
adopted IFRSs. The consolidated ﬁnancial statements were historically prepared in accordance with 
US GAAP, as permitted by Statutory Instrument 2015 No. 1675, “The Accounting Standards 
(Prescribed Bodies) (United States of America and Japan) Regulations 2015”. This Statutory 
Instrument permitted the use of US GAAP for the consolidated ﬁnancial statements for the ﬁrst four 
years following Orchard Therapeutics plc’s incorporation in 2018 through to the year ended 31 
December 2021, and the Group has transitioned to IFRS for the year ended 31 December 2022. 

 
Orchard Therapeutics plc 109
1
ACCOUNTING POLICIES continued 
Judgements made by the directors, in the application of these accounting policies that have a 
signiﬁcant effect on the ﬁnancial statements and estimates with a signiﬁcant risk of material 
adjustment in the next year are set out in note 2. 
1.2 TRANSITION TO UK-ADOPTED IFRSs 
The Group is preparing its ﬁnancial statements in accordance with UK-adopted IFRS for the ﬁrst time 
and consequently has applied IFRS 1. An explanation of how the transition from US GAAP to 
UK-adopted IFRSs has affected the reported ﬁnancial position, ﬁnancial performance and cash ﬂows 
of the Group is provided in note 29. 
IFRS 1 grants certain exemptions from the full requirements of UK-adopted IFRSs in the transition 
period. The following exemptions have been taken in these ﬁnancial statements: 
–
Leases - the right-of-use asset is measured at an amount equal to the lease liability on the date 
of transition. 
–
Financial instruments – classiﬁcation of ﬁnancial instruments is based on facts and circumstances 
which existed at the date of transition. 
1.3 BASIS OF PREPARATION 
The ﬁnancial statements are prepared on the historical cost basis modiﬁed by the revaluation of 
certain items, as stated in the accounting policies and on a going concern basis. 
The accompanying consolidated ﬁnancial statements have been prepared in accordance with 
UK-adopted IFRS and with the requirements of the Companies Act 2006 as applicable to companies 
reporting under those standards. These ﬁnancial statements include the accounts of the Company 
and its wholly owned subsidiaries, after elimination of all intercompany accounts and transactions. 
Items included in the ﬁnancial statements of each of the group’s entities are measured using the 
currency of the primary economic environment in which the entity operates (‘the functional currency’). 
The consolidated ﬁnancial statements are presented in US Dollars (USD), which is Orchard 
Therapeutics plc’s functional and presentation currency. 
Amounts reported are based in thousands, except percentages, per share amounts or as otherwise 
noted. 
1.4 GOING CONCERN 
The accompanying consolidated ﬁnancial statements have been prepared on a going concern basis. 
The Group expects that its cash, cash equivalents, and short-term investments as of 31 December 
2022, of $143.8 million, together with expected proceeds from sales of Libmeldy and the $34 million 
received in March 2023 from the 2023 Private Placement (see note 28), will be sufﬁcient to fund its 
operations and capital expenditure requirements for at least twelve months from the date of signing 
of this Annual Report and Financial Statements. Management have prepared a budget to support 
the going concern assumption of the Group which shows the Group has sufﬁcient resources to 
continue as a going concern into 2025. 
Notes to the Annual Report and Financial Statements 
continued 

1
ACCOUNTING POLICIES continued 
1.5 BASIS OF CONSOLIDATION 
Subsidiaries 
Subsidiaries are entities controlled by the Group. The Group controls an entity when it is exposed to, 
or has rights to, variable returns from its involvement with the entity and has the ability to affect those 
returns through its power over the entity. In assessing control, the Group takes into consideration 
potential voting rights. The acquisition date is the date on which control is transferred to the acquirer. 
The ﬁnancial statements of subsidiaries are included in the consolidated ﬁnancial statements from 
the date that control commences until the date that control ceases.  
Transactions eliminated on consolidation 
Intra-group balances and transactions, and any unrealised income and expenses arising from 
intra-group transactions, are eliminated. 
1.6 FOREIGN CURRENCY 
Transactions in foreign currencies are translated to the respective functional currencies of Group 
entities at the foreign exchange rate ruling at the date of the transaction. Monetary assets and 
liabilities denominated in foreign currencies at the Consolidated statement of ﬁnancial position date 
are retranslated to the functional currency at the foreign exchange rate ruling at that date. Foreign 
exchange differences arising on translation are recognised in the Consolidated statement of proﬁt 
or loss. Non-monetary assets and liabilities that are measured in terms of historical cost in a foreign 
currency are translated using the exchange rate at the date of the transaction. Non-monetary assets 
and liabilities denominated in foreign currencies that are stated at fair value are retranslated to the 
functional currency at foreign exchange rates ruling at the dates the fair value was determined. 
The Group includes realised and unrealised foreign currency transaction losses in the Consolidated 
statement of proﬁt and loss.  
The assets and liabilities of foreign operations are translated to the Group’s presentational currency, 
US dollars, at foreign exchange rates ruling at the Consolidated statement of ﬁnancial position date. 
The revenues and expenses of foreign operations are translated at an average rate for the year where 
this rate approximates to the foreign exchange rates ruling at the dates of the transactions. 
Exchange differences arising from this translation of foreign operations are reported as an item of 
other comprehensive income and accumulated in the translation reserve.  
1.7 FINANCIAL INSTRUMENTS 
The Group ﬁnancial instruments include trade and other receivables, trade and other payables, lease 
liabilities, cash and cash equivalents, deposits, loans and borrowings and short-term investments.  
Cash and cash equivalents 
The Group considers all highly liquid investments purchased with original maturities of 90 days or 
less at the date of acquisition to be cash equivalents.  
Restricted cash and construction deposits 
Cash and cash equivalents that are restricted as to withdrawal or use under the terms of certain 
contractual agreements are recorded as restricted cash on the Consolidated statement of ﬁnancial 
position, classiﬁed within other receivables. The Group includes the restricted cash balance in cash 
and cash equivalents when reconciling beginning-of-period and end-of-period total amounts shown 
on the consolidated statement of cash ﬂows. 
Notes to the Annual Report and Financial Statements 
continued
 
110 Orchard Therapeutics plc 

1
ACCOUNTING POLICIES continued 
1.7 FINANCIAL INSTRUMENTS continued 
Trade and other receivables  
Trade receivables arise from product revenue and amounts due from the Group’s collaboration 
partners and have payment terms that generally require payment within 30 to 90 days. For some 
Libmeldy customers, our payment terms can range from 30 days to under one year. The amount from 
product revenue represents amounts due from distributors in Europe, which are recognised initially 
at fair value, net of reserves for trade discounts and allowances, and other incentives to the extent 
such amounts are payable to the customer by the Group. 
The Group holds the trade receivables with the objective to collect the contractual cash ﬂows and 
therefore measures them subsequently at amortised cost using the effective interest rate method, 
less any impairment losses. 
The Group monitors economic conditions to identify facts or circumstances that may indicate that its 
receivables are at risk of collection. The Group will provide against trade receivables for any expected 
credit loss that may result from a customer's inability to pay based on the composition of its accounts 
receivable, current economic conditions, and historical credit loss activity. Any impairment loss is 
recognised directly in the Consolidated statement of proﬁt or loss.  
Trade and other payables 
Trade and other payables are recognised initially at fair value. Subsequent to initial recognition they 
are measured at amortised cost using the effective interest rate method. 
Short-term investments 
Short-term investments consist of debt securities with original maturities of greater than ninety days. 
The Group has classiﬁed its investments with maturities beyond one year as short term, based on 
their highly liquid nature and because such debt securities represent the investment of cash that is 
available for current operations. 
Short-term investments in debt securities have been classiﬁed as measured at fair value through 
other comprehensive income (FVOCI) as a) they are held within a business model whose objective 
is achieved by both collecting contractual cash ﬂows and selling ﬁnancial assets; and b) their 
contractual terms give rise on speciﬁed dates to cash ﬂows that are solely payments of principal and 
interest on the principal amount outstanding. 
Short-term investments in debt securities are subsequently measured at fair value. Interest income 
calculated using the effective interest method, foreign exchange gains and losses and impairment are 
recognised in proﬁt or loss. Other net gains and losses are recognised in other comprehensive income 
(OCI). On derecognition, gains and losses accumulated in OCI are reclassiﬁed to proﬁt or loss. 
Borrowings  
Interest-bearing borrowings are initially measured at fair value (with direct transaction costs being 
amortised over the life of the loan) and are subsequently measured at amortised cost using the 
effective interest rate method at each reporting date. 
Lease liabilities 
Lease liabilities are initially measured at fair value and are subsequently measured at amortised cost 
using the effective interest rate method at each reporting date. 
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 111

1
ACCOUNTING POLICIES continued 
1.7 FINANCIAL INSTRUMENTS continued 
Lease receivables  
Lease receivables are initially recognised at an amount equal to the Group’s net investment in the 
lease, which comprises of the present value of lease payments and initial direct costs. Lease 
receivables are subsequently measured at amortised cost using the effective interest rate method, 
less any impairment losses. 
1.8 PROPERTY, PLANT AND EQUIPMENT 
Property, plant and equipment are stated at cost less accumulated depreciation and accumulated 
impairment losses. 
Where parts of an item of property, plant and equipment have different useful lives, they are 
accounted for as separate items of property and equipment. 
Depreciation is charged to the Consolidated statement of proﬁt or loss on a straight-line basis over 
the estimated useful lives of each part of an item of property, plant and equipment. The estimated 
useful lives are as follows: 
Lab equipment 
5-10 years 
Leasehold improvements
Shorter of lease term or estimated useful life 
Furniture and ﬁxtures
4 years 
Computer equipment
3-5 years 
Depreciation methods, useful lives and residual values are reviewed at each statement of ﬁnancial 
position date. 
Repairs and maintenance expenditures, which are not considered improvements and do not extend 
the useful life of property, plant and equipment, are expensed as incurred. Upon retirement or sale, 
the cost of assets disposed of, and the related accumulated depreciation are removed from the 
accounts, and any resulting gain or loss is included in the consolidated statement of proﬁt and loss 
and other comprehensive loss. 
1.9 INTANGIBLE ASSETS  
Research and development costs 
Research and development expenses consist of costs incurred in performing research and 
development activities, including salaries, share-based compensation and beneﬁts, facilities costs, 
depreciation, third-party license fees, certain milestone payments, and external costs of outside 
vendors engaged to conduct clinical development activities and clinical trials, the purchase of 
in-process research and development assets, as well as costs to develop a manufacturing process, 
perform analytical testing and manufacture clinical trial materials. Non-refundable prepayments for 
goods or services that will be used or rendered for future research and development activities are 
recorded as prepaid expenses. 
Expenditure on research activities is recognised in the Consolidated statement of proﬁt or loss as an 
expense as incurred.  
Internal development expenditure is capitalised only if it meets the recognition criteria of IAS 38 
Intangible Assets. Where regulatory and other uncertainties are such that the criteria are not met, 
the expenditure is charged to proﬁt and loss. Where the recognition criteria are met, development 
costs are capitalised and amortised on a straight-line basis over their useful economic lives from 
product launch. 
Notes to the Annual Report and Financial Statements 
continued
 
112 Orchard Therapeutics plc 

1
ACCOUNTING POLICIES continued 
1.9 INTANGIBLE ASSETS continued 
Other Intangibles 
Other intangible assets comprise capitalised upfront payments and milestone payments to acquire 
license intangibles from external parties in relation to both products in development and approved 
products. Other intangible assets are amortised on a straight-line basis over their estimated useful 
economic life.  
The Group makes payments to third parties for in process research and development projects. 
Payments generally take the form of upfront payments and milestone payments. Such payments are 
expensed if they represent consideration for sub-contracted future research and development 
services. Payments are capitalised if they represent consideration for the transfer of identiﬁable 
intellectual property developed at the risk of the third party. Any upfront or milestone payments for 
research activities where there is no associated identiﬁable intellectual property are expensed. 
Milestone payments related to identiﬁable intellectual property are capitalised when they fall due. 
Intangible assets are amortised over their estimated economic lives from product launch and 
periodically reviewed for impairment.  
Amortisation  
Amortisation is charged to the Consolidated statement of proﬁt or loss on a straight-line basis over 
the estimated useful lives of intangible assets. The estimated useful lives are as follows: 
License intangibles                                                    10 years 
1.10
INVENTORIES 
Prior to the initial date that regulatory approval is received, costs related to the production of inventory 
are recorded as research and development expense on the Group's consolidated statement of proﬁt 
or loss. 
Inventories are stated at the lower of cost and estimated selling price less costs to complete and 
sell. Inventories are recognised as an expense in the period in which the related revenue is 
recognised. 
Cost is determined on the ﬁrst-in, ﬁrst-out (FIFO) method. Cost includes the purchase price, including 
taxes and duties and transport and handling directly attributable to bringing the inventory to its 
present location and condition. The cost of ﬁnished products and work in progress includes design 
costs, raw materials, direct labour and other direct costs and related production overheads (based 
on normal operating capacity). 
At the end of each reporting period inventories are assessed for impairment. If an item of inventory 
is impaired, the identiﬁed inventory is reduced to its selling price less costs to complete and sell and 
an impairment charge is recognised in the proﬁt and loss account. Where a reversal of the impairment 
is recognised the impairment charge is reversed, up to the original impairment loss, and is recognised 
as a credit in the Consolidated statement of proﬁt and loss. 
1.11
PROVISIONS 
A provision is recognised in the Consolidated statement of ﬁnancial position when the Group has a 
present legal or constructive obligation as a result of a past event, that can be reliably measured 
and it is probable that an outﬂow of economic beneﬁts will be required to settle the obligation. 
Provisions are determined by discounting the expected future cash ﬂows at a pre-tax rate that reﬂects 
risks speciﬁc to the liability.  
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 113

1
ACCOUNTING POLICIES continued 
1.12
EMPLOYEE BENEFITS  
Defined contribution plans 
A deﬁned contribution plan is a post-employment beneﬁt plan under which the Group pays ﬁxed 
contributions into a separate entity and will have no legal or constructive obligation to pay further 
amounts. Obligations for contributions to deﬁned contribution pension plans are recognised as an 
expense in the Consolidated statement of proﬁt or loss in the periods during which services are 
rendered by employees. 
Short-term benefits 
Short-term employee beneﬁt obligations are measured on an undiscounted basis and are expensed 
as the related service is provided. A liability is recognised for the amount expected to be paid under 
short-term cash bonus or proﬁt-sharing plans if the Group has a present legal or constructive 
obligation to pay this amount as a result of past service provided by the employee and the obligation 
can be estimated reliably. 
Share-based payment transactions 
Share-based payment arrangements in which the Group receives goods or services as consideration 
for its own equity instruments have been classiﬁed as equity-settled share-based payment 
transactions. 
The Group measures share-based awards granted to employees, consultants and directors based 
on the fair value of the shares and options on the date of the grant and recognises compensation 
expense for those awards over the requisite service period, which is the vesting period of the 
respective award. A corresponding increase in the share-based payment reserve in equity is made. 
The expense is recognised accordance with IFRS2 so that awards with graded vesting are treated 
as separate grants and the expense associated with each of these separate grants is recognised 
over the associated vesting period. The expense is included in the Consolidated statement of proﬁt 
or loss and allocated to either research and development expenses of selling, general and 
administrative expenses depending on the cost centre of the employee to which the award relates. 
The fair value of the awards granted is measured using the Black Scholes model, which utilizes a 
number of inputs to estimate the fair value of share options such as the current share price, expected 
term, volatility, interest rate, dividend rate and exercise price. Until the completion of the parent 
company's initial public offering in November 2018, the parent company had been a private company 
and lacked company-speciﬁc historical and implied volatility information for its shares. Therefore the 
expected share price volatility was estimated based on both the historical volatility of publicly traded 
peer companies and the Group’s own volatility history. This approach is expected to continue until 
adequate historical data regarding the volatility of the Group’s own traded share price is held. 
The amount recognised as an expense is adjusted to reﬂect the actual number of awards for which 
the related service and non-market vesting conditions are expected to be met, such that the amount 
ultimately recognised as an expense is based on the number of awards that do meet the related 
service and non-market performance conditions at the vesting date.  
The Group has also granted Performance-based share awards (PSUs) which vest on achievement 
of speciﬁc milestones, known as a non-market performance condition. Expense associated with these 
awards is recognised from the point in time that vesting of the award is considered probable. 
 
Notes to the Annual Report and Financial Statements 
continued
 
114 Orchard Therapeutics plc 

1
ACCOUNTING POLICIES continued 
1.13
REVENUE 
Revenue comprises product sales and collaboration revenue. Product sales are revenues arising 
from contracts with customers. Collaboration revenue arises from other contracts, however, the 
recognition and measurement principles of IFRS 15 ‘Revenue from Contracts with Customers’ are 
applied as set out below. 
Product sales  
Strimvelis 
The Group’s product sales of Strimvelis are currently distributed exclusively at the San Raffaele 
Hospital in Milan, Italy. The hospital will purchase and pay for the products and submit a claim to the 
payer. The Group’s contracted sales with the hospital contain a single performance obligation and 
the Group recognises revenue from product sales when the Group has satisﬁed its performance 
obligation, which is upon transferring control of the products to the hospital.  
The Group evaluated the variable consideration under IFRS 15 and there is currently no variable 
consideration included in the transaction price for the products. Costs to manufacture and deliver 
the product and those associated with administering the therapy are included in cost of product 
sales. As the product is sold in direct relation to a scheduled treatment, the Group estimates there is 
limited risk of product return, including the risk of product expiration.  
Libmeldy 
In January 2022, the Group began generating product revenue from sales of Libmeldy in Europe 
following the approval of Libmeldy by the European Commission in December 2020 for the treatment 
of early onset MLD, characterized by biallelic mutations in the ARSA gene leading to a reduction of 
the ARSA enzymatic activity in children with (i) late infantile or early juvenile forms, without clinical 
manifestations of the disease, or (ii) the early juvenile form, with early clinical manifestations of the 
disease, who still have the ability to walk independently and before the onset of cognitive decline. 
The Group recognises revenue when control of promised goods is transferred to a customer at an 
amount that reﬂects the consideration to which the Group expects to be entitled in exchange for those 
goods. Control of the product transfers upon infusion of the product.  
To determine revenue recognition, the Group performs the following ﬁve steps: (i) identify the 
contract(s) with a customer; (ii) identify the performance obligations in the contract; (iii) determine 
the transaction price, including variable consideration, if any; (iv) allocate the transaction price to the 
performance obligations in the contract; and (v) recognise revenue when (or as) the Group satisﬁes 
the performance obligations. The Group only applies the ﬁve-step model to contracts when 
collectability of the consideration to which it is entitled in exchange for the goods the Group transfers 
to the customer is determined to be probable.  
In certain regions of Europe and the Middle East, the Group utilizes distributors to act in an agent 
capacity including for patient identiﬁcation and other related functions. The Group is exclusively 
responsible for product fulﬁlment and retains inventory risk and pricing discretion of the product. 
Evaluation of these key indicators support the assertion that the Group maintains control over the 
product prior to delivery to the patient. The Group has concluded that it is the principal in these 
transactions and records the associated revenue on a gross basis with any payments to these entities 
being recorded as a cost of sale.  
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 115

1
ACCOUNTING POLICIES continued 
1.13
REVENUE continued 
Amounts are recorded as trade receivables when the right to the consideration is unconditional. The 
Group does not assess whether a contract has a signiﬁcant ﬁnancing component if the expectation at 
contract inception is that the period between payment by the customer and the transfer of the promised 
goods or services to the customer will be one year or less. The Group expenses incremental costs of 
obtaining a contract as and when incurred if the expected amortization period of the asset that would 
have been recognised is one year or less or the amount is immaterial. As 31 December 2022, the Group 
has not capitalized any costs to obtain contracts. 
The Group recognises product revenue, net of variable consideration related to certain allowances and 
accruals, when the customer takes control of the product, which is at a point in time once the patient 
has been infused. Product revenue is recorded at the net sales price, or transaction price. Where there 
is uncertainty over variable consideration, the Group includes it in the transaction price only to the extent 
that it is highly probable that a signiﬁcant reversal of revenue will not occur (‘the revenue constraint’). 
The Group records estimated product revenue reserves, which are classiﬁed as a reduction in product 
revenue, to account for the components of variable consideration. Variable consideration includes the 
following components: government rebates, including performance-based rebates, and trade discounts 
and allowances which are described below. 
These reserves are based on estimates of the amounts earned or to be claimed on the related sales 
and are classiﬁed as a liability and are included within trade and other payables on the consolidated 
statement of ﬁnancial position. The Group's estimates of reserves established for variable consideration 
are calculated based upon an application of the expected value method, which is the sum of 
probability-weighted amounts in a range of possible consideration amounts. These estimates reﬂect 
the Group's historical experience, current contractual and statutory requirements, speciﬁc known market 
events and trends, industry data, and current expectations around ﬁnal pricing. The amount of variable 
consideration that is included in the transaction price may be subject to constraint and is included in 
net product revenue only to the extent that it is probable that a signiﬁcant reversal in the amount of the 
cumulative revenue recognised will not occur in a future period. Actual amounts of consideration 
received may ultimately differ from the Group's estimates. If actual results vary, the Group adjusts these 
estimates, which could have an effect on proﬁt or loss in the period of adjustment. The following is a 
summary of the types of variable consideration the Group records: 
–
Government rebates: The Group is subject to statutory government rebates on sales in certain 
European countries as well as estimated rebates in certain European countries because ﬁnal pricing 
has not yet been negotiated. The Group records reserves for rebates in the same period the related 
product revenue is recognised, resulting in a reduction of product revenue and a current liability that 
is included in accrued expenses on the Group’s consolidated statement of ﬁnancial position. The 
Group is also subject to potential rebates in connection with performance criteria agreed upon with 
certain payors. The estimate for rebates is based on statutory discount rates, industry pricing data, 
current expectations around ﬁnal pricing to be obtained, and historical experience of the 
performance of the Group’s products during clinical trials. The Group classiﬁes rebates within 
accrued expenses in the Group consolidated statement of ﬁnancial position.  
–
Trade discounts and allowances: The Group may offer customers discounts, such as prompt pay 
discounts to remit payment in accordance with the stated terms of the invoice. These discounts are 
explicitly stated in the contracts and recorded in the period the related product revenue is 
recognised. The Group estimates which customers will earn these discounts and fees and deducts 
these discounts and fees in full from gross product revenue and accounts receivable at the time 
the Group recognises the related revenue. The Group classiﬁes trade discounts and allowances as 
a reduction of accounts receivable within the Group consolidated statement of ﬁnancial position. 
Notes to the Annual Report and Financial Statements 
continued
 
116 Orchard Therapeutics plc 

1
ACCOUNTING POLICIES continued 
1.13
REVENUE continued 
–
Product returns: Based on the timing of revenue recognition upon treatment with the patient, the 
Group does not expect any returns of the Group’s products.  
Collaboration revenue 
The terms of the Group’s collaboration agreements may include consideration such as 
non-refundable license fees, funding of research and development services, payments due upon 
the achievement of clinical and preclinical performance-based development milestones, regulatory 
milestones, manufacturing services, sales-based milestones and royalties on product sales. 
The Group ﬁrst evaluates collaboration arrangements to determine whether the arrangement (or part 
of the arrangement) represents a joint venture or joint arrangement in accordance with IAS 28 
Investment in Associates and Joint Ventures and IFRS 11 Joint Arrangements pursuant to the 
contractual arrangement. The Group accounts for any collaborative arrangement or elements within 
the contract that are deemed to be a collaborative arrangement, and not a customer relationship, in 
accordance with these standards. Currently there are no collaborative arrangements that the Group 
believes fall within either of these standards. The Group has entered into one agreement with 
Pharming Group N.V. (the “Pharming Agreement”, see Note 3) that is accounted for in line with 
IFRS 15 set out below. 
Under IFRS 15, an entity recognises revenue when its customer obtains control of promised goods 
or services, in an amount that reﬂects the consideration which the entity expects to receive in 
exchange for those goods or services. To determine the appropriate amount of revenue to be 
recognised for arrangements determined to be within the scope of IFRS 15, the Group performs the 
following ﬁve steps: (i) identiﬁcation of the contract(s) with the customer, (ii) identiﬁcation of the 
promised goods or services in the contract and determination of whether the promised goods or 
services are performance obligations, (iii) measurement of the transaction price, (iv) allocation of 
the transaction price to the performance obligations, and (v) recognition of revenue when (or as) the 
Group satisﬁes each performance obligation. The Group only applies the ﬁve-step model to contracts 
when it is probable that the entity will collect consideration it is entitled to in exchange for the goods 
or services it transfers to the customer. 
The Group recognises the transaction price allocated to upfront license payments as revenue upon 
delivery of the license to the customer and resulting ability of the customer to use and beneﬁt from 
the license, if the license is determined to be distinct from the other performance obligations identiﬁed 
in the contract. If the license is considered to not be distinct from other performance obligations, the 
Group utilises judgment to assess the nature of the combined performance obligation to determine 
whether the combined performance obligation is satisﬁed (i) at a point in time, but only for licenses 
determined to be distinct from other performance obligations in the contract, or (ii) over time, and, if 
over time, the appropriate method of measuring progress for purposes of recognising revenue from 
license payments. The Group evaluates the measure of progress each reporting period and, 
if necessary, adjusts the measure of performance and related revenue recognition.  
The Pharming Agreement entitles the Group to additional payments upon the achievement of 
performance-based milestones. These milestones are generally categorised into three types: 
development milestones, regulatory milestones, and sales-based milestones. The Group is also 
eligible to receive from Pharming tiered royalty payments on worldwide net sales. The Group evaluates 
whether it is probable that the consideration associated with each milestone will not be subject to a 
signiﬁcant reversal in the cumulative amount of revenue recognised. Amounts that meet this threshold 
are included in the transaction price using the most likely amount method, whereas amounts that do 
not meet this threshold are considered constrained and excluded from the transaction price until they 
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 117

meet this threshold. Milestones tied to regulatory approval, and therefore not within the Group’s 
control, are considered constrained until such approval is received. Upfront and ongoing 
development milestones per the collaboration agreements are not subject to refund if the 
development activities are not successful. 
At the end of each subsequent reporting period, the Group re-evaluates the probability of a 
signiﬁcant reversal of the cumulative revenue recognised for the milestones, and, if necessary, adjusts 
the estimate of the overall transaction price. Any such adjustments are recorded on a cumulative 
catch-up basis, which would affect revenues from collaborators in the period of adjustment.  
The Group may enter into an agreement that includes sales-based milestone payments and royalties 
in exchange for a license of intellectual property. The Group considers the underlying facts and 
circumstances of these agreements, noting whether the future payments are contingent upon future 
sales and whether they are dependent on a third party’s ability to successfully commercialise a 
product using the licensed intellectual property.  
The Group also considers whether the license is the only, or predominant, item to which the milestone 
payments and royalties relate. If the Group concludes the license is the predominant item in the 
agreement, therefore the primary driver of value, the Group excludes sales-based milestone 
payments and royalties from the transaction price until the sale occurs (or, if later, until the underlying 
performance obligation to which some or all of the royalty has been allocated has been satisﬁed or 
partially satisﬁed). Currently, the Group has not recognised any royalty revenue resulting from the 
Pharming Agreement. 
IFRS 15 requires the Group to allocate the arrangement consideration on a relative standalone selling 
price basis for each performance obligation after determining the transaction price of the contract 
and identifying the performance obligations to which that amount should be allocated. The relative 
standalone selling price is deﬁned in IFRS 15 as the price at which an entity would sell a promised 
good or service separately to a customer. If other observable transactions in which the Group has 
sold the same performance obligation separately are not available, the Group is required to estimate 
the standalone selling price of each performance obligation. Key assumptions to determine the 
standalone selling price may include forecasted revenues, development timelines, reimbursement 
rates for personnel costs, discount rates and probabilities of technical and regulatory success. 
Consideration that does not meet the requirements to satisfy the above revenue recognition criteria 
is a contract liability and is recorded as deferred income in the consolidated statement of ﬁnancial 
position. Short-term deferred income consists of amounts that are expected to be recognised as 
revenue in the next 12 months. Amounts that the Group expects will not be recognised within the next 
12 months are classiﬁed as long-term deferred income. 
The Group recognises as revenue the amount of the transaction price that is allocated to the 
respective performance obligation when (or as) each performance obligation is satisﬁed, either at a 
point in time or over time. In particular, for the Group’s collaborations with Pharming, revenue 
attributable to research services is recognised as those services are provided, based on the costs 
incurred to date. 
1.14
EXPENSES 
Research contract costs and accruals  
The Group has entered into various research and development contracts. These agreements are 
cancellable, and related costs are recorded as research and development expenses as incurred. When 
Notes to the Annual Report and Financial Statements 
continued
 
118 Orchard Therapeutics plc 
1
ACCOUNTING POLICIES continued 
1.13
REVENUE continued

billing terms under these contracts do not coincide with the timing of when the work is performed, the 
Group is required to make estimates of outstanding obligations as of period end to those third parties. 
Any accrual estimates are based on a number of factors, including the Group's knowledge of the 
progress towards completion of the research and development activities, invoicing to date under the 
contracts, communication from the research institution or other companies of any actual costs incurred 
during the period that have not yet been invoiced, and the costs included in the contracts. 
Signiﬁcant judgments and estimates may be made in determining the accrued balances at the end 
of any reporting period. There may be instances in which payments made to our vendors will exceed 
the level of services provided and result in a prepayment of the expense. Actual results could differ 
from the estimates made by the Group. The historical accrual estimates made by the Group have not 
been materially different from the actual costs. 
Finance income and expenses 
Finance expenses include interest payable and ﬁnance charges on lease liabilities recognised in the 
Consolidated statement of proﬁt or loss using the effective interest method, and the unwinding of 
the discount on provisions. Finance income comprises interest receivable on funds invested and 
interest income on lease receivables. Interest income and interest payable is recognised in proﬁt or 
loss as it accrues, using the effective interest method.  
1.15
TAXATION 
The Group is primarily subject to corporation taxes in the United Kingdom and the United States. The 
calculation of the Group's tax provision involves the application of both United Kingdom and United 
States tax law and requires judgement and estimates. 
Tax on the proﬁt or loss for the year comprises current and deferred tax. Tax is recognised in the 
Consolidated statement of proﬁt or loss except to the extent that it relates to items recognised directly 
in equity, in which case it is recognised in equity.  
Current tax is the expected tax payable or receivable on the taxable income or loss for the year, using 
tax rates enacted or substantively enacted at the statement of ﬁnancial position date, and any 
adjustment to tax payable in respect of previous years. 
Deferred tax is provided on temporary differences between the carrying amounts of assets and liabilities 
for ﬁnancial reporting purposes and the amounts used for taxation purposes. The following temporary 
differences are not provided for: the initial recognition of goodwill; the initial recognition of assets or 
liabilities that affect neither accounting nor taxable proﬁt other than in a business combination, and 
differences relating to investments in subsidiaries to the extent that they will probably not reverse in the 
foreseeable future. The amount of deferred tax provided is based on the expected manner of realisation 
or settlement of the carrying amount of assets and liabilities, using tax rates enacted or substantively 
enacted at the statement of ﬁnancial position date. 
A deferred tax asset is recognised only to the extent that it is probable that future taxable proﬁts will 
be available against which the temporary difference can be utilised. 
United Kingdom Research and development income tax credits  
As the Group carries out research and development activities, it is able to submit tax credit claims 
from two UK research and development tax relief programs: the Small and Medium-Sized Enterprises 
research and development tax credit (“SME”) program and the Research and Development 
Expenditure Credit (“RDEC”), depending on eligibility. Qualifying expenditures largely comprise 
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 119
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ACCOUNTING POLICIES continued 
1.14
EXPENSES continued

employment costs for research staff, consumables, and certain internal overhead costs incurred as 
part of research projects for which the Group does not receive income.  
The RDEC and SME credits are not dependent on the Group generating future taxable income or on 
the ongoing tax status or tax position of the Group. Each reporting period, the Group assesses its 
research and development activities and expenditures to determine whether the nature of these costs 
will qualify for credit under the tax relief programs and whether the claims will ultimately be realized 
based on the allowable reimbursable expense criteria established by the UK government. The Group 
expects a proportion of expenditures incurred in relation to its pipeline research, clinical trials 
management, and manufacturing development activities to be eligible for the research and 
development tax relief programs for the year ended 31 December 2022. The Group has qualiﬁed 
under the more favourable SME regime for the year ended 31 December 2021 and expects to qualify 
under the SME regime for the year ended 31 December 2022. 
The Group recognises credits from the research and development incentives when the relevant 
expenditure has been incurred and there is reasonable assurance that the reimbursement will be 
received. The SME program credits as a tax beneﬁt and RDEC program credits as an offset against 
research and development expenses in the Consolidated statement of proﬁt or loss.  
1.16
LEASES 
At the inception of a contract, the Group assesses whether a contract is, or contains, a lease. 
A contract is, or contains, a lease if the contract conveys the right to control the use of an identiﬁed 
asset for a period of time in exchange for consideration.  
Leases as a lessee  
Right of use assets represent a right to use an underlying asset for the lease term and operating 
lease liabilities represent an obligation to make lease payments arising from the lease. Lease liabilities 
with a term greater than one year and their corresponding right-of-use assets are recognised on the 
Consolidated statement of ﬁnancial position at the commencement date of the lease based on the 
present value of lease payments over the expected lease term. 
The Group recognises a right-of-use asset and a lease liability at the lease commencement date. 
The right-of-use asset is initially measured at cost, which comprises the initial amount of the lease 
liability adjusted for any lease payments made at or before the commencement date, plus any initial 
direct costs incurred, less any lease incentives received.  
The Group made an accounting policy election to not record a right-of-use asset or lease liability for 
leases with a term of one year or less. To date, the Group has not identiﬁed any material short-term 
leases, either individually or in the aggregate. 
As the Group's leases do not provide an implicit rate, the Group utilised the appropriate incremental 
borrowing rate, which is the rate incurred to borrow on a collateralised basis over a similar term as 
the lease an amount equal to the lease payments in a similar economic environment. The Group 
estimated the incremental borrowing rate based on the Group's currently outstanding credit facility 
as inputs to the analysis to calculate a spread, adjusted for factors that reﬂect the proﬁle of secured 
borrowing over the expected term of the lease.  
The Group allocates the consideration in the contract to each lease component on the basis of its 
relative stand-alone price and the aggregate stand-alone price of the non-lease components in 
accordance with the principles of IFRS 16. The Group calculated the stand-alone prices of the lease 
and non-lease components using ﬁnancial information readily available as part of its master services 
arrangement and other representative data. 
Notes to the Annual Report and Financial Statements 
continued
 
120 Orchard Therapeutics plc 
1
ACCOUNTING POLICIES continued 
1.15
TAXATION continued

The right-of-use asset is subsequently depreciated using the straight-line method from the 
commencement date to the earlier of the end of the lease term or the end of the useful life of the 
right-of-use asset. In addition, the right-of-use asset is periodically reduced by impairment losses, 
if any, and adjusted for certain remeasurements of the lease liability.  
The lease liability is initially measured at the present value of the lease payments that are not paid at 
the commencement date, discounted using the interest rate implicit in the lease or, if that rate cannot 
be readily determined, the Group's incremental borrowing rate.  
Lease payments included in the measurement of the lease liability comprise the following:  
–
ﬁxed payments, including in-substance ﬁxed payments 
–
variable lease payments that depend on an index or a rate, initially measured using the index or 
rate as at the commencement date  
–
lease payments in an optional renewal period if the Group is reasonably certain to exercise an 
extension option, and  
–
penalties for early termination of a lease unless the Group is reasonably certain not to terminate 
early. 
The lease liability is measured at amortised cost using the effective interest method. It is remeasured 
when there is a change in future lease payments arising from a change in an index or rate, there is 
a change in the Group's estimate of the amount expected to be payable under a residual value 
guarantee, if the Group changes its assessment of whether it will exercise a purchase, extension or 
termination option or if there is a revised in-substance ﬁxed lease payment.  
When the lease liability is remeasured in this way, a corresponding adjustment is made to the carrying 
amount of the right-of-use asset, to the extent that the right-of-use asset is reduced to nil, with any 
further adjustment required from the remeasurement being recorded in proﬁt or loss. 
Leases as a lessor 
When the Group acts as a lessor, it determines at lease inception whether each lease is a ﬁnance 
lease or an operating lease.  
To classify each lease, the Group makes an overall assessment of whether the lease transfers 
substantially all of the risks and rewards incidental to ownership of the underlying asset. If this is the 
case, then the lease is a ﬁnance lease; if not, then it is an operating lease. As part of this assessment, 
the Group considers certain indicators such as whether the lease is for the major part of the 
economic life of the asset.  
When the Group is an intermediate lessor, it accounts for its interests in the head lease and the sub-lease 
separately. It assesses the lease classiﬁcation of a sub-lease with reference to the right-of-use asset 
arising from the head lease, not with reference to the underlying asset. 
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 121
1
ACCOUNTING POLICIES continued 
1.16
LEASES continued

1
ACCOUNTING POLICIES continued 
1.17
NET LOSS PER SHARE 
Basic net loss per share is computed by dividing the net loss by the weighted average number of 
ordinary shares outstanding for the period. Diluted net loss is computed by adjusting net loss based 
on the potential impact of dilutive securities. Diluted net loss per share is computed by dividing the 
diluted net loss by the weighted average number of ordinary shares outstanding for the period, 
including potential dilutive ordinary shares. For the purpose of this calculation, outstanding options 
and unvested restricted shares are considered potential dilutive ordinary shares. Since the Group 
was in a loss position for all periods presented, basic net loss per share is the same as diluted net 
loss per share for all periods as the inclusion of all potential ordinary share equivalents outstanding 
would have been anti-dilutive. 
Share option and unvested shares from share plans and consulting agreements are considered to 
be ordinary share equivalents, but were not included in the computation of diluted net loss per 
ordinary share because to do so would have been anti-dilutive. 
1.18
EQUITY 
Share Capital and Share Premium 
Ordinary shares are classiﬁed as equity. The nominal value of the shares is recorded in share capital. 
Any excess proceeds received  for the issuance of ordinary shares over the nominal value is recorded 
in share premium. 
Incremental costs directly attributable to the issue of new shares or options are shown in share 
premium in equity as a deduction, net of tax, from the proceeds. 
Translation Reserve 
The translation reserve comprises all foreign exchange differences arising from the translation of the 
ﬁnancial statements of foreign operations. 
1.19
UK-ADOPTED IFRS NOT YET ADOPTED 
The following UK-adopted IFRSs have been issued but have not been adopted by the Group in these 
consolidated ﬁnancial statements. Their adoption is not expected to have a material effect on the 
ﬁnancial statements unless otherwise indicated: 
–
IFRS 17 Insurance Contracts 
–
Amendments to IAS 8 Accounting Policies, Changes in Accounting Estimates and Errors: 
Deﬁnition of accounting estimates  
–
Amendments to IAS 1 Presentation of  Financial Statements and IFRS Practice Statement 2 Making 
Materiality Judgements: Disclosure of  Accounting Policies  
–
Amendments to IAS 1 Presentation of  Financial Statements: Classiﬁcation of Liabilities as Current 
or Non-current 
–
Amendments to IAS 12 Income Taxes: Deferred Tax Related to Assets and Liabilities Arising from 
a Single Transaction  
–
Initial Application of IFRS 17 and IFRS 9 – Comparative Information (Amendments to IFRS 17) 
–
Amendments to IFRS 10 and IAS 28: Sale or Contribution of Assets between an Investor and its 
Associate or Joint Venture 
Notes to the Annual Report and Financial Statements 
continued
 
122 Orchard Therapeutics plc 

2
ACCOUNTING ESTIMATES AND JUDGEMENTS 
In preparing the ﬁnancial statements, management had made judgements and estimates that affect 
the application of the Group’s accounting policies and the reported amounts of assets and liabilities, 
income and expenses. Management have not identiﬁed any estimates or judgements which they 
believe are signiﬁcant and may present a signiﬁcant risk of material adjustment in the next 
ﬁnancial period. 
Estimates and underlying assumptions are reviewed on an ongoing basis. Revisions to estimates are 
recognised prospectively. 
Our signiﬁcant accounting policies are described in greater detail in Note 1 to our consolidated 
ﬁnancial statements in this Annual Report. 
Whilst there are no signiﬁcant estimates identiﬁed, other areas of estimation uncertainty have been 
identiﬁed as follows: 
A) EXPENSES, ACCRUALS AND PREPAYMENTS FOR CLINICAL 
RESEARCH ARRANGEMENTS 
The Group has entered into various research and development contracts with clinical research 
organisations (CROs), clinical manufacturing organisations (CMOs), research institutions and other 
vendors. The ﬁnancial terms of these agreements are subject to negotiation, vary from contract to 
contract and may result in uneven payment ﬂows. Payments under some of these contracts depend 
on factors such as the successful enrollment of patients and the completion of clinical trial milestones. 
When billing terms under these contracts do not coincide with the timing of when the work is 
performed, management is ﬁrst required to make estimates of the expense to be recognised in 
respect of the contracts such that the expense reﬂects the pattern of work performed.  This process 
involves reviewing open contracts and purchase orders, communicating with our personnel to identify 
services that have been performed on our behalf and estimating the level of service performed and 
the associated cost incurred for the service. 
Subsequently, management is required to calculate the associated accrual or prepayment balance 
for each contract, based on the difference between the cumulative amount expensed under the 
contract to date and the cumulative amount invoiced to date. Given the difﬁculty in estimating the 
stage of completion of a clinical trial, or with obtaining the required information from the CRO/CMO, 
this is considered an area of estimation uncertainty. 
B) IMPAIRMENT OF INTANGIBLE ASSETS 
Annually, the Group considers whether intangible assets are impaired. Where an indication of 
impairment is identiﬁed the estimation of recoverable value requires estimation of the recoverable 
value of the asset. This requires estimation of the value in use of the asset. 
The recoverable amounts of the intangible assets are a source of estimation uncertainty and 
determining this involved the use of assumptions around the potential cash ﬂows from the assets. 
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 123

2
ACCOUNTING ESTIMATES AND JUDGEMENTS continued 
C) VALUATION OF SHARE-BASED COMPENSATION 
We measure share-based awards granted to employees, non-employees and directors based on the 
fair value on the date of the grant and recognise compensation expense for those awards over the 
requisite service period, which is generally the vesting period of the respective award. Forfeitures 
are accounted for as they occur. Generally, we issue share-based awards in the form of stock options 
with only service-based vesting conditions. We have also issued share-based awards with 
performance-based vesting conditions for which the expense is recognised when achievement of 
such performance conditions becomes probable. 
The fair value of each share option is estimated on the date of grant using the Black-Scholes option 
pricing model. Until the completion of our initial public offering in November 2018, we had been a 
private company and lacked company-speciﬁc historical and implied volatility information for our 
shares. Therefore, we estimate our expected share price volatility based on the historical volatility of 
publicly traded peer companies and expect to continue to do so until such time as we have adequate 
historical data regarding the volatility of our own traded share price. The expected term of our share 
options has been determined utilising the “simpliﬁed method” for awards that qualify as “plain-vanilla” 
options.  
The risk-free interest rate is determined by reference to the U.S. Treasury yield curve in effect at the 
time of grant of the award for time periods approximately equal to the expected term of the award. 
Expected dividend yield is based on the fact that we have never paid cash dividends on our ordinary 
shares and do not expect to pay any cash dividends in the foreseeable future. 
D) RESEARCH AND DEVELOPMENT TAX CREDIT 
Each reporting period, management evaluates which tax relief programs the Group is expected to 
be eligible for and calculates a tax credit based on the amount of relevant expenditure that it expects 
to qualify under the programs, that it plans to submit a claim for, and it has reasonable assurance 
that the amount will ultimately be realised. Based on criteria established by HM Revenue and Customs 
(“HMRC”), management of the Group expects a proportion of expenditures being carried in relation 
to its pipeline research, clinical trials management and manufacturing development activities to be 
eligible for the research and development tax relief programs 
The Group has assessed its research and development activities and expenditures to determine 
whether the nature of the activities and expenditures will qualify for credit under the tax relief 
programs and whether the claims will ultimately be realised based on the allowable reimbursable 
expense criteria established by the U.K. government which are subject to interpretation. At each 
period end, the Group estimates the reimbursement available to the Group based on available 
information at the time. The Group is required to estimate the percentage of staff time allocated to 
each project as well as the percentage of some allowable costs. 
The Group recognises tax credits from the research and development incentives when the relevant 
expenditure has been incurred and there is reasonable assurance that the reimbursement will be 
received.  
Notes to the Annual Report and Financial Statements 
continued
 
124 Orchard Therapeutics plc 

3
REVENUE FROM CONTRACTS WITH CUSTOMERS  
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Product sales                                                                                                    20,610                         700 
Collaboration revenue                                                                                        2,045                         975 
Total                                                                                                                 22,655                      1,675 
(I)
PRODUCT REVENUE  
In the following table, revenue is disaggregated by product and primary geographical market.  
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Libmeldy                                                                                                           18,796                             – 
Strimvelis                                                                                                            1,814                         700 
Total product revenue                                                                                    20,610                         700 
Primary geographical markets                                                                                                                 
  Libmeldy                                                                                                                    
    United Kingdom                                                                                           6,322                             – 
    Italy                                                                                                              5,544                             – 
    France                                                                                                         3,883                             – 
    Germany                                                                                                      3,047                             – 
                                                                                                                         18,796                                
  Strimvelis                                                                                              
    Italy                                                                                                              1,814                         700 
Total product revenue                                                                                    20,610                         700 
As at 31 December 2022, the Group recognises in its consolidated statement of financial position the 
following revenue deduction and reserves associated with Libmeldy contracts: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Variable consideration and other deductions from revenue  
in the period recognised as a credit against trade receivables.                       4,390                             – 
Government rebate recognised as an other current liability                              2,300                             – 
                                                                                                                           6,690                             – 
(II) COLLABORATION REVENUE  
On 1 July 2021, the Group entered into a strategic collaboration with Pharming Group N.V. (“Pharming”) to 
research, develop, manufacture, and commercialize OTL-105, an investigational ex vivo autologous HSC 
gene therapy for the treatment of hereditary angioedema (HAE), a life-threatening rare disorder that causes 
recurring swelling attacks in the face, throat, extremities and abdomen (the “Collaboration Agreement”). 
Under the terms of the Collaboration Agreement, Pharming was granted worldwide rights to OTL-105 and 
will be responsible for clinical development, regulatory ﬁlings and commercialization of the investigational 
gene therapy, including associated costs. The Group will lead the completion of IND-enabling activities 
and oversee manufacturing of OTL-105 during preclinical and clinical development, which will be funded 
by Pharming. In addition, both the Group and Pharming will explore the application of non-toxic 
conditioning regimen for use with OTL-105 administration. 
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 125

3
REVENUE FROM CONTRACTS WITH CUSTOMERS continued 
The Group received an upfront payment of $10.0 million in cash from Pharming. The Group is also eligible 
to receive up to $189.5 million in development, regulatory and sales milestones as well as mid-single to 
low double-digit percentage royalty payments on future worldwide sales. 
The Group also entered into a Share Purchase Agreement with Pharming on 1 July 2021 (the “SPA”), 
pursuant to which the Group issued 1,227,738 ordinary shares to Pharming for total consideration of 
$7.5 million. The consideration is payment for the fair value of ordinary shares with a fair value of 
$4.1 million plus a $3.4 million premium on the fair value of the Group’s ordinary shares. The “Collaboration 
Agreement” and the “SPA” are referred to together as the “Pharming Agreements.” 
Accounting analysis 
At the commencement of the arrangement, two units of accounting were identiﬁed, which are the 
issuance of 1,227,738 of the Group’s ordinary shares as part of the SPA, and the license and 
collaboration agreement, which conveys the license and provides for the Group to provide research, 
development, manufacturing services for OTL-105. The Pharming Agreements were entered into 
concurrently as part of a single commercial objective and the Group considers them a single 
arrangement for accounting purposes. The total upfront payments of $17.5 million are comprised of 
$4.1 million attributed to the equity sold to Pharming and $13.4 million attributed to the Collaboration 
Agreement. 
The Group has concluded that the conveyance of the license for the HAE program and the provision of 
research, development, and manufacturing services for the HAE program represent a series of distinct 
services that are accounted for as a single performance obligation within the Collaboration Agreement. 
The Group determined that the transaction price includes: the $13.4 million attributed to the 
Collaboration Agreement and the variable consideration for estimated reimbursement payments at 
agreed upon contractual rates to be received from Pharming for the Group’s on-going research, 
development, and manufacturing services. The potential future variable consideration is associated 
with the reimbursement for research, development, and manufacturing services provided by the 
Group to Pharming at agreed upon contractual rates which is the only remaining unsatisﬁed 
performance obligation. The milestone payments included in the Collaboration Agreement are fully 
constrained as a result of the uncertainty regarding whether any of the associated milestones will 
be achieved. The Group re-evaluates the transaction price as of the end of each reporting period. 
The Group recognizes revenue associated with the performance obligation as the research, 
development, and manufacturing services are provided using an input method, based on the cumulative 
costs incurred compared to the total estimated costs expected to be incurred to satisfy the performance 
obligation. The transfer of control to the customer occurs over the time period that the research, 
development and manufacturing services are to be provided by the Group. Reimbursement for 
research, development, and manufacturing services are recognized as the costs are incurred consistent 
with the cost-to-cost method. The estimated costs associated with the remaining efforts required to 
complete the performance obligations may change which may impact revenue recognition and the 
Group regularly evaluates and, when necessary, updates the costs associated with the remaining 
efforts. Accordingly, revenue may ﬂuctuate from period to period due to revisions to estimated costs 
resulting in a change in the measure of progress for the performance obligation or if the transaction 
price changes due to inclusion of any milestone payments that become unconstrained. 
Notes to the Annual Report and Financial Statements 
continued
 
126 Orchard Therapeutics plc 

3
REVENUE FROM CONTRACTS WITH CUSTOMERS continued 
The following table summarizes research and development costs incurred and collaboration revenue 
recognized in connection with the Group’s performance under the Collaboration Agreement: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Reimbursement revenue                                                                                    1,776                         843 
Upfront and milestone payment revenue                                                              269                         132 
                                                                                                                           2,045                         975 
The Group had $0.5 million due from Pharming included in trade receivables as of 31 December 
2022 (2021: $0.8 million). 
As of 31 December 2022, the Group had contract liabilities of $11.3 million, of which $1.0 million was 
classiﬁed as current and $10.3 million was classiﬁed as long-term in the consolidated statement of 
ﬁnancial position. The deferred income balance represents the portion of the upfront payments received 
related to the performance obligation that remains partially unsatisﬁed as of 31 December 2022. The 
upfront and milestone payment revenue recognised in each year was previously included in the deferred 
income balance at the previous reporting date. 
4
SEGMENT INFORMATION 
The Group operates in a single segment focusing on researching, developing and commercializing 
potentially curative gene therapies. Consistent with its operational structure, its chief operating 
decision maker manages and allocates resources at a global, consolidated level. Therefore, results 
of the Group’s operations are reported on a consolidated basis for purposes of segment reporting.  
All material long-lived assets of the Group reside in the United States or United Kingdom. The Group 
had property and equipment, net, of $7.5 million and $0.6 million located in the United Kingdom and 
United States, respectively, as of 31 December 2022. The Group had property and equipment, net, 
of $3.6 million and $1.2 million located in the United Kingdom and United States, respectively, as of 
31 December 2021. The Group had right-of-use assets in the United States and United Kingdom of 
$ 2.3 million and $10.5 million, respectively as of 31 December 2022. The Group had right-of-use 
assets in the United States and United Kingdom of $3.1 million and $10.8 million, respectively as of 
31 December 2021. 
5
OPERATING LOSS 
                                                                                                                                                    2022                            2021 
                                                                                                                            Note                $000                            $000 
The following items have been included in operating loss:                                         
Depreciation – Property, plant and equipment                                   12           2,397                      2,152 
Depreciation – Right-of-use assets                                                     25           4,367                      6,560 
Amortisation of intangible assets                                                       13           9,225                    15,652 
Impairment loss on intangible assets                                                 13                  –                    40,358 
Loss on sale of property, plant and equipment                                 12               114                         166 
Cost of inventories included in cost of sales                                                     2,281                         148 
Net foreign exchange loss                                                                                24,344                      1,148 
Notes to the Annual Report and Financial Statements 
continued 
 
Orchard Therapeutics plc 127

6
LOSS PER SHARE 
The calculation of basic and diluted loss per share has been based on the following loss attributable 
to ordinary shareholders and the weighted-average number of ordinary shares outstanding. 
                                                                                                                                                    2022                            2021 
Loss attributable to ordinary shareholders ($000)                                        (153,870)               (198,275) 
Weighted-average number of ordinary shares                                       127,975,062           123,963,762 
Basic / diluted loss per share ($)                                                                        (1.20)                     (1.60) 
Since the Group was in a loss position for all periods presented, basic net loss per share is the same 
as diluted net loss per share for all periods as the inclusion of all potential ordinary share equivalents 
outstanding would have been anti-dilutive. 
The following securities, presented based on amounts outstanding at each period, are considered 
to be ordinary share equivalents, but were not included in the computation of diluted net loss per 
ordinary share because to do so would be anti-dilutive: 
                                                                                                                                                    2022                            2021 
Share options                                                                                            13,076,959             14,042,781 
Uninvested shares from share plan and consulting agreement                 2,253,199                  512,908 
                                                                                                                  15,330,158             14,555,689 
7
AUDITORS’ REMUNERATION 
During the year the Group obtained the following services from the Company’s auditors: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Fees payable to PricewaterhouseCoopers LLP and its associates: 
  Audit of the parent company and consolidated ﬁnancial statements            1,014                         986 
  Audit of subsidiaries pursuant to legislation                                                     317                         246 
  Audit-related assurance services                                                                     163                         123 
  Other services                                                                                                      5                             5 
Total fees paid to PricewaterhouseCoopers LLP                                          1,499                      1,360 
PricewaterhouseCoopers LLP (“PwC”) has been the Group's auditors beginning in ﬁscal year 2016. 
PwC operates procedures to safeguard against the possibility of its objectivity and independence 
being compromised. This includes PwC’s use of quality review partners, consultation with internal 
compliance teams and carrying out an annual independence procedure. PwC reports to the Audit 
Committee of the Company's Board of Directors (the “Audit Committee”) on matters including 
independence and non-audit fees on an annual basis. The PwC audit partner changes every 
ﬁve years. The amount charged by the external auditors for the provision of services during the 
twelve-month period under review is set forth above. The Audit Committee assesses PwC’s 
performance and is comfortable that PwC has operated effectively during the twelve-month period 
under review. Resolutions to reappoint PwC as the Group's auditors will be put to shareholders at 
the Company's 2023 Annual General Meeting (“AGM”).  
Notes to the Annual Report and Financial Statements 
continued
 
128 Orchard Therapeutics plc 

8
EMPLOYEE COSTS AND NUMBERS  
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Salaries and bonus                                                                                          40,095                    43,804 
Social security contributions                                                                              4,700                      3,209 
Other employee beneﬁts                                                                                    1,869                      2,419 
Contributions to deﬁned contribution plans                                                       1,618                      1,736 
Equity-settled share-based payments                                                              11,418                    19,900 
Termination beneﬁts                                                                                          1,781                             – 
                                                                                                                         61,481                    71,068 
The average number of persons employed by the Group (including directors) during the year was 
as follows: 
                                                                                                                                                    2022                            2021 
UK                                                                                                                          138                         146 
Offshore                                                                                                                   66                           92 
                                                                                                                              204                         238 
Transactions with key management personnel are contained within note 27. 
Director’s emoluments are contained within note 12 of the Parent Company ﬁnancial statements. 
9
FINANCE INCOME AND EXPENSE 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Finance income                                                                                                          
Interest income on debt securities measured at FVOCI                                    1,543                         412 
Interest income on lease receivable                                                                  1,037                      1,057 
                                                                                                                           2,580                      1,469 
Finance expense 
Interest expense on loan and borrowings                                                        (3,079)                   (2,497) 
Interest expense on lease liabilities                                                                  (2,260)                   (3,302) 
                                                                                                                          (5,339)                   (5,799) 
Net finance expense                                                                                       (2,759)                   (4,330) 
 
Orchard Therapeutics plc 129
Notes to the Annual Report and Financial Statements 
continued 

 
130 Orchard Therapeutics plc 
10 TAXATION 
RECOGNISED IN THE CONSOLIDATED STATEMENT OF PROFIT OR 
LOSS 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Current tax expense/(credit) 
Current year tax credit                                                                                      (4,125)                 (10,011) 
Adjustments for prior years                                                                               (1,962)                   (2,594) 
Current tax expense/(credit)                                                                             (6,087)                 (12,605) 
Deferred tax expense                                                                                                                                 
Origination and reversal of temporary differences                                           (1,957)                      (200) 
Adjustments for prior years                                                                                    (14)                    1,469 
Deferred tax (credit)/expense                                                                           (1,971)                    1,269 
Total tax credit                                                                                                   (8,058)                 (11,336) 
Current tax expense/(credit)                                                                                                                       
United Kingdom                                                                                                (7,000)                 (12,302) 
Overseas                                                                                                               913                       (303)    
                                                                                                                          (6,087)                 (12,605) 
Deferred tax (credit)/expense                                                                                                                     
United Kingdom                                                                                                        –                             – 
Overseas                                                                                                           (1,971)                    1,269 
                                                                                                                          (1,971)                    1,269 
Total tax credit                                                                                                   (8,058)                 (11,336) 
RECOGNISED DIRECTLY IN EQUITY 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Deferred tax on share-based payments recognised directly in equity                 399                  (14,305) 
RECONCILIATION OF EFFECTIVE TAX RATE 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Loss for the year                                                                                            (153,870)               (198,275) 
Total tax credit                                                                                                    8,058                    11,336 
Loss excluding taxation                                                                                 (161,928)               (209,611) 
Tax using the UK corporation tax rate of 19 % (2021: 19%)                          (30,766)                 (39,826) 
Effect of tax rates in foreign jurisdictions                                                              (69)                       116 
Change in tax rate                                                                                             (8,240)                 (38,785) 
Tax effect of:                                                                                                                                                
Non-deductible expenses                                                                                  1,324                       (485) 
Research and development tax credit and beneﬁt of other tax incentives      (5,909)                   (5,519) 
Employee share options                                                                                    1,626                      3,030 
Unrecognised deferred tax asset                                                                    35,465                    70,329 
Others                                                                                                               (1,489)                      (196) 
Total tax credit                                                                                                  (8,058)                 (11,336) 
Notes to the Annual Report and Financial Statements 
continued

10 TAXATION continued 
The Group's income tax credit for the year ended 31 December 2022, compared to the year ended 
31 December 2021, decreased primarily due to a reduction in the UK Research and Development 
Tax Credit the Group was able to claim for the year. 
During 2021, the U.K. Government announced that from 1 April 2023, the corporation tax rate would 
increase to 25%. This new law was substantively enacted on 24 May 2021.  
11 DEFERRED TAX ASSETS AND LIABILITIES  
Movement in recognised deferred tax balances during the year 
                                                                                                                                                                                          31 December 2022 
                                                                                                   Recognised in                                                                                                      
                                                                                                     Consolidated                                                                                                      
                                                                               1 January      statement of             Directly                                   Deferred    Deferred tax 
                                                                                        2022     profit or loss           in equity                   Net        tax assets         liabilities 
                                                                                        $000                   $000                  $000                $000                 $000                 $000 
Tax losses                                                                                   11                      (11)                       –                      –                       –                       – 
Research and development tax credit                                   587                     160                        –                  747                   747                       – 
Research and development capitalisation                                –                  2,285                        –               2,285                2,285                       – 
Share–based payments                                                        1,632                    (662)                   399               1,369                1,369                       – 
Accrued expenses                                                                   784                     171                        –                  955                   955                       – 
Fixed assets                                                                              (26)                     (46)                       –                   (72)                      –                   (72) 
Leases                                                                                      (232)                    101                        –                 (131)                      –                 (131) 
Other                                                                                          357                      (27)                       –                  330                   330                       – 
                                                                                       3,113                  1,971                    399               5,483                5,686                 (203) 
Movement in recognised deferred tax during the prior year 
                                                                                                                                                                                          31 December 2021 
                                                                                                   Recognised in                                                                                                      
                                                                                                     Consolidated                                                                                                      
                                                                               1 January      statement of             Directly                                   Deferred    Deferred tax 
                                                                                        2021     profit or loss           in equity                   Net        tax assets         liabilities 
                                                                                        $000                   $000                  $000                $000                 $000                 $000 
Tax losses                                                                                 357                    (346)                       –                     11                      11                       – 
Research and development tax credit                                       –                     587                        –                  587                   587                       – 
Research and development capitalisation                                –                         –                        –                      –                       –                       – 
Share–based payments                                                      17,234                 (1,297)             (14,305)              1,632                1,632                       – 
Accrued expenses                                                                1,001                    (217)                       –                  784                   784                       – 
Fixed assets                                                                                  2                      (28)                       –                   (26)                      –                   (26) 
Leases                                                                                      (225)                       (7)                       –                 (232)                      –                 (232) 
Other                                                                                          318                       39                        –                  357                   357                       – 
                                                                                     18,687                 (1,269)             (14,305)              3,113                3,371                 (258) 
 
Orchard Therapeutics plc 131
Notes to the Annual Report and Financial Statements 
continued 

 
132 Orchard Therapeutics plc 
11 DEFERRED TAX ASSETS AND LIABILITIES continued 
Unrecognised deferred tax assets  
For the years ended 31 December 2022 and 2021, the Group had cumulative U.K. net operating loss 
carry forwards of approximately $633.4 million and $506.2 million, respectively. U.K. losses not 
surrendered may be carried forward indeﬁnitely, subject to numerous utilization criteria and 
restrictions.  
For the years ended 31 December 2022 and 2021, the Group also had U.S. federal orphan drug tax 
credits of $0.7 million and $0.6 million, respectively, and U.S. state research and development tax 
credits of $2.2 million and $2.4 million.  The U.S. federal orphan drug tax credits expire in 2042, while 
the U.S. state research and development credits may be carried forward indeﬁnitely. 
A deferred tax asset is recognised only to the extent that it is probable that future taxable proﬁts will 
be available against which the temporary difference can be utilised. 
In measuring the Group’s deferred tax assets, the Group considers all available evidence, both 
positive and negative, to determine whether, based on the weight of that evidence, it is probable that 
future taxable proﬁts will be available against which the temporary difference can be utilised. 
Judgment is required in considering the relative impact of the negative and positive evidence, and 
weight given to each category of evidence is commensurate with the extent to which it can be 
objectively veriﬁed.  
Management has considered the Group’s history of cumulative net losses in the U.K., along with 
estimated future taxable income and has concluded that it is more likely than not that the Group will 
not realize the beneﬁts of its U.K. deferred tax assets and U.S. state research and development tax 
credits. Accordingly, no deferred tax asset is recognised in respect of these. 
Notes to the Annual Report and Financial Statements 
continued

 
Orchard Therapeutics plc 133
12 PROPERTY, PLANT AND EQUIPMENT 
                                                                              Leasehold     Furniture &       Computer                 Lab                         
                                                                       improvements           fixtures      equipment      equipment                Total 
                                                                                        $000                $000                $000                $000                $000 
Cost 
Balance at 1 January 2021                              2,521              304           1,066           5,114           9,005 
Additions                                                              51                   –           1,075           1,237           2,363 
Disposals                                                             (51)                 –               (43)            (237)            (331) 
Foreign exchange movements                            (21)                (1)              (10)              (80)            (112) 
Balance at 31 December 2021                       2,500              303           2,088           6,034         10,925 
Balance at 1 January 2022                              2,500              303           2,088           6,034         10,925 
Additions                                                         4,072                                   210           2,128           6,410 
Disposals                                                        (1,246)              (71)              (52)                 –          (1,369) 
Foreign exchange movements                          (257)                (6)              (93)            (681)         (1,037) 
Balance at 31 December 2022                       5,069              226           2,153           7,481         14,929 
Depreciation and impairment 
Balance at 1 January 2021                              1,190              111              262           2,661           4,224 
Charge for the year                                            644                72              354           1,082           2,152 
Disposals                                                             (28)                 –               (25)              (95)            (148) 
Foreign exchange movements                            (17)                (1)                (3)              (49)              (70) 
Balance at 31 December 2021                       1,789              182              588           3,599           6,158 
Balance at 1 January 2022                              1,789              182              588           3,599           6,158 
Charge for the year                                            648                64              636           1,049           2,397 
Disposals                                                        (1,128)              (65)              (29)                 –          (1,222) 
Foreign exchange movements                           (111)                (5)              (28)            (398)            (542) 
Balance at 31 December 2022                       1,198              176           1,167           4,250           6,791 
Net book value 
At 1 January 2021                                           1,331              193              804           2,453           4,781 
At 31 December 2021                                        711              121           1,500           2,435           4,767 
At 31 December 2022                                    3,871                50              986           3,231           8,138 
Notes to the Annual Report and Financial Statements 
continued 

 
134 Orchard Therapeutics plc 
13 INTANGIBLE ASSETS 
                                                                                                                                                                                Licenses 
                                                                                                                                                                                        $000 
Cost 
Balance at 1 January 2021                                                                                                           164,719 
Additions                                                                                                                                           1,253 
Effect of movements in foreign exchange                                                                                       (1,912) 
Balance at 31 December 2021                                                                                                     164,060 
Balance at 1 January 2022                                                                                                           164,060 
Effect of movements in foreign exchange                                                                                     (16,502) 
Balance at 31 December 2022                                                                                                     147,558 
Amortisation and impairment 
Balance at 1 January 2021                                                                                                             44,520 
Amortisation for the year                                                                                                                 15,652 
Impairment charge                                                                                                                         40,358 
Effect of movements in foreign exchange                                                                                           122 
Balance at 31 December 2021                                                                                                     100,652 
Balance at 1 January 2022                                                                                                           100,652 
Amortisation for the year                                                                                                                   9,225 
Effect of movements in foreign exchange                                                                                     (10,611) 
Balance at 31 December 2022                                                                                                       99,266 
Net book value 
At 1 January 2021                                                                                                                         120,199 
At 31 December 2021 and 1 January 2022                                                                                    63,408 
At 31 December 2022                                                                                                                    48,292 
Intangible assets comprise capitalised upfront payments and milestone payments to acquire license 
intangibles from external parties in relation to both products in development and approved products. 
IMPAIRMENT 
In March 2022, the Group announced a new strategic plan and restructuring, which included 
reducing its investment in the future development of OTL-102 for treatment of X-CGD, OTL-103 for 
treatment of WAS and Strimvelis. As a result of this announcement, the Group recorded an 
impairment of $40.4 million in 2021 against licenses for X-CGD, X-SCID, OTL-103, WAS and Strimvelis. 
No impairment losses were recognised in 2022. 
Notes to the Annual Report and Financial Statements 
continued

 
Orchard Therapeutics plc 135
13 INTANGIBLE ASSETS continued 
AMORTISATION AND IMPAIRMENT CHARGE 
The amortisation and impairment charge are recognised in the following line items in the Consolidated 
statement of proﬁt or loss: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Research and development expense                                                                 9,225                    56,010 
14 SUBSIDIARY UNDERTAKINGS 
The table below provides details of the Company’s subsidiary undertakings as at 31 December 2022. 
                                                                                      Class of              Proportion                                                           
                                                                                      shareholding                held      Nature of business 
Orchard Therapeutics (Europe) Limited           Ordinary                100%     Research and development 
Orchard Therapeutics North America              Ordinary                100%      
Orchard Therapeutics (Netherlands) B.V         Ordinary                100%      
Orchard Therapeutics (France) SAS                Ordinary                100% 
Orchard Therapeutics (Italy) S.r.l                      Ordinary                100% 
Orchard Therapeutics (Germany) GmbH         Ordinary                100% 
Orchard Therapeutics (Switzerland) GmbH     Ordinary                100% 
Orchard Therapeutics (Sweden) AB                Ordinary                100%     
 
The following table outlines the country of incorporation and registered ofﬁce of each of the 
subsidiary undertakings: 
                                                                                      Country of                                                                                       
 
                                                                                      incorporation             Registered office 
Orchard Therapeutics (Europe) Limited           United Kingdom    245 Hammersmith Road, 3rd Floor, 
London, W6 8PW United Kingdom 
Orchard Therapeutics North America              United States         101 Seaport Blvd., Boston,  
MA 02210, United States 
Orchard Therapeutics (Netherlands) B.V         Netherlands           Basisweg 10, 1043 AP, Amsterdam, 
Netherlands 
Orchard Therapeutics (France) SAS                France                    23 rue du Roule 75001, Paris, France 
Orchard Therapeutics (Italy) S.r.l                      Italy                        Largo Guido, Donegani 2 Cap 20121, 
Milano (Ml), Italy 
Orchard Therapeutics (Germany) GmbH         Germany                TRIBES Dusseldorf GAP,  
Graf-Adolf-Platz 15, 40213 
Dusseldorf, Germany 
Orchard Therapeutics (Switzerland) GmbH     Switzerland            KD Zug-Treuhand AG Untermuli  
7 6300 Zug, Switzerland 
Orchard Therapeutics (Sweden) AB                Sweden                  c/o (Intertrust Sweden) AB, 
                                                                                                        Norra Vallgatan 70, 211 22 Malmo, 
                                                                                                        Sweden 
All outstanding liabilities of Orchard Therapeutics (Europe) Limited as at 31 December 2022 have 
been provided with a parent company guarantee under s.479C of the Companies Act 2006. Their 
individual ﬁnancial statements for the year ended 31 December 2022 are therefore entitled to 
exemption from audit under s.479A of the Companies Act 2006.
Selling, general and 
administrative
Notes to the Annual Report and Financial Statements 
continued 

15 SHORT-TERM INVESTMENTS 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Current 
U.S. government securities                                                                                 1,984                             – 
Corporate bonds                                                                                              25,475                    94,794 
Commercial paper                                                                                            47,867                    69,401 
                                                                                                                         75,326                  164,195 
Investments in commercial paper have ﬁxed coupon rates at 1.1% - 5.1% (2021: 0.1–0.3%) and 
mature between 1 January 2023 and 31 August 2023 (2021: 1 January 2022 and 30 November 2022). 
Investments in corporate bonds have ﬁxed coupon rates at 0.4% - 5.7% (2021: 0.2–3.2%) and mature 
between 1 January 2023 and 31 October 2024 (2021: 1 January 2022 and 31 October 2023). 
16 INVENTORIES 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Raw materials                                                                                                        492                      1,719 
Work in progress                                                                                                2,906                         296 
                                                                                                                           3,398                      2,015 
Included within inventories is $nil (2021: $nil) expected to be recovered in more than 12 months. 
The Group recognised $2,281,000 (2021: $148,000) of inventories as an expense within cost of sales 
during the year. Inventory write-offs in the year amounted to $nil (2021: $nil). The write-down of 
inventories to net realisable value amounted to $nil (2021: $nil). 
17 TRADE AND OTHER RECEIVABLES 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Amounts due within one year 
Trade receivables                                                                                               8,467                      1,480 
Prepaid external research and development expenses                                       881                      2,438 
Other prepayments                                                                                            1,817                      6,128 
VAT receivable                                                                                                    1,077                      1,169 
Construction deposit                                                                                                 –                      7,909 
Other receivables                                                                                               2,706                      3,311 
                                                                                                                         14,948                    22,435 
Amounts due in more than one year 
Deposits                                                                                                             1,048                      1,404 
Restricted cash                                                                                                  4,215                      4,266 
Other receivables                                                                                                  462                         693 
                                                                                                                           5,725                      6,363 
                                                                                                                         20,673                    28,798 
 
136 Orchard Therapeutics plc 
Notes to the Annual Report and Financial Statements 
continued

17 TRADE AND OTHER RECEIVABLES continued 
RESTRICTED CASH 
Cash and cash equivalents that are restricted as to withdrawal or use under the terms of certain 
contractual agreements are recorded as restricted cash on the Group's consolidated statement of 
ﬁnancial position. The Group has an outstanding letter of credit for $3.0 million associated with a 
lease and is required to hold this amount in a standalone bank account as of 31 December 2022 
(2021: $3.0 million). The Group is also contractually required to maintain a cash collateral account 
associated with corporate credit cards and other leases in the amount of $1.2 million as of 
31 December 2022 (2021: $1.3 million). 
The Group includes the restricted cash balance in cash and cash equivalents when reconciling 
beginning-of-period and end-of-period total amounts shown on the consolidated statement of cash 
ﬂows. 
18 CASH AND CASH EQUIVALENTS 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Cash deposits held at bank                                                                             41,263                    14,308 
Money market funds                                                                                           1,239                    21,085 
Government bonds                                                                                             5,200                      7,321 
Corporate bonds                                                                                                6,600                             – 
Commercial papers                                                                                          14,122                    13,198 
Cash and cash equivalents per statement of ﬁnancial position                      68,424                    55,912 
Restricted cash                                                                                                  4,215                      4,266 
Cash and cash equivalents per cash ﬂow statement                                      72,639                    60,178 
19 INTEREST-BEARING LOANS AND BORROWINGS 
This note provides information about the contractual terms of the Group’s interest-bearing loans and 
borrowings, which are measured at amortised cost. For more information about the Group’s exposure 
to interest rate and foreign currency risk, see note 24. 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Non-current liabilities 
Term Loan                                                                                                         22,991                    32,086 
Lease liabilities                                                                                                 19,246                    19,278 
                                                                                                                         42,237                    51,364 
Current liabilities 
Term Loan                                                                                                           9,429                         786 
Lease liabilities                                                                                                   6,424                      7,335 
                                                                                                                         15,853                      8,121 
                                                                                                                         58,090                    59,485 
 
Orchard Therapeutics plc 137
Notes to the Annual Report and Financial Statements 
continued 

 
138 Orchard Therapeutics plc 
19 INTEREST-BEARING LOANS AND BORROWINGS continued 
TERMS AND REPAYMENT SCHEDULE 
The terms and conditions of outstanding loans are as follows. 
                                                                                                                                                         Carrying         Carrying  
                                                                                                                                                           amount           amount 
                                                                                        Maturity                       Interest                      2022                2021 
                                                              Currency                 date                             rate                      $000                $000 
Term loan                                           USD            2026       LIBOR+5.95%              32,665         33,203 
Lease liabilities                                  USD       2023-30             8.6%-9.6%              14,508         16,264 
Lease liabilities                                  GBP       2023-32                    9.60%                6,151           1,021 
Lease liabilities                                  EUR            2024                    8.00%                 5,011           9,328 
                                                                                                                                   58,335         59,816 
Less: unamortised debt issue costs                                                                              (245)            (331) 
Total interest-bearing liabilities                                                                                   58,090         59,485 
During the year ended 31 December 2022, the Group recognised $3.1 million of interest expense 
related to the bank loan (2021: $2.5 million). The effective annual interest rate as of 31 December 
2022 on the outstanding debt under the Term Loan was approximately 9.2% (2021: 8.4%). 
TERM LOAN 
In May 2019, the Group entered into a senior term facilities agreement, which was amended in April 
2020 (the “Original Credit Facility”) with MidCap Financial (Ireland) Limited (“MidCap Financial”), as 
agent, and additional lenders from time to time (together with MidCap Financial, the “Lenders”), to 
borrow up to $75.0 million in term loans. 
In May 2021, the Group amended and restated the Original Credit Facility (the “Amended Credit 
Facility”). Under the Amended Credit Facility, the Lenders agreed to make term loans available to 
the Group in the aggregate amount of $100.0 million, including increasing the principal on the initial 
term loan to $33.0 million, from $25.0 million. To date, the Group has borrowed $33.0 million under 
the amended initial term loan. 
The remaining $67.0 million under the Amended Credit Facility may be drawn down in the form of a 
second and third term loan, the second term loan being a $33.0 million term loan available no earlier 
than 1 July 2022 and no later than 1 July 2023 upon certain regulatory approvals and evidence of 
the Group having $100 million in cash and cash equivalent investments; and the third term loan being 
a $34.0 million term loan available no earlier than 1 July 2023 and no later than 1 July 2024 upon 
evidence of the Group having $100 million in cash and cash equivalent investments and attaining a 
pre-speciﬁed trailing 12-month revenue target. 
Each term loan under the Amended Credit Facility bears interest at an annual rate equal to 5.95% plus 
LIBOR. The Group is required to make interest-only payments on the term loan for 18 months following 
the date of the Amended Credit Facility, unless the Group is eligible for the second tranche, in which 
case the Group may elect to make interest-only payments for 30 months following the date of the 
Amended Credit Facility. The term loans under to the Amended Credit Facility begin amortizing on either 
the 18-month or the 30-month anniversary of the Amended Credit Facility (as applicable), with equal 
monthly payments of principal plus interest to be made by the Group to the Lenders in consecutive 
monthly instalments until the loan maturity date. In addition, a ﬁnal payment of 3.5% of the principal is 
due on the loan maturity date. The Group is accruing the ﬁnal payment amount of $1.2 million associated 
with the ﬁrst term loan of the Amended Credit Facility, to outstanding debt by charges to interest expense 
using the effective-interest method from the date of issuance through the loan maturity date. 
Notes to the Annual Report and Financial Statements 
continued

19 INTEREST-BEARING LOANS AND BORROWINGS continued 
The Amended Credit Facility includes afﬁrmative and negative covenants. The afﬁrmative covenants 
include, among others, covenants requiring the Group to maintain their legal existence and 
governmental approvals, deliver certain ﬁnancial reports, maintain insurance coverage, maintain 
property, pay taxes, satisfy certain requirements regarding accounts and comply with laws and 
regulations. The negative covenants include, among others, restrictions on the Group transferring 
collateral, incurring additional indebtedness, engaging in mergers or acquisitions, paying dividends 
or making other distributions, making investments, creating liens, amending material agreements and 
organizational documents, selling assets, changing the nature of the business and undergoing a 
change in control, in some cases subject to certain exceptions. The Group is also subject to an 
ongoing minimum cash ﬁnancial covenant in which the Group must maintain unrestricted cash in an 
amount not less than $20.0 million following the utilization of the second term loan and not less than 
$35.0 million following the utilization of the third term loan. 
In January 2023, the Group again amended and restated the credit facility to change from LIBOR to 
Secured Overnight Financing Rate (SOFR) The newly amended facility bears a variable interest rate 
of 5.95% above SOFR plus 0.10% per annum, plus a ﬁnal payment equal to 3.5% of the principal 
borrowed under the Amended Credit Facility. 
CHANGES IN LIABILITIES FROM FINANCING ACTIVITIES 
                                                                                                               Term                          Lease  
                                                                                                                loan                     liabilities                            Total 
                                                                                                                $000                            $000                            $000 
Balance at 1 January 2022                                              32,872                    26,613                    59,485 
Changes from financing cash flows 
Repayment of borrowings                                                     (786)                           –                       (786) 
Payment of lease liabilities                                                         –                    (5,218)                   (5,218) 
Total changes from financing cash flows                         (786)                   (5,218)                   (6,004) 
The effect of changes in foreign exchange rates                       –                       (820)                      (820) 
Other changes 
New leases                                                                                 –                      6,248                      6,248 
Lease modiﬁcation and remeasurements                                  –                    (1,153)                   (1,153) 
Capitalised borrowing costs                                                     86                             –                           86 
Interest expense                                                                  2,896                      2,260                      5,156 
Interest paid presented as ﬁnancing cashﬂow                  (2,648)                   (2,260)                   (4,908) 
Total other changes                                                              334                      5,095                      5,429 
Balance at 31 December 2022                                        32,420                    25,670                    58,090 
 
Orchard Therapeutics plc 139
Notes to the Annual Report and Financial Statements 
continued 

 
140 Orchard Therapeutics plc 
19 INTEREST-BEARING LOANS AND BORROWINGS continued 
CHANGES IN LIABILITIES FROM FINANCING ACTIVITIES 
                                                                                                               Term                         Lease  
                                                                                                                loan                     liabilities                            Total 
                                                                                                                $000                            $000                            $000 
Balance at 1 January 2021                                              25,065                    33,102                    58,167 
Changes from financing cash flows 
Proceeds from loans and borrowings                                 7,375                             –                      7,375 
Repayment of borrowings                                                          –                             –                             – 
Payment of lease liabilities                                                         –                    (5,523)                   (5,523) 
Total changes from financing cash flows                        7,375                    (5,523)                    1,852 
The effect of changes in foreign exchange rates                       –                       (968)                      (968) 
Other changes 
New leases                                                                                  –                         535                         535 
Lease modiﬁcations and remeasurements                                 –                       (533)                      (533) 
Capitalised borrowing costs                                                     10                             –                           10 
Interest expense                                                                  2,525                      3,302                      5,827 
Interest paid presented as ﬁnancing cashﬂow                  (2,103)                   (3,302)                   (5,405) 
Total other changes                                                              432                             2                         434 
Balance at 31 December 2021                                         32,872                    26,613                    59,485 
20 TRADE AND OTHER PAYABLES 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Current liabilities 
Trade payables                                                                                                   9,318                    10,008 
Accrued external research and development expenses                                 11,230                      9,273 
Accrued payroll and related expenses                                                            12,312                      8,521 
Accrued milestone payments                                                                                  85                      2,058 
Accrued professional fees                                                                                 2,263                         854 
Accrued other                                                                                                    2,823                      2,941 
Accrued government rebates                                                                            2,300                             – 
                                                                                                                         40,331                    33,655 
Non-current liabilities 
Other payables                                                                                                   6,616                      2,607 
                                                                                                                           6,616                      2,607 
                                                                                                                         46,947                    36,262 
Other payables consists of Royalty payments on product sales due in more than one year and 
deposits received from tenants on leases where the Group is a lessor.  
Notes to the Annual Report and Financial Statements 
continued

 
Orchard Therapeutics plc 141
21 EMPLOYEE BENEFITS 
DEFINED CONTRIBUTION PLANS 
The Group makes contributions to private deﬁned contribution pension plans on behalf of its 
employees. The Group matches its employee contributions up to six percent of each employee’s 
annual salary based on the jurisdiction the employees are located. The Group paid $1.6 million in 
matching contributions for the year 31 December 2022 (2021: $1.7 million). 
SHARE-BASED PAYMENTS 
The Group maintains four equity compensation plans; the Orchard Therapeutics Limited Employee 
Share Option Plan with Non-Employee Sub-Plan and U.S. Sub-Plan (the “2016 Plan”), the Orchard 
Therapeutics plc 2018 Share Option and Incentive Plan (the “2018 Plan”), the 2018 Employee Share 
Purchase Plan (the “ESPP”), and the 2020 Inducement Equity Plan (the “Inducement Plan”). 
The board of directors has determined not to make any further awards under the 2016 plan. As of 
31 December 2022, there were 5,341,768 shares available for grant under the 2018 Plan, 721,500 
available for grant under the Inducement Equity Plan, and 627,677 shares available for grant under 
the ESPP. 
The numbers of options and restricted stock units, the weighted average grant date fair values per 
stock option and per share, and the weighted average exercise prices are all shown below on a per 
ordinary share basis. As at 31 December 2022 the parent company’s ADSs that are listed on the 
NASDAQ Capital Market each represent one ordinary share. Following the ratio change on 10 March 
2023 (see note 28) each ADS represents ten ordinary shares. 
On 4 October 2022, the Group’s Compensation Committee approved a one-time stock option 
repricing for certain previously granted and still outstanding options held by the Group’s employees 
and certain independent contractors which had an exercise price above $1.25. As a result of the 
repricing, the exercise price for 7,946,139 vested and unvested options outstanding was lowered to 
$0.58. No other terms of the repriced options were modiﬁed and the repriced stock will continue to 
vest according to their original vesting schedules and will retain their original expiration dates. The 
repricing resulted in one-time stock-based compensation expense of $0.9 million related to vested 
options and an incremental stock option expense of $0.8 million related to unvested options which 
will be amortized on a straight-line basis over the remaining vesting period of those options. 
Measurement of fair value 
The fair value of each stock option award is determined on the date of grant using the Black-Scholes 
option-pricing model. The risk-free interest rate is based on a U.S. treasury instrument whose term is 
consistent with the expected term of the stock options. The expected term of the Company’s options 
has been determined utilising historical data. Until the completion of the parent company's initial 
public offering in November 2018, the parent company had been a private company and lacked 
company-speciﬁc historical and implied volatility information for the shares. Therefore, management 
estimate the expected share price volatility based on both the historical volatility of publicly traded 
peer companies and our own volatility history. It is expected to continue to do so until such time as 
we have adequate historical data regarding the volatility of our own traded share price. The peer 
companies are taken from a representative group of companies with similar characteristics to the 
Company, including those in the early stages of product development with a similar and therapeutic 
focus. For these analyses, the Company selects companies with comparable characteristics to its 
own including enterprise value, risk proﬁles, position within the industry, and with historical share 
price information sufﬁcient to meet the expected term of the options. The relevant data used to 
determine the value of stock option awards are as follows: 
Notes to the Annual Report and Financial Statements 
continued 

 
142 Orchard Therapeutics plc 
21 EMPLOYEE BENEFITS continued 
                                                                                                                                                        2022                        2021 
Risk-free interest rate                                                                                  1.3% - 4.2%        0.4% - 1.5% 
Expected term (in years)                                                                                  3.1 - 7.7              5.0 - 7.0 
Expected volatility                                                                                   70.8% - 80.4%    70.4% - 76.8% 
Expected dividend rate                                                                                         0.0%                   0.0% 
SHARE OPTIONS 
The number and weighted average exercise prices of share options are as follows: 
                                                                                                                                           Weighted                   Weighted  
                                                                                                                                              average                      average  
                                                                                                                                             exercise                  remaining  
                                                                                                                                                   price                     contract  
                                                                                                            Shares                    per share                               life 
                                                                                                          Number                                  $                          Years 
Outstanding at 1 January 2022                                  17,300,740                        6.57 
Granted during the year                                               4,600,154                        0.56 
Exercised during the year                                              (699,234)                           – 
Forfeited during the year                                             (4,777,493)                      6.81 
Outstanding at 31 December 2022                            16,424,167                        1.56                        7.38 
Exercisable as at 31 December 2022                          9,212,552                        2.28                        6.26 
                                                                                                                                           Weighted                   Weighted  
                                                                                                                                              average                      average  
                                                                                                                                             exercise                  remaining  
                                                                                                                                                   price                     contract  
                                                                                                            Shares                    per share                               life 
                                                                                                          Number                                  $                          Years 
Outstanding at 1 January 2021                                  13,895,643                        7.96                        7.16 
Granted during the year                                               8,489,856                        4.75 
Exercised during the year                                           (1,727,254)                      1.59 
Forfeited during the year                                             (3,357,505)                    10.30 
Outstanding at 31 December 2021                            17,300,740                        6.57                        7.82 
Exercisable as at 31 December 2021                          7,880,668                        6.90                        6.26 
The options outstanding at the year-end have an exercise price in the range of nil to $15.09. 
RESTRICTED SHARE UNITS 
CEO Award 
The Group granted 195,000 performance-based Restricted Share Units (‘RSUs’) with a total grant 
date fair value of $1.4 million to its Chief Executive Ofﬁcer, Bobby Gaspar, M.D., Ph.D., in April 2020. 
The award vests on 2 January 2024 as to 1/3 of the award for each of the ﬁrst three to occur of four 
milestones, if each such milestone is achieved by the Company on or before 31 December 2023 and 
Dr. Gaspar remains continuously employed with the Group through to 2 January 2024. The milestones 
relate to the achievement of speciﬁc clinical and regulatory milestones. No performance-based share 
unit performance conditions associated with the CEO award were deemed probable and none vested 
during the year ended 31 December 2022 (2021: none). 
Notes to the Annual Report and Financial Statements 
continued

21 EMPLOYEE BENEFITS continued 
Time-based restricted share units 
Time-based restricted share units vest in equal annual instalments over a three-year period. During 
the year ended 31 December 2022, the total fair value of time-based RSU’s that vested was 
$0.3 million (2021: $0.3 million). 
                                                                                                                                                                               Weighted  
                                                                                                                                                                        average grant  
                                                            Performance-                                                                Total            date fair value  
                                                               based RSUs     Time-based RSUs                          RSUs                    per share 
                                                                      Number                      Number                      Number                                  $ 
Outstanding at 1 January 2022         195,000                  123,333                  318,333                        6.41 
Granted during the year                               –               2,192,988               2,192,988                        0.46 
Vested during the year                                 –                  (55,001)                 (55,001)                      5.58 
Forfeited during the year                              –                (392,444)               (392,444)                      0.60 
Outstanding at 31 December 2022    195,000               1,868,876               2,063,876                        0.55 
                                                                                                                                                                               Weighted  
                                                                                                                                                                        average grant  
                                                            Performance-                                                                Total            date fair value  
                                                               based RSUs     Time-based RSUs                          RSUs                    per share 
                                                                      Number                      Number                      Number                                  $ 
Outstanding at 1 January 2021         464,000                  180,000                  644,000                        8.75 
Granted during the year                               –                    47,500                    47,500                        4.94 
Vested during the year                       (89,667)                 (41,667)               (131,334)                      9.94 
Lapsed during the year                    (179,333)                 (62,500)               (241,833)                    10.32 
Outstanding at 31 December 2021    195,000                  123,333                  318,333                        6.41 
EXPENSE RECOGNISED IN PROFIT OR LOSS 
                                                                                                                                                    2022                            2021 
                                                                                                                                                   $’000                           $’000 
Research and development                                                                               4,962                      7,754 
Selling, general and administrative                                                                    6,456                    12,146 
                                                                                                                         11,418                    19,900 
By award type 
Restricted share units                                                                                            838                         550 
Share options                                                                                                   10,580                    19,350 
                                                                                                                         11,418                    19,900 
 
Orchard Therapeutics plc 143
Notes to the Annual Report and Financial Statements 
continued 

 
144 Orchard Therapeutics plc 
22 PROVISIONS 
                                                                                                      Strimvelis             Dilapidations 
                                                                                               loss provision                    provision                            Total 
                                                                                                                $000                            $000                            $000 
Balance at 1 January 2021                                                  4,482                         433                      4,915 
Provisions used during the year                                         (1,037)                            –                    (1,037) 
Movement in foreign exchange rates                                      (26)                          (5)                        (31) 
Balance at 31 December 2021                                            3,419                         428                      3,847 
Balance at 1 January 2022                                                  3,419                         428                      3,847 
Provisions made during the year                                                –                      1,160                      1,160 
Provisions used during the year                                            (274)                           –                       (274) 
Movement in foreign exchange rates                                    (329)                        (75)                      (404) 
Provisions released during the year                                   (2,816)                           –                    (2,816) 
Balance at 31 December 2022                                                   –                      1,513                      1,513 
Non-current                                                                                 –                         908                         908 
Current                                                                                        –                         605                         605 
                                                                                                   –                      1,513                      1,513 
In April 2018, the Group acquired Strimvelis (ADA-SCID), OTL-200 (MLD), OTL-103 (WAS) and OTL-
300 (TDT) from Glaxo Group Limited and GlaxoSmithKline Intellectual Property Development LTD 
(together, GSK) (the “GSK Transaction”). As part of the GSK transaction, the Group is required to 
maintain commercial availability of Strimvelis in the European Union until such time that an alternative 
gene therapy is available. Strimvelis is not currently expected to generate sufﬁcient cash ﬂows to 
overcome the costs of maintaining the product and certain regulatory commitments; therefore, the 
Group recorded a provision associated with the loss contract of $18.4 million in 2018, the ‘Strimvelis 
loss provision’. 
The provision is an estimate of the expected future losses associated with maintaining the commercial 
availability of Strimvelis for the required period. The amortization of the provision is recorded as a 
reduction to research and development expense. 
The Group announced its intention to discontinue its investment in Strimvelis in March 2022 and seek 
alternatives. The future cash ﬂows were reassessed and it was concluded that no further net cash 
outﬂow was to be expected following an agreement with a third party to cover ongoing costs. 
Notes to the Annual Report and Financial Statements 
continued

 
Orchard Therapeutics plc 145
23 CAPITAL AND RESERVES 
SHARE CAPITAL 
                                                                                                                                              Ordinary shares 
In thousands of shares                                                                                                             2022                            2021 
In issue at 1 January                                                                                      125,674                    98,283 
Issued for share options                                                                                     1,268                      2,024 
Issued as part of a consulting agreement                                                                5                           23 
Issued as part of a collaboration agreement                                                           –                      1,228 
Issuance of shares from private placement                                                             –                    24,116 
In issue at 31 December – fully paid                                                             126,947                  125,674 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Ordinary shares allotted and fully paid, £0.10 nominal value                          16,409                    16,243 
Each holder of ordinary shares is entitled to one vote per ordinary share and to receive dividends 
when and if such dividends are recommended by the board of directors and declared by the 
shareholders. 
SHARE PREMIUM 
Share premium represents the excess paid for the issuance of ordinary shares, over and above their 
nominal value. 
SHARE BASED PAYMENT RESERVE 
The share-based payment reserve arises due to the share options issued by the group to its 
employees within the wider Group. 
TRANSLATION RESERVE 
The translation reserve comprises all foreign exchange differences arising from the translation of the 
ﬁnancial statements of foreign operations. 
FAIR VALUE RESERVE 
The fair value reserve includes the cumulative net change in the fair value of debt securities measured 
at FVOCI. 
Notes to the Annual Report and Financial Statements 
continued 

 
146 Orchard Therapeutics plc 
24 FINANCIAL INSTRUMENTS 
24 (A) FAIR VALUES OF FINANCIAL INSTRUMENTS 
Fair values of financial instruments 
The following table shows the carrying amounts and fair value of ﬁnancial assets and ﬁnancial 
liabilities, including their levels in the fair value hierarchy. It does not include fair value for ﬁnancial 
assets and ﬁnancial liabilities not measured at fair value if the carrying amount is reasonable 
approximation of fair value. 
The Group believes that the carrying amount reﬂected on the consolidated statement of ﬁnancial 
position for cash and cash equivalents, trade and other receivables, and trade and other payables 
approximate fair value due to their short-term maturities. The carrying value of the Group’s 
outstanding Term Loan and lease liabilities approximates fair value (a Level 2 fair value measurement), 
as they reﬂect interest rates currently available to the Group. There are therefore no ﬁnancial liabilities 
which require inclusion in the table below. 
                                                           Carrying value                   Fair value                   Fair value                   Fair value 
                                                                           Total                        Level 1                        Level 2                            Total 
31 December 2022                                             $000                            $000                            $000                            $000 
Financial assets 
Debt securities within  
recognised as part of cash  
and cash equivalents (note 18)           27,161                      1,239                    25,922                    27,161 
Short-term investments (note 15)        75,326                             –                    75,326                    75,326 
                                                          102,487                      1,239                  101,248                  102,487 
                                                           Carrying value                   Fair value                   Fair value                   Fair value 
                                                                           Total                        Level 1                        Level 2                            Total 
31 December 2021                                             $000                            $000                            $000                            $000 
Financial assets 
Debt securities within  
recognised as part of cash  
and cash equivalents                          41,604                    21,085                    20,519                    41,604 
Short-term investments (note 15)      164,195                             –                  164,195                  164,195 
                                                          205,799                    21,085                  184,714                  205,799 
Fair values hierarchy 
Level 1: quoted prices (unadjusted) in active markets for identical assets or liabilities 
Level 2: inputs other than quoted prices included within Level 1 that are observable for the asset or 
liability, either directly (i.e., as prices) or indirectly (i.e., derived from prices) 
Level 3: inputs for the asset or liability that are not based on observable market data (unobservable 
inputs). 
The Group classiﬁes its money market funds as Level 1 assets since it measures fair value using 
quoted prices in active markets for identical assets. The Level 2 assets include commercial paper, 
U.S. government securities, U.S. treasuries, and corporate bonds and are valued based on quoted 
prices for similar assets in active markets and inputs other than quoted prices that are derived from 
observable market data. The Group did not hold any Level 3 assets during the periods presented. 
The Group evaluates transfers between levels at the end of each reporting period. There were no 
transfers between Level 1 and Level 2 assets during the periods presented. 
Notes to the Annual Report and Financial Statements 
continued

24 FINANCIAL INSTRUMENTS continued 
24 (B) CREDIT RISK 
The Group has no signiﬁcant off-balance sheet risk, such as foreign currency contracts, options 
contracts, or other foreign hedging arrangements. Financial instruments that potentially expose the 
Group to concentrations of credit risk consist primarily of cash, cash equivalents, short-term 
investments and receivables including restricted cash. 
The Group invests its excess cash, in line with its investment policy, in money market funds and high 
credit quality debt instruments. The Group's cash is deposited in ﬁnancial institutions that it believes 
have high credit quality and has not experienced any losses on such accounts and does not believe 
it is exposed to any unusual credit risk beyond the normal credit risk associated with commercial 
banking relationships or entities for which it has a receivable. 
24 (C) LIQUIDITY RISK 
Liquidity risk is the risk that the Group will not be able to meet its ﬁnancial obligations as they fall 
due. The Group’s objective when managing liquidity is to ensure, as far as possible, that it will have 
sufﬁcient liquidity to meet its liabilities when they are due, under both normal and stressed conditions, 
without incurring unacceptable losses or risk damaged to the Group’s reputation. 
The Group currently has $33.0 million of principal indebtedness outstanding under the senior term 
facilities agreement, or the Amended Credit Facility, with MidCap Financial (Ireland) Limited. The 
Group has the ability to borrow up to an additional $67.0 million in the future under the Amended 
Credit Facility upon satisfaction of certain conditions. The existing indebtedness and any additional 
indebtedness the Group may incur could require us to divert funds identiﬁed for other purposes for 
debt service and impair the Group’s liquidity position. 
 
Orchard Therapeutics plc 147
Notes to the Annual Report and Financial Statements 
continued 

24 FINANCIAL INSTRUMENTS continued 
The table below set outs the contractual maturities of the Group’s ﬁnancial instruments at the 
reporting date. The amounts are gross and undiscounted, and include estimated contractual interest 
payments and exclude the effect of netting agreements. 
                                               Carrying value                                         Contractual cash flows 
                                                                                                                                                                                   5 years 
                                                                                                             1 year                  1 to                  2 to                  and 
                                                               Total                Total            or less          <2years          <5years                over 
31 December 2022                                 $000                $000                $000                $000                $000                $000 
Financial assets 
Cash and cash equivalents      68,424         68,424         68,424                  –                  –                  – 
Trade and other receivables     16,436         16,436         16,436                  –                  –                  – 
Lease receivables                     14,199         18,363           2,246           2,313           7,372           6,432 
Short-term investments             75,326         75,326         75,326                  –                  –                  – 
                                                174,385       178,549       162,432           2,313           7,372           6,432 
Financial liabilities 
Trade and other payables        (45,498)       (45,498)       (41,888)            (520)           (520)          (2,570) 
Lease liabilities                        (25,670)       (40,373)         (6,517)         (6,972)       (14,618)       (12,266) 
Borrowings                               (32,665)       (33,371)         (9,429)         (9,429)       (14,513)                 – 
                                              (103,833)     (119,242)       (57,834)       (16,921)       (29,651)       (14,836) 
Total                                           70,552         59,307       104,598        (14,608)       (22,279)         (8,404) 
                                               Carrying value                                         Contractual cash flows 
                                                                                                                                                                                   5 years 
                                                                                                             1 year                  1 to                  2 to                  and 
                                                               Total                Total            or less          <2years          <5years                over 
31 December 2021                                 $000                $000                $000                $000                $000                $000 
Financial assets 
Cash and cash equivalents      55,912         55,912         55,912                   –                   –                   – 
Trade and other receivables     18,370         18,370         18,370                   –                   –                   – 
Lease receivables                     15,343         20,543           2,180           2,246           7,150           8,967 
Short-term investments           164,195       164,195       164,195                   –                   –                   – 
                                                253,820       259,020       240,657           2,246           7,150           8,967 
Financial liabilities 
Trade and other payables        (34,524)       (34,524)       (31,954)                 –                   –          (2,570) 
Lease liabilities                        (26,613)       (41,311)         (7,326)         (6,773)       (15,880)       (11,332) 
Borrowings                               (33,203)       (34,155)            (786)         (9,429)       (23,940)                 – 
                                                (94,340)     (109,990)       (40,066)       (16,202)       (39,820)       (13,902) 
Total                                         159,480       149,030       200,591        (13,956)       (32,670)         (4,935) 
 
148 Orchard Therapeutics plc 
Notes to the Annual Report and Financial Statements 
continued

 
Orchard Therapeutics plc 149
24 FINANCIAL INSTRUMENTS continued 
24 (D) MARKET RISK 
Financial risk management 
Market risk is the risk that changes in market prices, such as foreign exchange rates, interest rates 
and equity prices will affect the Group’s income or the value of its holdings of ﬁnancial instruments 
Market risk - Foreign currency risk 
The Group is exposed to foreign currency exchange risk because it currently operates in the United 
Kingdom and the United States. The reporting currency of the Group is the U.S. dollar. The Group 
has determined the functional currency of the ultimate parent company, Orchard Therapeutics plc, 
is U.S. dollars because it predominantly raises ﬁnance and expends cash in U.S. dollars and expects 
to continue to do so in the future. 
Monetary assets and liabilities denominated in currencies other than the functional currency are 
translated into the functional currency of the relevant entity at rates of exchange prevailing at the 
statement of ﬁnancial position dates. Non-monetary assets and liabilities denominated in foreign 
currencies are translated into the functional currency at the exchange rates prevailing at the date of 
the transaction. Exchange gains or losses arising from foreign currency transactions are included in 
the determination of net income (loss) for the respective periods. The Group recorded realised and 
unrealised foreign currency losses of $24.3 million for the year ended 31 December 2022 (2021: 
$1.1 million) These foreign currency transaction gains and losses are included in the consolidated 
statements of proﬁt or loss and comprehensive loss. 
Assets and liabilities have been translated at the exchange rates at the statement of ﬁnancial position 
dates, while revenue and expenses are translated at the average exchange rates over the reporting 
period and shareholders’ equity amounts are translated based on historical exchange rates as of 
the date of each transaction. Translation adjustments are not included in determining net loss but 
are included in the translation reserve, a separate component of equity. 
The Group does not currently engage in currency hedging activities in order to reduce the currency 
exposure, but it may begin to do so in the future. Instruments that may be used to hedge future risks 
include foreign currency forward and swap contracts. These instruments may be used to selectively 
manage risks, but there can be no assurance that we will be fully protected against material foreign 
currency ﬂuctuations. 
Foreign currency exchange rates 
The following signiﬁcant exchange rates have been applied: 
                                                                         Average rate                                             Year-end spot rate 
                                                                            2022                            2021                            2022                            2021 
                                                                            $000                            $000                            $000                            $000 
Sterling                                                1.2438                    1.3342                    1.2103                    1.3497 
Euros                                                   1.0584                    1.1335                    1.0736                    1.1318 
Notes to the Annual Report and Financial Statements 
continued 

 
150 Orchard Therapeutics plc 
24 FINANCIAL INSTRUMENTS continued 
Sensitivity analysis 
A 10 percent weakening of the following currencies against the U.S. Dollar at 31 December 2022 
would have increased loss after taxation by the amounts shown below. This calculation assumes that 
the change occurred at the statement of ﬁnancial position date and had been applied to risk 
exposures existing at that date. 
This analysis assumes that all other variables, in particular other exchange rates and interest rates, 
remain constant. The analysis is performed on the same basis for the year ended 31 December 2021. 
                                                                                                                                                            Profit or loss 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Sterling                                                                                                            (24,497)                   (6,363) 
Euros                                                                                                                 (1,750)                   (1,867) 
A 10 percent strengthening of the above currencies against the U.S. Dollar at 31 December 2022 
would have had the equal but opposite effect on the above currencies to the amounts shown above, 
on the basis that all other variables remain constant. 
Market risk – Interest rate risk 
As of 31 December 2022, the Group had cash, cash equivalents, short-term investments and 
restricted cash of $148.0 million. The Group’s exposure to interest rate sensitivity is impacted by 
changes in the underlying UK and U.S. bank interest rates. The Group’s surplus cash has been 
invested in corporate bonds, commercial paper, U.S. treasuries, and money market accounts. We 
have not entered into investments for trading or speculative purposes. Due to the conservative nature 
of our investment portfolio, which is predicated on capital preservation of investments with short-term 
maturities, an immediate one percentage point change in interest rates would not have a material 
effect on the fair market value of the Group’s portfolio, and therefore neither operating results or cash 
ﬂows are expected to be signiﬁcantly affected by changes in market interest rates. 
The Group has borrowed $33.0 million under its credit facility. Amounts outstanding under the credit 
facility bear interest at a variable interest rate of 5.95% plus LIBOR. As of 31 December 2022, the 
carrying value of the Term Loans under the credit facility was $32.7 million. 
In 2017, the United Kingdom’s Financial Conduct Authority announced that after 2021 it would no 
longer compel banks to submit the rates required to calculate the London Interbank Offered Rate 
(LIBOR) and other interbank offered rates, which have been widely used as reference rates for various 
securities and ﬁnancial contracts, including loans, debt and derivatives. Regulators in the U.S. and 
other jurisdictions have been working to replace these rates with alternative reference interest rates 
that are supported by transactions in liquid and observable markets, such as the Secured Overnight 
Financing Rate (SOFR). At 31 December 2022 the Group’s credit facilities referenced LIBOR-based 
rates. In January 2023, the Group amended and restated our credit facility to change from LIBOR to 
SOFR. The newly amended facility bears a variable interest rate of 5.95% above SOFR plus 0.10% 
per annum, plus a ﬁnal payment equal to 3.5% of the principal borrowed under the Amended Credit 
Facility.
Notes to the Annual Report and Financial Statements 
continued

 
Orchard Therapeutics plc 151
24 FINANCIAL INSTRUMENTS continued 
The table below sets outs the interest rate proﬁle of the Group’s interest-bearing ﬁnancial instruments: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Fixed rate instruments 
Lease receivables                                                                               25         14,199                    15,343 
Lease liabilities                                                                                    18        (25,670)                 (26,613) 
                                                                                                                        (11,471)                 (11,270) 
Variable rate instruments 
Cash and cash equivalents                                                                              68,424                    55,912 
Short-term investments                                                                                    75,326                  164,195 
Term Loan                                                                                           18        (32,655)                 (33,203) 
                                                                                                                       111,095                  186,904 
Fixed-rate instruments are measured at amortised cost, therefore, a change in interest rate at the 
reporting date would not affect proﬁt or loss. 
A change of 100 basis points in interest rates at the statement of ﬁnancial position date would have 
increased or decreased equity by $0.3 million (2021: $0.3 million). This calculation assumes that the 
change occurred at the statement of ﬁnancial position date and had been applied to risk exposures 
existing at that date. This analysis assumes that all other variables, in particular foreign currency 
rates, remain constant and considers the effect of ﬁnancial instruments with variable interest rates. 
24 (E) CAPITAL MANAGEMENT 
The Group’s capital management objective is to ensure the Group’s ability to continue as a going 
concern so that it can provide returns for shareholders and beneﬁts for other stakeholders. To meet 
this objective the Group reviews the budgets and forecasts on a regular basis to ensure there is 
sufﬁcient capital to meet the needs of the Group.  
The capital structure of the Group consists of total parent shareholders’ equity as set out in the 
Consolidated Statement of Changes in Equity. 
To date, the Group has ﬁnanced its operations primarily with proceeds from the sale of ADSs in the 
IPO and follow-on offering, proceeds from the sale of ordinary shares in the private placement, 
proceeds from the sale of convertible preferred shares, reimbursements associated with two UK 
research and development tax relief programs, the Small and Medium-sized Enterprises research 
and development tax credit (“SME”) program and the Research and Development Expenditure 
(“RDEC”) program, upfront payments from our collaboration agreement with Pharming Group N.V., 
our Original Credit Facility and our Amended Credit Facility with MidCap, and through proceeds from 
sales of Libmeldy in Europe beginning in 2022.  
25 LEASES 
25 (A) LEASES AS A LESSEE 
The Group leases ofﬁce and laboratory space in London, United Kingdom and Boston, Massachusetts, 
United States. The Group’s facility leases generally contain customary provisions allowing the landlords 
to terminate the leases if the Group fails to remedy a breach of any obligations under any such lease 
within speciﬁed time periods, or upon bankruptcy or insolvency. The leases do not include any 
restrictions or covenants that had to be accounted for under the lease guidance. 
Notes to the Annual Report and Financial Statements 
continued 

25 LEASES continued 
Right-of-use assets 
                                                                                                                                                                                Land and  
                                                                                                                                                                                buildings 
                                                                                                                                                                                        $000 
Net book values 
Balance at 1 January 2021                                                                                                             18,746 
Additions to right-of-use assets                                                                                                           535 
Depreciation charge for the year                                                                                                     (4,523) 
Modiﬁcation or remeasurement of the lease liability                                                                          (664) 
Movement in foreign exchange rates                                                                                                  (221) 
Balance at 31 December 2021                                                                                                       13,873 
Additions to right-of-use assets                                                                                                        6,248 
Depreciation charge for the year                                                                                                     (4,367) 
Modiﬁcation or remeasurement of the lease liability                                                                       (1,791) 
Movement in foreign exchange rates                                                                                               (1,194) 
Balance at 31 December 2022                                                                                                       12,769 
Amounts recognised in profit or loss 
The following amounts have been recognised in proﬁt or loss for which the Group is a lessee: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Interest expense on lease liabilities                                                                   2,260                      3,302 
Expenses relating to variable lease payments not included in the  
measurement of lease liabilities                                                                         1,602                      1,696 
Amounts recognised in statement of cash flows 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Repayment of capital                                                                                         5,218                      5,523 
Repayment of interest                                                                                        2,260                      3,302 
Total cash outﬂow for leases                                                                              7,478                      8,825 
Information on lease liabilities is disclosed in note 19.
 
152 Orchard Therapeutics plc 
Notes to the Annual Report and Financial Statements 
continued

 
Orchard Therapeutics plc 153
25 LEASES continued 
25 (B) LEASES AS A LESSOR 
Fremont sublease agreements 
In December 2018, the Group leased manufacturing, laboratory, and ofﬁce space in Fremont, 
California (the “Fremont facility” and the “Head Lease”) which terminates in May 2030. In May 2020, 
the Group committed to a restructuring plan whereby we ceased construction and build-out of the 
Fremont facility. In December 2020, the Group entered into a sublease agreement (the “Sublease”) 
with an unrelated third-party (the “subtenant”) whereby the Group subleased the entire Fremont 
facility to the subtenant. The Group accounts for the Head Lease and Sublease as two separate 
contracts. The Sublease commenced in December 2020 and is in force for the remainder of the Head 
Lease term, through May 2030. The Sublease is assessed to be a ﬁnance lease under IFRS 16 as 
risk and rewards incidental to ownership of the underlying right-of-use asset arising from the Head 
Lease have substantially been transferred to the sublessee. 
The following amounts have been recognised in proﬁt or loss in respect of the sublease: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Interest income on lease receivables                                                                 1,037                      1,057 
The following table sets out a maturity analysis of lease payments receivable, showing the 
undiscounted lease payments to be received after the reporting date: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Less than one year                                                                                             2,246                      2,180 
Between one and two years                                                                               2,313                      2,246 
Between two and three years                                                                             2,382                      2,313 
Between three and four years                                                                            2,454                      2,382 
Between four and ﬁve years                                                                               2,535                      2,454 
More than ﬁve years                                                                                           6,432                      8,968 
Total undiscounted lease receivable                                                            18,362                    20,543 
Unearned ﬁnance income                                                                                 (4,163)                   (5,200) 
Net investment in the lease                                                                           14,199                    15,343 
Amounts due within one year                                                                             1,294                      1,143 
Amounts due in more than one year                                                                12,905                    14,200 
Net investment in the lease                                                                           14,199                    15,343 
Notes to the Annual Report and Financial Statements 
continued 

 
154 Orchard Therapeutics plc 
26 COMMITMENTS 
Manufacturing and technology development master agreement with AGC 
Biologics S.pA. (“AGC”) 
On 2 July 2020, the Group entered into the AGC Agreement pursuant to which AGC will develop, 
manufacture, and supply certain viral vectors and conduct cell processing activities for certain Group 
development and commercial programs. Under the terms of the AGC Agreement, the Group is 
obligated to pay AGC for a minimum product manufacturing commitment, dedicated manufacturing 
and development resources, and for a lease component associated with the right of use of exclusive 
manufacturing suites within AGC’s existing facilities. The following table outlines the annual 
commitments associated with the contract as of 31 December 2022: 
                                                                                                      Dedicated  
                                                                      Product           manufacturing                   Exclusive                                     
                                                           manufacturing      and development              transduction                  Total AGC  
                                                            commitments                 resources(1)                       suites(2)             Commitment 
                                                                            $000                            $000                            $000                            $000 
Due in: 
2023                                                      1,933                      5,655                      2,147                      9,735 
2024                                                      1,933                      5,655                      2,147                      9,735 
2025                                                         966                      2,827                      1,074                      4,867 
Total manufacturing commitments        4,832                    14,137                      5,368                    24,337 
The following table outlines the annual commitments associated with the contract as of 31 December 2021: 
                                                                                                      Dedicated  
                                                                      Product           manufacturing                   Exclusive                                     
                                                           manufacturing      and development              transduction                  Total AGC  
                                                            commitments                 resources(1)                       suites(2)             Commitment 
                                                                            $000                            $000                            $000                            $000 
Due in: 
2022                                                      2,627                      8,379                      2,626                    13,632 
2023                                                      3,051                      7,831                      3,079                    13,961 
2024                                                      3,051                      7,831                      3,079                    13,961 
2025                                                      1,525                      3,915                      1,539                      6,979 
Total manufacturing commitments      10,254                    27,956                    10,323                    48,533 
The tabular disclosure above has been translated from Euros to U.S. Dollars using an exchange rate of €1.00 to $1.07. 
(1) The Group may increase or decrease the usage of dedicated development services on a rolling basis with between six and 
12-months’ prior written notice to AGC. The above table assumes continued usage of dedicated development services at 
current rates. 
(2) In July 2020, the Group entered into a manufacturing and technology development master agreement for research and 
development and commercial production with AGC Biologics, S.p.A. (formerly MolMed S.p.A.) (“AGC”) pursuant to which 
AGC will develop, manufacture and supply certain viral vectors and conduct cell processing activities for certain Group 
development and commercial programs (“AGC Agreement”).  
The AGC Agreement has an initial term of ﬁve years, beginning on the Effective Date and ending 2 July 2025. The agreement 
may be extended for an additional two years by mutual agreement of the Group and AGC. 
Notes to the Annual Report and Financial Statements 
continued

26 COMMITMENTS continued 
The Group incurred $13.7 million and $16.4 million in expenses related to the AGC Agreement in the 
years ended 31 December 2021 and 2022, respectively. The AGC Agreement has an initial term of 
ﬁve years, beginning on the Effective Date and ending 2 July 2025. The AGC Agreement may be 
extended for an additional two years by mutual agreement of the Group and AGC. The Group has 
the right to terminate the AGC Agreement at its discretion upon 12-month’s prior written notice to 
AGC, and beginning no earlier than 2 July 2022, AGC has the right to terminate the AGC Agreement 
at its discretion upon 24-month’s prior written notice to the Group. Each party may terminate the AGC 
Agreement upon prior notice to the other party for an uncured material breach that the breaching 
party does not cure within the notice period. 
Other funding commitments 
The Group has entered into several license agreements outlined below. In connection with these 
agreements the Group is required to make milestone payments and annual license maintenance 
payments or royalties on future sales of speciﬁed products. 
GSK asset purchase and license agreement  
In April 2018, the Group completed an asset purchase and license agreement (the “GSK Agreement”) 
with subsidiaries of GSK to acquire a portfolio of autologous ex vivo gene therapy assets and licenses 
for rare diseases and option rights on three additional programs in pre-clinical development from 
Telethon Foundation and San Raffaele Hospital (“Telethon-OSR”). The portfolio of approved and 
investigational rare disease gene therapies included Strimvelis and OTL-200 for MLD, among other 
programs. GSK also simultaneously novated to us their R&D Agreement with Telethon-OSR.   
The Group accounted for the GSK Agreement as an asset acquisition, since the asset purchase and 
licensing arrangement did not meet the deﬁnition of a business combination, resulting in total 
consideration of $133.6 million, which was recorded in 2018. 
The Group is also required to use commercially reasonable efforts to obtain a priority review voucher, 
or PRV, from the FDA for certain programs, including OTL-200, and to transfer the ﬁrst such PRV to 
GSK. GSK also has an option to acquire at a deﬁned price any PRVs granted to the Group thereafter 
for certain programs. In the event that GSK does not exercise this option with respect to any PRV, the 
Group may sell the PRV to a third party and must share any proceeds in excess of a speciﬁed sale 
price equally with GSK. As part of the GSK Agreement the Group is also required to use its best 
endeavors to make Strimvelis commercially available in the European Union until such time as an 
alternative gene therapy is commercially available for patients in Italy, and at all times at the San 
Raffaele Hospital in Milan, provided that a minimum number of patients continue to be treated at this 
site.  
Under the GSK Agreement the Group is also obligated to pay non-refundable royalties and milestone 
payments in relation to the gene therapy programs acquired. For example, for Libmeldy, the Group 
pays a tiered royalty rate at percentages from the mid-teens to the low twenties. These royalties owed 
to GSK are in addition to any royalties owed to other third parties under various license agreements 
for the GSK programs. In aggregate, the Group may pay up to £90.0 million in milestone payments 
upon achievement of certain sales milestones applicable to GSK. The Group’s royalty obligations 
with respect to OTL-200 may be deferred for a certain period in the interest of prioritizing available 
capital to develop each product. The Group’s royalty obligations are subject to reduction on a 
product-by-product basis in the event of market control by biosimilars and will expire in April 2048. 
Other than Strimvelis and OTL-200, these royalty and milestone payments were not determined to 
be probable and estimable at the date of the acquisition or through 31 December 2022, and are not 
included as part of consideration. 
 
Orchard Therapeutics plc 155
Notes to the Annual Report and Financial Statements 
continued 

 
156 Orchard Therapeutics plc 
26 COMMITMENTS continued 
Telethon-OSR research and development collaboration and license agreements 
In connection with the Group’s entering into the GSK Agreement in April 2018, the Group also 
acquired and assumed agreements with Telethon Foundation and San Raffaele Hospital, together 
referred to as Telethon-OSR, for the research, development and commercialization of autologous ex 
vivo gene therapies for ADA-SCID, WAS, MLD and TDT.  
As consideration for the licenses, the Group will be required to make payments to Telethon-OSR upon 
achievement of certain product development milestones, up to an aggregate of approximately €31.0 
million ($33.4 million at 31 December 2022). Additionally, the Group will be required to pay to Telethon-
OSR a tiered mid-single to low-double digit royalty percentage on annual sales of licensed products 
covered by patent rights on a country-by-country basis, as well as a low double-digit percentage of 
sublicense income received from any certain third-party sublicenses of the collaboration programs. 
In May 2019, the Group entered into a license agreement with Telethon-OSR, under which Telethon-
OSR granted to the Group an exclusive worldwide license for the research, development, manufacture 
and commercialization of Telethon-OSR’s ex vivo autologous HSC lentiviral based gene therapy for 
the treatment of mucopolysaccharidosis type I, including the Hurler variant (“MPS-IH”). Under the 
terms of the agreement, Telethon-OSR received €15.0 million in upfront and milestone payments from 
the Group upon entering into the agreement. The Group is also required to pay up to €28.0 million 
($30.1 million at 31 December 2022) related to milestone payments contingent upon achievement of 
certain development, regulatory and commercial milestones. Additionally, the Group will be required 
to pay Telethon a tiered mid-single to low-double digit royalty percentage on annual net sales of 
licensed products.  
UCLB/UCLA license agreement  
In February 2016, and amended in July 2017, the Group completed the UCLB/UCLA license 
agreement, under which the Group has been granted exclusive and non-exclusive, sublicensable 
licenses under certain intellectual property rights controlled by UCLB and UCLA to develop and 
commercialize gene therapy products in certain ﬁelds and territories.  
In exchange for these rights, in 2016, the Group made upfront cash payments consisting of $0.8 
million for the license to the joint UCLB/UCLA technology and $1.1 million for the license to the UCLB 
technology and manufacturing technology. The Group also issued an aggregate of 4,665,384 
ordinary shares to UCLB, of which 1,224,094, and 3,441,290 ordinary shares were issued in 2017 
and 2016, respectively. The Group recorded research and development expenses based on the fair 
value of the ordinary shares as of the time the agreement was executed or modiﬁed.  
Under the UCLB/UCLA License Agreement, the Group may become obligated to make payments to 
the parties of up to an aggregate of £19.9 million ($24.1 million at 31 December 2022) upon the 
achievement of speciﬁed regulatory milestones as well as royalties ranging from low to mid-single-
digit percentage on net sales of the applicable gene therapy product.  
In June 2021, the Group terminated the license to its OTL-101 program for ADA-SCID, which was 
granted pursuant to the UCLB/UCLA license agreement. Except for the termination of such license, 
the UCLB/UCLA license agreement continues in full force and effect. Unless terminated earlier by 
either party, the UCLB/UCLA license agreement will expire on the 25th anniversary of the agreement.  
Oxford BioMedica license, development and supply agreement  
In November 2016, and amended in June 2017, May 2018, July 2018, September 2018, May 2019 
and April 2020, the Group entered into an arrangement with Oxford BioMedica plc whereby Oxford 
BioMedica granted an exclusive intellectual property license to the Group for the purposes of 
Notes to the Annual Report and Financial Statements 
continued

research, development, and commercialization of collaboration products, and whereby Oxford 
BioMedica will provide process development services (“Oxford BioMedica Development 
Agreement”). As part of the consideration to rights and licenses granted under the Oxford BioMedica 
Development Agreement, the Group issued 588,220 ordinary shares to Oxford BioMedica. The Group 
is also obligated to make certain development milestone payments in the form of issuance of 
additional ordinary shares if the milestones are achieved. In November 2017, the ﬁrst milestone was 
achieved, and the Group was committed to issue another 150,826 ordinary shares, and issued these 
shares in 2018. In September 2018, the second and fourth milestones were achieved, and the Group 
issued 150,826 ordinary shares. In April 2020, the ﬁfth milestone was deemed to have been met upon 
execution of the amended agreement in April 2020, and the Group issued another 75,413 ordinary 
shares to Oxford BioMedica with a total value of $0.8 million which was recorded to research and 
development expense. No milestones were met during the year ended 31 December 2022. The Group 
may also pay low single-digit percentage royalties on net sales of collaborated products generated 
under the Oxford BioMedica Agreement. 
Legal proceedings 
The Group is not a party to any litigation and does not have contingency reserves established for 
any litigation liabilities 
Indemnification agreements 
In the ordinary course of business, the Group may provide indemniﬁcation of varying scope and terms 
to vendors, lessors, business partners, and other parties with respect to certain matters including, 
but not limited to, losses arising out of breach of such agreements or from intellectual property 
infringement claims made by third parties. In addition, the Group has entered into indemniﬁcation 
agreements with members of its board of directors and senior management that will require the Group, 
among other things, to indemnify them against certain liabilities that may arise by reason of their status 
or service as directors or ofﬁcers. The maximum potential amount of future payments the Group could 
be required to make under these indemniﬁcation agreements is, in many cases, unlimited. To date, 
the Group has not incurred any material costs as a result of such indemniﬁcations. The Group is not 
aware of any claims under indemniﬁcation arrangements, and it has not accrued any liabilities related 
to such obligations in its consolidated ﬁnancial statements as of 31 December 2021 or 2022. 
27 RELATED PARTY TRANSACTIONS 
TRANSACTIONS WITH KEY MANAGEMENT PERSONNEL 
Directors of the Parent Company and their immediate relatives control 0.4% (2021: 0.4%) per cent 
of the voting shares of the Company. 
The compensation of key management personnel (including the directors) is as follows: 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Key management remuneration including social security costs                        2,165                      2,083 
Company contributions to money purchase pension schemes                              12                           12 
Equity settled share-based payments                                                               3,206                      5,941 
                                                                                                                           5,383                      8,036 
ULTIMATE CONTROLLING PARTY 
There is no ultimate controlling party of the Group as ownership is split between the Group’s 
shareholders. 
 
Orchard Therapeutics plc 157
Notes to the Annual Report and Financial Statements 
continued 
26 COMMITMENTS continued

 
158 Orchard Therapeutics plc 
28 SUBSEQUENT EVENTS 
RATIO CHANGE 
On 10 February 2023, the Group announced that the Company’s Board of Directors approved a 
change to the ratio of the Group’s ADSs to ordinary shares (the "ADS Ratio") from the current ADS 
Ratio of one ADS to one ordinary share to a new ADS Ratio of one ADS to 10 ordinary shares. The 
ratio change became effective on 10 March, 2023. The change in the ADS Ratio will have the same 
effect as a one-for-ten reverse ADS split and is intended to enable the Group to regain compliance 
with the Nasdaq minimum bid price requirement. As all ﬁnancial statement and disclosure information 
is presented in ordinary share amounts, not ADSs, there was no impact to the consolidated ﬁnancial 
statements. 
ISSUANCE OF SHARES THROUGH 2023 PRIVATE PLACEMENT 
On 6 March 2023, the Group entered into a Securities Purchase Agreement (the “Purchase 
Agreement”) pursuant to which the Group agreed to sell, in an unregistered offering, up to an 
aggregate of (i) 99,166,900 shares, consisting of a combination of Ordinary Shares, nominal value 
£0.10 per share (“Ordinary Shares”) and Non-Voting Ordinary Shares, nominal value £0.10 per share 
(“Non-Voting Ordinary Shares” and together with the Ordinary Shares, “Shares”) and (ii) warrants to 
purchase an aggregate of 109,083,590 Ordinary Shares or Non-Voting Ordinary Shares (the 
“Warrants”). 
The 2023 Private Placement consists of two closings. The Group agreed to sell and issue in the initial 
closing of the 2023 Private Placement (i) 56,666,900 Shares and (ii) Warrants to purchase an 
aggregate of 62,333,590 Shares, at a purchase price of $6.00 per unit, where each unit consists of 
ten (10) Shares and an accompanying Warrant to purchase eleven (11) Shares. The initial closing of 
the 2023 Private Placement occurred on 10 March 2023. The Group received gross proceeds of 
approximately $34.0 million from the initial closing of the 2023 Private Placement, before deducting 
fees to the placement agent and other offering expenses payable by the Group. 
In addition, the Group agreed to sell and issue in the second closing of the 2023 Private Placement 
(i) 42,500,000 Shares and (ii) Warrants to purchase an aggregate of 46,750,000 Shares, at a 
purchase price of $8.00 per unit, where each unit consists of ten (10) Shares and an accompanying 
Warrant to purchase eleven (11) Shares. The second closing is conditioned upon (x) the Group’s 
announcement of its intention to ﬁle a biologics license application (“BLA”) submission following 
receipt of the minutes from the U.S. Food and Drug Administration (“FDA”) in connection with the 
Group’s pre-BLA (Type B) meeting for OTL-200, provided such minutes do not expressly advise the 
Group not to proceed with a BLA submission, and (y) receipt of Shareholder Approval (as deﬁned 
below) (collectively, the “Second Closing Trigger”). 
In connection with the Private Placement, the Group has agreed to hold a meeting of its shareholders 
no later than 120 days following the initial closing of the Private Placement to seek approval to give 
the Group’s directors authority under s551 of the Companies Act 2006 to issue the securities to be 
issued and sold in the second closing of the Private Placement and the Shares issuable upon 
exercise of the Warrants to be issued and sold in the Private Placement, and to disapply pre-emption 
rights in respect of such authority under s570 of the Companies Act 2006 (collectively, “Shareholder 
Approval”). 
The second closing is expected to occur on the ﬁfth trading day after the Group notiﬁes the 
purchasing parties that the Second Closing Trigger has occurred and is subject to additional, 
customary closing conditions. If the Second Closing Trigger occurs, the Group anticipates receiving 
gross proceeds of approximately $34.0 million from the second closing of the 2023 Private 
Placement, before deducting fees to the placement agent and other offering expenses payable by 
the Group. 
Notes to the Annual Report and Financial Statements 
continued

28 SUBSEQUENT EVENTS continued 
Each Warrant will have an exercise price equal to $1.10 per Share in the event the Vesting Event (as 
deﬁned below) occurs on or prior to 31 December 2024, and $0.95 per Share in the event the Vesting 
Event occurs after 31 December 2024. The Warrants will be exercisable during the 30 days following 
the Group’s announcement of receipt of marketing approval of its BLA with respect to OTL-200 (the 
“Vesting Event”); provided that exercise of any Warrant is conditioned upon the receipt of Shareholder 
Approval. Commencement of the 30-day exercise period may be delayed as set forth in the Warrants 
in the event the Vesting Event occurs prior to Shareholder Approval. The Warrants will expire at the 
conclusion of the 30- day exercise period or, if the Vesting Event does not occur, 10 March 2026. 
29 EXPLANATION OF TRANSITION TO UK-ADOPTED IFRS 
As stated in note 1, these are the Group’s ﬁrst consolidated ﬁnancial statements prepared in 
accordance with UK-adopted IFRSs. 
The accounting policies set out in note 1 have been applied in preparing the ﬁnancial statements for 
the year ended 31 December 2022, the comparative information presented in these ﬁnancial 
statements for the year ended 31 December 2021 and in the preparation of an opening IFRS 
Consolidated statement of ﬁnancial position at 1 January 2021(the Group’s date of transition). 
In preparing its opening IFRS Consolidated statement of ﬁnancial position, the Group has adjusted 
amounts reported previously in ﬁnancial statements prepared in accordance with its previous basis 
of accounting (US GAAP). An explanation of how the transition from US GAAP to UK-adopted IFRSs 
has affected the Group’s ﬁnancial performance, ﬁnancial position and cash ﬂows is set out in the 
following tables and the notes that accompany the tables. 
 
Orchard Therapeutics plc 159
Notes to the Annual Report and Financial Statements 
continued 

29 EXPLANATION OF TRANSITION TO UK-ADOPTED IFRS 
continued 
RECONCILIATION OF TOTAL COMPREHENSIVE LOSS FOR 2021 
                                                                                                                                                         Effect of 
                                                                                                                                                   transition to 
                                                                                                                                                   UK-adopted   UK-adopted  
                                                                                                                Note        US GAAP              IFRSs              IFRSs 
                                                                                                                                        $000                $000                $000 
Product sales                                                                                              700                   –              700 
Collaboration revenue                                                                                 975                   –              975 
Total revenue                                                                                          1,675                   –           1,675 
Cost of sales                                                                                              (226)                 –             (226) 
Gross profit                                                                                             1,449                   –           1,449 
Research and development expense                                  c, d, f        (86,977)       (66,668)     (153,645) 
Selling, general and administrative expense                  a, b, c, d        (54,905)          3,058        (51,847) 
Other operating income and expense                                                         (90)                 –               (90) 
Net foreign exchange loss                                                                      (1,148)                 –          (1,148) 
Operating loss                                                                                   (141,671)       (63,610)     (205,281) 
Finance income                                                                          b              412           1,057           1,469 
Finance expenses                                                                       a          (2,497)         (3,302)         (5,799) 
Net finance expense                                                                             (2,085)         (2,245)         (4,330) 
Loss before tax                                                                                  (143,756)       (65,855)     (209,611) 
Taxation                                                                                        f             (828)        12,164         11,336 
Loss for the year                                                                               (144,584)       (53,691)     (198,275) 
Foreign currency translation differences –  
foreign operations                                                                                    3,124          (2,027)          1,097 
Net change in fair value of debt investments at 
fair value through other comprehensive income                                        (251)                 –             (251) 
Tax on items that may be classiﬁed subsequently  
to statement of proﬁt or loss 
Other comprehensive loss, net of income tax                                     2,873          (2,027)             846 
Total comprehensive loss for the year                                            (141,711)       (55,718)     (197,429) 
 
160 Orchard Therapeutics plc 
Notes to the Annual Report and Financial Statements 
continued

29 EXPLANATION OF TRANSITION TO UK-ADOPTED IFRS 
continued 
RECONCILIATION OF EQUITY 
                                                                                 1 January 2021                                           31 December 2021 
                                                                                              Effect of                                                        Effect of  
                                                                                       transition to                                                 transition to  
                                                                                        UK-adopted     UK-adopted                        UK-adopted     UK-adopted  
                                                                  US GAAP               IFRSs               IFRSs   US GAAP               IFRSs               IFRSs 
                                                       Note           $000                 $000                 $000           $000                 $000                 $000 
Non-current assets 
  Property, plant and equipment                     4,781                        –                4,781          4,767                       –                4,767 
  Right-of-use assets                       a, b        29,815             (11,069)             18,746        24,316             (10,443)             13,873 
  Intangible assets                               c          3,076            117,123            120,199          4,149              59,259              63,408 
  Lease receivable                              b                 –              14,466              14,466                 –              14,200              14,200 
  Other receivables                             b        14,511               (1,553)             12,958          9,770               (3,407)               6,363 
  Deferred tax assets                           e          5,219              13,468              18,687          4,086                  (973)               3,113 
                                                                       57,402            132,435            189,837        47,088              58,636            105,724 
Current assets 
  Inventories                                                        665                        –                   665          2,015                       –                2,015 
  Lease receivable                              b                 –                        –                        –                 –                1,143                1,143 
  Trade and other receivables             b        13,577                    (39)             13,538        22,475                    (40)             22,435 
  Research and development tax  
credit receivable                                         17,344                                        17,344        30,723                       –              30,723 
  Short-term investments                             136,813                        –            136,813      164,195                       –            164,195 
  Cash and cash equivalents                        55,135                        –              55,135        55,912                       –              55,912 
                                                                     223,534                    (39)           223,495      275,320                1,103            276,423 
Total assets                                                 280,936            132,396            413,332      322,408              59,739            382,147 
Current liabilities 
  Loans and borrowings                                  4,861                        –                4,861             786                       –                   786 
  Lease liabilities                                              8,934                        –                8,934          7,335                       –                7,335 
  Trade and other payables                           36,850                        –              36,850        33,655                       –              33,655 
  Deferred income                                                  –                        –                        –             346                       –                   346 
  Provisions                                                         916                        –                   916             671                       –                   671 
                                                                       51,561                        –              51,561        42,793                       –              42,793 
Non-current liabilities 
  Loans and borrowings                                20,204                        –              20,204        32,086                       –              32,086 
  Lease liabilities                                            24,168                        –              24,168        19,278                       –              19,278 
  Other payables                                              2,571                        –                2,571          2,607                       –                2,607 
  Deferred income                                                  –                        –                        –        12,519                       –              12,519 
  Provisions                                                      3,999                        –                3,999          3,176                       –                3,176 
                                                                       50,942                        –              50,942        69,666                       –              69,666 
Total liabilities                                             102,503                        –            102,503      112,459                       –             112,459 
Net assets                                                    178,433            132,396            310,829      209,949              59,739            269,688 
  Equity attributable to equity  
holders of the parent 
  Share capital                                               12,497                        –              12,497        16,243                       –              16,243 
  Share premium                                          339,435                        –            339,435      486,382                       –            486,382 
  Translation reserve                            g             293                        –                   293          3,417               (2,028)               1,389 
  Share-based payment reserve         g        55,417              27,297              82,714        77,951              10,358              88,309 
  Fair value reserve                                               80                        –                     80            (171)                      –                  (171) 
  Retained earnings                                    (229,289)           105,099           (124,190)    (373,873)             51,409           (322,464) 
Total equity                                                  178,433            132,396            310,829      209,949              59,739            269,688 
 
Orchard Therapeutics plc 161
Notes to the Annual Report and Financial Statements 
continued 

29 EXPLANATION OF TRANSITION TO UK-ADOPTED IFRS 
continued 
Notes to the reconciliation of equity and loss 
a
The Group elected to adopt IFRS 16 using the practical expedient permitted under IFRS 1 to initially measure the right-of-
use asset at an amount equal to the lease liability as at the date of transition, being 1 January 2021. Subsequent to its initial 
recognition, the right-of-use asset is amortised under IFRS 16 on a straight-line basis over the lease term. Under US GAAP, 
the Group’s leases were classiﬁed as operating leases; the amortisation charge was, therefore, calculated as the total lease 
payment less interest for the period. The interest payable on lease liabilities is presented as a ﬁnance expense as opposed 
to an operating expense under US GAAP. 
b
Under US GAAP, a lessor classiﬁes a sublease as either a ﬁnance or operating lease with reference to the underlying lease 
assets. Under IFRS 16, a lessor classiﬁes a sublease as either a ﬁnance or operating lease with reference to the right-of-use 
asset arising from the head lease. The Fremont sublease has been classiﬁed as a ﬁnance lease under IFRS 16; consequently, 
the right-of-use asset associated with the headlease has been derecognised and a ﬁnance lease receivable recognised in 
respect of this sublease arrangement. Under US GAAP, the sublease was classiﬁed as an operating lease with the lease 
income received recognised directly in the Consolidated statement of proﬁt or loss on a straight-line basis. 
c
Under US GAAP, the Group expensed acquired research and development assets as no alternative future use was identiﬁed. 
Under IFRS, the probability recognition criterion for intangibles assets under IAS 38 is always considered to be met for 
separately acquired intangible assets as the price paid reﬂects expectations about the probability that future economic 
beneﬁts of the asset will ﬂow to the entity. Consequently, the Group has recognised additional intangible assets under IAS 38 
in relation to externally acquired licenses used in the Group’s research and development activities. Subsequent to their initial 
recognition, these licenses are measured at cost less accumulated amortisation and impairment. 
d
The Group has granted Share Options to employees and directors of the Group with various vesting schedules which are 
capable of being exercised as they vest in monthly tranches over a period of three to four years from the grant date. Under 
US GAAP, the Group measured the awards granted to employees based on the fair value on the date of grant and recognised 
a compensation expense on a straight-line basis over the vesting period. Under IFRS 2, each tranche is accounted for as a 
separate share-based payment. The Group has determined and adjusted the fair value, and associated share-based payment 
expense recognised, for all options with monthly vesting which remain outstanding from the date of transition. 
e
Under US GAAP, the Group recorded deferred tax on its equity-settled share options based on the amount of share-based 
payment expense recognised. Changes in share price do not impact the deferred tax asset recognised. Under IAS 12, 
deferred tax is recognised on equity-settled share options based on an estimate of future tax deduction for the award 
measured at each reporting period. Where the tax deduction is based on a future share price, the estimate is based on the 
current share price. 
In addition to this, the deferred tax impact of GAAP adjustments identiﬁed has been recognised primarily in respect of share-
based payments.  
f
Under US GAAP, the Group recognised investment tax credits received under the SME regime as operating income. Under 
IFRS, as the tax credits are linked to taxable losses, these are recognised under the scope of IAS 12 and are recognised as 
part of income tax expense.   
g
The impact of GAAP adjustments set out in a to f above  arising in foreign operations, primarily in Orchard Therapeutics 
(Europe) Limited, on the foreign currency translation reserve has been calculated and recognised.  
 
EXPLANATION OF MATERIAL ADJUSTMENTS TO THE CASH FLOW 
STATEMENT FOR THE YEAR ENDED 31 DECEMBER 2021 
Under IFRS 16, the Group has elected to present lease payments made as a lessee as a ﬁnancing 
cash ﬂow. Under US GAAP, lease payments made by the group as a lessee were recognised as an 
operating cash ﬂow. 
Under IFRS 16, the sublease has been assessed to be a ﬁnance lease is classiﬁed as an investing 
cash ﬂow. Under US GAAP, the sublease was an operating lease and the associated cash inﬂows 
were recognised as an operating cash ﬂow. 
Under US GAAP, research and development tax credit receivable under the SME scheme was 
recognised as operating income. Under IFRS, this is recognised within income tax, and the 
associated in ﬂow cash ﬂows presented as part of tax paid/received. 
There was no overall impact to the total change in net cash during the year as a result of the transition. 
 
162 Orchard Therapeutics plc 
Notes to the Annual Report and Financial Statements 
continued

 
Orchard Therapeutics plc 163
ORCHARD THERAPEUTICS PLC 
PARENT COMPANY FINANCIAL STATEMENTS 
FOR THE YEAR ENDED 31 December 2022 

 
164 Orchard Therapeutics plc 
Parent Company Balance Sheet 
at 31 December 2022 
                                                                                                                Note                            2022                            2021 
                                                                                                                                                    $000                            $000 
Fixed assets                                                                                                                                               
Investments in subsidiaries                                                        3                             –                             – 
Current assets                                                                                                                                           
Debtors                                                                                       4                      1,669                    20,434 
Short-term investments                                                              5                    50,918                  147,996 
Cash and cash equivalents                                                                              27,474                    35,809 
                                                                                                                        80,061                  204,239 
Current liabilities                                                                                                                                       
Creditors: amounts falling due within one year                          6                   (11,207)                   (1,606) 
Net current assets                                                                                          68,854                  202,633 
Total assets less current liabilities                                                              68,854                  202,633 
Non-current liabilities                                                                                                                               
Creditors: amounts falling due after more than one year           6                  (22,991)                 (32,086) 
Net assets                                                                                                       45,863                  170,547 
Equity                                                                                                                                                         
Share capital                                                                               8                    16,409                    16,243 
Share premium                                                                           8                  486,405                  486,382 
Share-based payment reserve                                                   8                    98,941                    87,523 
Other comprehensive income                                                    8                       (121)                      (137) 
Accumulated losses                                                                   8                (555,771)               (419,464) 
Equity attributable                                                                                         45,863                  170,547 
The Company has elected to take the exemption under section 408 of the Companies Acts 2006 
from presenting the Company Statement of Comprehensive Income. The Company loss for the year 
ended 31 December 2022 was a loss of $136.3 million (2021: loss of $428.5 million). 
These Parent Company ﬁnancial statements were approved by the board of directors on 27 April 
2023 and were signed on its behalf by: 
 
Hubert Gaspar 
Director 
27 April 2023 
Company registered number: 11494381 

 
Orchard Therapeutics plc 165
Parent Company Statement of Changes in Equity 
for the year ended 31 December 2022 
                                                                                                                  Share-                Other                    
                                                                                                                   based           compre-                                         
                                                                            Share         Share     payment            hensive    Retained            Total 
                                                                           capital    premium       reserve             income    earnings          Equity 
                                                                              $000           $000            $000                  $000           $000             $000 
Balance at 1 January 2022                   16,243   486,382      87,523               (137) (419,464)   170,547 
Total comprehensive loss  
for the year 
Loss for the year                                            –              –               –                    –  (136,307)  (136,307) 
Other comprehensive income                        –              –               –                  16               –              16 
Total comprehensive loss for the year            –              –               –                  16  (136,307)  (136,291) 
Transactions with owners,  
recorded directly in equity 
Issue of shares under employee  
equity plans                                               166            24               –                    –               –            190 
Issue of shares under consulting  
agreements                                                    –             (1)              –                    –               –              (1) 
Share-based compensation expense            –              –      11,418                    –               –       11,418 
Total transactions with owners                   166            23      11,418                    –               –       11,607 
Balance at 31 December 2022            16,409   486,405      98,941               (121) (555,771)     45,863 
 
                                                                                                                  Share-                Other                    
                                                                                                                   based           compre-                                         
                                                                            Share         Share     payment            hensive    Retained            Total 
                                                                           capital    premium       reserve             income    earnings          Equity 
                                                                              $000           $000            $000                  $000           $000             $000 
Balance at 1 January 2021                   12,497   339,435      67,623                  83        9,056     428,694 
Total comprehensive loss  
for the year 
Loss for the year                                            –              –               –                    –  (428,520)  (428,520) 
Other comprehensive loss                             –              –               –               (220)              –          (220) 
Total comprehensive loss for the year            –              –               –               (220) (428,520)  (428,740) 
Transactions with owners,  
recorded directly in equity 
Issue of shares under employee  
equity plans                                               263       2,650               –                    –               –         2,913 
Issue of shares under collaboration  
agreements                                                170       3,965               –                    –               –         4,135 
Issue of shares under consulting  
agreements                                                    3             (3)              –                    –               –                – 
Issue of shares from private  
placement                                               3,310   146,690               –                    –               –     150,000 
Share issue costs                                           –      (6,355)              –                    –               –       (6,355) 
Share-based compensation expense            –              –      19,900                    –               –       19,900 
Total transactions with owners                3,746   146,947      19,900                    –               –     170,593 
Balance at 31 December 2021            16,243   486,382      87,523               (137) (419,464)   170,547

 
166 Orchard Therapeutics plc 
1
ACCOUNTING POLICIES  
1.1 NATURE OF BUSINESS 
The Company is a public limited company incorporated pursuant to the laws of England and Wales. 
The registered number is 11494381 and the registered address is 245 Hammersmith Road, 3rd Floor, 
London, England, W6 8PW, United Kingdom.  
Orchard Therapeutics plc (the “Company”) is a global gene therapy company dedicated to 
transforming the lives of people affected by severe diseases through the development of innovative, 
potentially curative gene therapies. The Company's ex vivo autologous hematopoietic stem cell 
(“HSC”) gene therapy approach utilises genetically modiﬁed blood stem cells and seeks to correct 
the underlying cause of disease in a single administration. The Company's gene therapy product 
candidate pipeline spans multiple therapeutic areas where the disease burden on children, families 
and caregivers is immense and current treatment options are limited or do not exist.  
The Company has American Depositary Shares (“ADSs”) registered with the U.S. Securities and 
Exchange Commission (the “SEC”) and has been listed on the Nasdaq Global Select Market since 
31 October 2018. As at 31 December 2022 the Company's ADSs each represent one ordinary share 
of the Company, following the ratio change on 10 March 2023 each ADS represents 10 ordinary 
shares of the Company (see note 11).  
On 9 February 2021, the Company issued and sold (i) 20,900,321 ordinary shares, nominal value 
$0.10 per share, at a purchase price of $6.22 per share (the “Purchase Price”), which was the closing 
sale price of the Company's ADSs on the Nasdaq Global Select Market on 4 February 2021, and 
(ii) 3,215,434 non-voting ordinary shares, nominal value $0.10 per share, at the Purchase Price 
(together (i) and (ii) the “Private Placement”). The Private Placement resulted in net proceeds to the 
Company of $143.6 million after deducting placement agent fees of $6.0 million and other issuance 
costs of $0.4 million. The ordinary shares and non-voting ordinary shares were sold pursuant to a 
securities purchase agreement entered into between the Company and the purchasers named 
therein on 4 February 2021. At 31 December 2021 all outstanding non-voting shares have been 
converted to voting ordinary shares. 
On 10 March 2023, the Company issued and sold (i) 56,666,900 ordinary shares and non-voting 
ordinary shares, nominal value £0.10 per share and (ii) warrants to purchase an aggregate of 
62,333,590 ordinary shares or non-voting ordinary shares, at a purchase price of $6.00 per ten shares 
and accompanying warrant, in an unregistered offering (together (i) and (ii) the “2023 Private 
Placement”). The 2023 Private Placement resulted in gross proceeds of approximately $34.0 million. 
The ordinary shares, non-voting ordinary shares, and warrants were sold pursuant to a securities 
purchase agreement entered into between the Company and the purchasers named therein on 
6 March 2023.  
The Company’s business is subject to risks and uncertainties common to development-stage 
companies in the biotechnology industry. There can be no assurance that the Company’s research 
and development will be successfully completed, that adequate protection for the Company’s 
technology will be obtained, that any products developed will obtain necessary government 
regulatory approval or that any products, if approved, will be commercially viable. The Company 
operates in an environment of rapid technological innovation and substantial competition from 
pharmaceutical and biotechnology companies. In addition, the Company is dependent upon the 
services of its employees, consultants and service providers. Even if the Company’s product 
development efforts are successful in gaining regulatory approval, it is uncertain when, if ever, the 
Company will realize signiﬁcant revenue from product sales. The future developments of the 
COVID-19 pandemic may also directly or indirectly impact the Company’s business, including impacts 
due to travel restrictions, supply chain disruptions, business closures, and other measures. 
Notes to the Parent Company Financial Statements 

1.2 BASIS OF PREPARATION 
These ﬁnancial statements were prepared in accordance with Financial Reporting Standard 101 
Reduced Disclosure Framework (“FRS 101”).  
In preparing these ﬁnancial statements, the Company applies the recognition, measurement and 
disclosure requirements of UK-adopted international accounting standards (“UK-adopted IFRS”), 
but makes amendments where necessary in order to comply with Companies Act 2006 and has set 
out below where advantage of the FRS 101 disclosure exemptions has been taken. 
The ﬁnancial statements were historically prepared in accordance with UK GAAP, Financial Reporting 
Standard 102.  In the transition to FRS 101, the Company has applied IFRS 1 whilst ensuring that its 
assets and liabilities are measured in compliance with FRS 101.  An explanation of how the transition 
to FRS 101 has affected the reported ﬁnancial position and ﬁnancial performance of the Company 
is provided in note 13. 
IFRS 1 grants certain exemptions from the full requirements of UK-adopted IFRSs in the transition 
period. The following exemptions have been taken in these ﬁnancial statements: 
Recognise, as permitted under IFRS 1.D15, the carrying amount of the Company’s investment in 
ordinary shares held in Orchard Therapeutics (Europe) Limited at the date of transition at deemed 
cost, being the previous GAAP carrying amount at this date. 
The Company is included in the consolidated ﬁnancial statements of Orchard Therapeutics plc, which 
are prepared in accordance with UK-adopted IFRS and are included within this Annual Report.  
In these ﬁnancial statements, the Company has applied the exemptions available under FRS 101 in 
respect of the following disclosures: 
–
Cash Flow Statement and related notes;  
–
Comparative period reconciliations for share capital; 
–
Disclosures in respect of transactions with wholly owned subsidiaries;  
–
Disclosures in respect of capital management;  
–
The effects of new but not yet effective IFRSs; 
–
An additional balance sheet for the beginning of the earliest comparative period following the 
retrospective change in accounting policy; and 
–
Disclosures in respect of the compensation of Key Management Personnel.  
As the consolidated ﬁnancial statements of Orchard Therapeutics plc include the equivalent 
disclosures, the Company has also taken the exemptions under FRS 101 available in respect of the 
following disclosures: 
–
IFRS 2 Share-Based Payments in respect of group settled share-based payments 
–
Certain disclosures required by IFRS 13 Fair Value Measurement and the disclosures required 
by IFRS 7 Financial Instrument Disclosures. 
The accounting policies set out below have, unless otherwise stated, been applied consistently to all 
periods presented in these ﬁnancial statements. 
Judgements made by the directors, in the application of these accounting policies that have 
a signiﬁcant effect on the ﬁnancial statements and estimates with a signiﬁcant risk of material 
adjustment in the next year are discussed in note 2. 
 
Orchard Therapeutics plc 167
Notes to the Parent Company Financial Statements 
continued 

 
168 Orchard Therapeutics plc 
1.3 MEASUREMENT CONVENTION  
The ﬁnancial statements are prepared on the historical cost basis modiﬁed by the revaluation of 
certain items, as stated in the accounting policies and on a going concern basis. 
The Company’s ﬁnancial statements are presented in US dollars, which is the Company’s functional 
currency.  
Amounts reported are based in thousands, except percentages, per share amounts or as otherwise 
noted.  
1.4 GOING CONCERN 
The Company expects that its cash, cash equivalents, and short-term investments as of 31 December 
2022, of $78.4 million, together with the $34 million received in March 2023 from the 2023 Private 
Placement (see note 28 to the Consolidated ﬁnancial statements), will be sufﬁcient to fund its 
operations and capital expenditure requirements, as well as those of the wider Group, for at least 
twelve months from the date of signing of this Annual Report and Financial Statements. Management 
have prepared a budget to support the going concern assumption of the Company which shows the 
Company has sufﬁcient resources to continue as a going concern into 2025. 
1.5 INVESTMENTS IN SUBSIDIARIES  
The investment in the subsidiary arose on the reorganization of the Group in 2018. Investments in 
subsidiaries are carried at cost less impairment. On transition to FRS 101 on 1 January 2021, the 
Company elected to recognised investments in subsidiaries at deemed cost, being the previous 
GAAP carrying amount on this date. The Company recognises additions to the investment associated 
with the value of share-based payment charges associated with subsidiary employees, and 
conversion of intercompany debts to equity investments. Where at the year-end there is evidence of 
impairment, the carrying value of the investment is written down to its recoverable amount. 
1.6 FOREIGN CURRENCY 
Transactions in foreign currencies are translated to the Company’s functional currencies at the foreign 
exchange rate ruling at the date of the transaction. Monetary assets and liabilities denominated in 
foreign currencies at the balance sheet date are translated to the functional currency at the foreign 
exchange rate ruling at that date. Non-monetary assets and liabilities that are measured in terms of 
historical cost in a foreign currency are translated using the exchange rate at the date of the 
transaction. Foreign exchange differences arising on translation are recognised in the proﬁt and loss 
account. 
1.7 FINANCIAL INSTRUMENTS 
The Company’s ﬁnancial instruments include amounts owed by subsidiary undertakings, trade 
creditors, cash and cash equivalents, borrowings, and short-term investments.  
Cash and cash equivalents 
Cash and cash equivalents comprise cash balances, deposits held at call with banks and short-term 
highly liquid investments purchased with original maturities of 90 days or less at the date of 
acquisition.  
Intercompany receivables  
Receivables due from other group companies for services performed in the ordinary course of 
business are recognised initially at fair value and subsequently measured at amortised cost using 
the effective interest method, less any impairment losses. The Company applies IFRS 9 to measuring 
expected credit losses on all intercompany receivables (see note 2).  
Notes to the Parent Company Financial Statements 
continued

 
Orchard Therapeutics plc 169
1.7 FINANCIAL INSTRUMENTS continued 
Trade creditors 
Trade creditors represent obligations to pay for goods or services that have been acquired in the 
ordinary course of business from suppliers. Trade creditors are recognised initially at fair value and 
subsequently measured at amortised cost using the effective interest method. 
Short-term investments 
Short-term investments consist of debt securities with original maturities of greater than ninety days. 
The Company has classiﬁed its investments with maturities beyond one year as short term, based 
on their highly liquid nature and because such investments represent the investment of cash that is 
available for current operations 
Short-term investments have been classiﬁed as measured at fair value through other comprehensive 
income ‘FVOCI’ as a) they are held within a business model whose objective is achieved by both 
collecting contractual cash ﬂows and selling ﬁnancial assets; and b) their contractual terms give rise 
on speciﬁed dates to cash ﬂows that are solely payments of principal and interest on the principal 
amount outstanding. 
Short-term investments in debt securities are subsequently measured at fair value. Interest income 
calculated using the effective interest method, foreign exchange gains and losses and impairment 
are recognised in proﬁt or loss. Other net gains and losses are recognised in other comprehensive 
income ‘OCI’. On derecognition, gains and losses accumulated in OCI are reclassiﬁed to proﬁt or loss. 
Borrowings  
Interest-bearing borrowings are initially measured at fair value (with direct transaction costs being 
amortised over the life of the loan) and are subsequently measured at amortised cost using the effective 
interest rate method at each reporting date. Interest expenses are recognised in proﬁt or loss. 
1.8 SHARE CAPITAL  
Ordinary shares are classiﬁed as equity. Incremental costs directly attributable to the issuance of 
share capital are shown as a deduction to equity, net of tax. 
1.9 SHARE-BASED PAYMENTS 
Share-based payment arrangements in which the Company receives goods or services as 
consideration for its own equity instruments are accounted for as equity-settled share-based payment 
transactions. The Company operates a number of equity-settled, share-based compensation plans, 
under which the Company grants equity shares to employees of subsidiaries and Non-executive 
Directors.  
The fair value of each share option is estimated on the grant date using the Black Scholes option 
pricing model which utilizes a number of inputs to estimate the fair value of share options such as 
the current share price, expected term, volatility, interest rate, dividend rate and exercise price. 
The fair value of the employee services received in exchange for the grant of the options is 
recognised as an expense in the subsidiary’s proﬁt and loss account, with a corresponding capital 
contribution from the Company. The expense is recognised in accordance with IFRS2 so that awards 
with graded vesting are treated as separate grants and  the expense associated with each of these 
separate grants is recognised over the associated vesting period. The amount recognised as an 
expense is adjusted to reﬂect the actual number of awards for which the related service and non-
market vesting conditions are expected to be met, such that the amount ultimately recognised as an 
expense is based on the number of awards that do meet the related service and non-market 
performance conditions at the vesting date. For Performance-based share awards (PSUs) which vest 
on achievement of speciﬁc milestones, known as a non-market performance condition, the associated 
expense is recognised from the point in time that vesting of the award is considered probable. 
Notes to the Parent Company Financial Statements 
continued 

 
170 Orchard Therapeutics plc 
1.9 SHARE-BASED PAYMENTS continued 
The Company records an increase in the cost of investment in its subsidiaries equivalent to the equity-
settled share-based payment charge recognised by the subsidiary with the corresponding credit 
being recognised directly in equity. 
The expense associated with equity-based awards to our Non-executive Directors is recognized in 
the Company’s proﬁt and loss account. 
2
ACCOUNTING ESTIMATES AND JUDGEMENTS 
In preparing the ﬁnancial statements, management had made judgements and estimates that affect 
the application of the Company’s accounting policies and the reported amounts of assets and 
liabilities, income and expenses. Although these estimates are based on management's best 
knowledge of current events and actions, actual results ultimately may differ from those estimates. 
The estimates and assumptions that have a signiﬁcant risk of causing a material adjustment to the 
carrying amounts of assets and liabilities within the next ﬁnancial year are addressed below:  
INVESTMENT IN, AND RECEIVABLE FROM, SUBSIDIARIES 
Management performs an annual impairment assessment of the investment held in, and receivable 
due from, Orchard Therapeutics (Europe) Limited. The receivable is repayable on demand; the 
expected credit loss associated with the balance is therefore based on the assumption repayment 
of the loan is demanded at the reporting date, taking into consideration the expected manner of 
recovery. 
The valuation of the subsidiary is derived from publicly available information, being the market 
capitalisation of the Group, at the year-end date, given that the future value of the Group is expected 
to be generated from the products and treatments which are being developed by the subsidiary 
companies.  
On the balance sheet date, where the market capitalisation of the Group as a whole falls below the 
carrying value of the investment and intercompany receivable due, management will perform a fair 
value less cost to sell calculation and then consider whether an impairment of the investment or 
intercompany receivable is required. Any impairment charge required is recognised in the Company’s 
proﬁt and loss account.  
In the event the Group's market capitalisation increases and the reasons for any impairment loss 
have ceased to apply, an impairment loss may be reversed in a subsequent period in the Company’s 
proﬁt and loss account, to the extent the carrying value would have been determined had no 
impairment loss been recognized for the investment in prior years.  
In the year ended 31 December 2022 an impairment of $10.9 million (2021: $299.5 million) and $113.7 
million (2021: $121.2 million) have been recognised against the investment in subsidiary and 
receivable from subsidiary respectively. 
Management has performed sensitivity analysis over the inputs to the impairment calculation and 
concluded that no changes to inputs would result in a material difference to the carrying value of the 
investment or intercompany receivable that remains post impairments being recognised. 
Notes to the Parent Company Financial Statements 
continued

 
Orchard Therapeutics plc 171
3
INVESTMENT IN SUBSIDIARY UNDERTAKINGS  
                                                                                                                                                                                        $000 
Cost                                                                                                                                                            
At 1 January 2022                                                                                                                       299,527 
Share-based payments associated with subsidiary employees                                                   10,929 
At 31 December 2022                                                                                                                  310,455 
 
Provision for impairment  
At 1 January 2022                                                                                                                       299,527 
Impairment charge for the year                                                                                                      10,929 
At 31 December 2022                                                                                                                  310,455 
 
Net book value  
At 31 December 2022                                                                                                                             – 
At 1 January 2022                                                                                                                                   – 
Share-based payment cost of $10.9 million (2021: $19.9 million) was recorded as a capital 
contribution from Orchard Therapeutics plc, the Parent Company, to Orchard Therapeutics (Europe) 
Limited and subsidiaries, as a capital injection into the subsidiary’s Balance Sheet. 
As the market capitalisation of the Group declined further in 2022, the Parent Company performed 
an impairment analysis on a fair value less cost to sell basis, whereby the Parent Company used the 
market capitalisation of the Group as the approximate fair value and the cost to sell and control 
premium were deemed to be negligible. The carrying value of the investment exceeded the fair value 
less cost to sell of the investment as at 31 December 2022, and the Parent Company concluded that 
the investment was impaired by $10.9 million (2021: $299.5 million). If the market capitalisation of 
the Group increases subsequent to the year end, then all or a portion of this impairment charge 
could be reversed in future years to reﬂect any improvement in the underlying business of the Group. 
Details of the Company’s subsidiary undertakings as at 31 December 2022 are set out in note 14 in 
the consolidated group ﬁnancial statements of Orchard Therapeutics plc. 
The Company has provided a parent company guarantee under section 479C of the Companies Act 
2006 in respect of all liabilities outstanding at 31 December 2022 of its subsidiary undertaking, 
Orchard Therapeutics (Europe) Limited (the “Subsidiary”), in order that the Subsidiary may take 
advantage of the exemption from audit of its individual ﬁnancial statements for the year ended 
31 December 2022. 
4
DEBTORS 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Amounts due within one year 
Amounts owed by subsidiary undertakings                                                         998                    14,957 
Other receivables                                                                                                  183                         937 
Deferred ﬁnancing costs                                                                                       462                         693 
Prepaid expenses                                                                                                   26                      3,847 
                                                                                                                           1,669                    20,434 
Notes to the Parent Company Financial Statements 
continued 

 
172 Orchard Therapeutics plc 
4
DEBTORS continued 
Amounts owed by subsidiary undertakings are unsecured, interest free, have no ﬁxed date of 
repayment and are repayable on demand. 
The Company has an unrecognised deferred tax asset of $6.7 million at 31 December 2022 
(2021: $6.1 million). 
5
SHORT TERM INVESTMENTS 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Current 
Commercial paper                                                                                            40,991                    64,406 
Corporate bonds                                                                                                9,927                    83,590 
                                                                                                                         50,918                  147,996 
Investments in commercial paper have ﬁxed coupon rates at 1.1% - 4.9% (2021: 0.1–0.3%) and 
mature between 1 January 2023 and 31 October 2023 (2021: 1 January 2022 and 30 November 
2022). Investments in corporate bonds have ﬁxed coupon rates at 0.4% - 4.5% (2021: 0.2–3.2%) and 
mature between (2021: 1 January 2022 and 31 October 2023).  
6
CREDITORS 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Amounts due within one year 
Bank loans                                                                                                          9,429                         786 
Trade creditors                                                                                                      616                         308 
Accruals                                                                                                             1,162                         512 
                                                                                                                         11,207                      1,606 
Amounts falling due after more than one year 
Bank loans                                                                                                       22,991                    32,086 
                                                                                                                         34,198                    33,692 
7
INTEREST-BEARING LOANS AND BORROWINGS 
This note provides information about the contractual terms of the Group’s interest-bearing loans and 
borrowings, which are measured at amortised cost. For more information about the Group’s exposure 
to interest rate and foreign currency risk, see note 24 in the Consolidated ﬁnancial statements. 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Amounts due within one year 
Bank loans                                                                                                          9,429                         786 
Amounts falling due after more than one year 
Bank loans                                                                                                       23,236                    32,417 
                                                                                                                         32,665                    33,203 
Less: unamortised debt issue costs                                                                    (245)                      (331) 
                                                                                                                         32,420                    32,872 
Notes to the Parent Company Financial Statements 
continued

 
Orchard Therapeutics plc 173
7
INTEREST-BEARING LOANS AND BORROWINGS continued 
In May 2019, the Company entered into a senior term facilities agreement, which was amended in 
April 2020 (the “Original Credit Facility”) with MidCap Financial (Ireland) Limited (“MidCap Financial”), 
as agent, and additional lenders from time to time (together with MidCap Financial, the “Lenders”), 
to borrow up to $75.0 million in term loans. 
In May 2021, the Company amended and restated the Original Credit Facility (the “Amended Credit 
Facility”). Under the Amended Credit Facility, the Lenders agreed to make term loans available to the 
Company in the aggregate amount of $100.0 million, including increasing the principal on the initial 
term loan to $33.0 million, from $25.0 million. To date, the Company has borrowed $33.0 million under 
the amended initial term loan. The remaining $67.0 million under the Amended Credit Facility may be 
drawn down in the form of a second and third term loan, the second term loan being a $33.0 million 
term loan available no earlier than 1 July 2022 and no later than 1 July 2023 upon certain regulatory 
approvals and evidence of the Company having $100 million in cash and cash equivalent investments; 
and the third term loan being a $34.0 million term loan available no earlier than 1 July 2023 and no 
later than 1 July 2024 upon evidence of the Company having $100 million in cash and cash equivalent 
investments and attaining a prespeciﬁed trailing 12-month revenue target. 
Prior to execution of the Amended Credit Facility, each term loan under the Original Credit Facility 
bore interest at an annual rate equal to 6.0% plus LIBOR. The Company was required to make 
interest-only payments on the term loan for all payment dates prior to 24 months following the date 
of the Original Credit Facility, unless the third tranche was drawn, in which case for all payment dates 
prior to 36 months following the date of the Original Credit Facility. The term loans prior to the 
Amended Credit Facility were to begin amortising on either the 24-month or the 36-month anniversary 
of the Original Credit Facility (as applicable), with equal monthly payments of principal plus interest 
to be made by the Borrower to the Lenders in consecutive monthly instalments until the loan maturity 
date. In addition, a ﬁnal payment of 4.5% was due on the loan maturity date. The Company accrued 
the ﬁnal payment amount of $1.1 million associated with the ﬁrst term loan of the Original Credit 
Facility, to outstanding debt by charges to interest expense using the effective-interest method from 
the date of issuance through the date of the Amended Credit Facility. Upon execution of the 
Amended Credit Facility, the Company was required to make a payment of $0.5 million for the 
accrued ﬁnal payment associated with the Original Credit Facility, which was netted against proceeds 
from the additional initial term loan. 
Each term loan under the Amended Credit Facility bears interest at an annual rate equal to 5.95% 
plus LIBOR. The Company is required to make interest only payments on the term loan for 18 months 
following the date of the Amended Credit Facility, unless the Company is eligible for the second 
tranche, in which case the Company may elect to make interest-only payments for 30 months following 
the date of the Amended Credit Facility. The term loans under to the Amended Credit Facility begin 
amortising on either the 18-month or the 30-month anniversary of the Amended Credit Facility 
(as applicable), with equal monthly payments of principal plus interest to be made by the Company 
to the Lenders in consecutive monthly instalments until the loan maturity date. In addition, a ﬁnal 
payment of 3.5% of the amount borrowed is due on the loan maturity date. The Company is accruing 
the ﬁnal payment amount of $1.2 million associated with the ﬁrst term loan of the Amended Credit 
Facility, to outstanding debt by charges to interest expense using the effective-interest method from 
the date of issuance through the loan maturity date. 
Notes to the Parent Company Financial Statements 
continued 

 
174 Orchard Therapeutics plc 
7
INTEREST-BEARING LOANS AND BORROWINGS continued 
The Amended Credit Facility includes afﬁrmative and negative covenants. The afﬁrmative covenants 
include, among others, covenants requiring the Company to maintain their legal existence and 
governmental approvals, deliver certain ﬁnancial reports, maintain insurance coverage, maintain 
property, pay taxes, satisfy certain requirements regarding accounts and comply with laws and 
regulations. The negative covenants include, among others, restrictions on the Company transferring 
collateral, incurring additional indebtedness, engaging in mergers or acquisitions, paying dividends 
or making other distributions, making investments, creating liens, amending material agreements and 
organisational documents, selling assets, changing the nature of the business and undergoing a 
change in control, in some cases subject to certain exceptions. The Company is also subject to an 
ongoing minimum cash ﬁnancial covenant in which the Company must maintain unrestricted cash in 
an amount not less than $20.0 million following the utilisation of the second term loan and not less 
than $35.0 million following the utilisation of the third term loan. 
In January 2023, the Company again amended and restated the credit facility to change from LIBOR 
to secured overnight ﬁnancing rate (SOFR) administered by the Federal Reserve Bank of New York. 
The newly amended facility bears a variable interest rate of 5.95% above SOFR plus 
0.10% per annum, plus a ﬁnal payment equal to 3.5% of the principal borrowed under the Amended 
Credit Facility. 
During the year ended 31 December 2022, the Company recognized $3.0 million (2021:  $2.5 million) 
of interest expense related to the term loan The effective annual interest rate as of 31 December 
2022, on the outstanding debt under the Term Loan was approximately 9.2% (2021: 8.4%). 
8
CAPITAL AND RESERVES 
SHARE CAPITAL 
                                                                                                                                                                    Ordinary shares 
In thousands of  shares 
In issue at 1 January 2022                                                                                                                 125,674 
Issued for share options                                                                                                                         1,268 
Issued as part of a consulting agreement                                                                                                   5 
In issue at 31 December 2022 – fully paid                                                                                     126,947 
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Ordinary shares allotted and fully paid, £0.10 nominal value                       16,409                    16,243 
As of 31 December 2022, and 2021, the Company had authority to allot ordinary shares up to a 
maximum nominal value of £13,023,851.50 with a nominal value of £0.10 per share. As of 
31 December 2022, there were 126,947,225 ordinary shares issued and outstanding 
(2021: 125,674,095). As of 31 December 2022, there were a total of 16,424,167 share options in 
respect of ordinary shares outstanding (2021: 17,300,740). In addition, as of 31 December 2022 
there were 2,063,876 unvested restricted share units outstanding in respect of ordinary shares 
outstanding (2021: 318,333). 
Each holder of ordinary shares is entitled to one vote per ordinary share and to receive dividends 
when and if such dividends are recommended by the board of directors and declared by the 
shareholders. As of 31 December 2022, the Company. has not declared any dividends (2021: $nil). 
Notes to the Parent Company Financial Statements 
continued

 
Orchard Therapeutics plc 175
8
CAPITAL AND RESERVES continued 
SHARE PREMIUM 
Share premium represents the excess paid for the issuance of ordinary shares, over and above their 
nominal value. 
SHARE BASED PAYMENTS 
The share-based payment reserve arises due to the share options issued by the company to its 
employees within the Group. 
OTHER COMPREHENSIVE INCOME 
The Other comprehensive income reserve includes the cumulative net change in the fair value of 
debt securities measured at fair value through other comprehensive income.  
9
RELATED PARTY TRANSACTIONS 
Related party transactions are detailed in note 27 in the Company’s consolidated ﬁnancial statements. 
The Company has taken advantage of the exemption, under FRS 101 paragraph 8(k) to not disclose 
related party transactions with other companies that are wholly owned within the Group. 
10 ULTIMATE PARENT UNDERTAKING AND CONTROLLING 
PARTY  
There is no ultimate parent undertaking or controlling party of the Company as ownership is split 
between the Company's shareholders. 
11 SUBSEQUENT EVENTS 
Subsequent events are detailed in note 28 in the Company’s consolidated ﬁnancial statements. 
12 EMPLOYEES AND DIRECTOR EMOLUMENTS 
The monthly average number of people employed by the Company (including Directors) in 2022 was 
7 (2021: 7), which is comprised solely of the Directors of the Company. 
Amounts paid to Directors consists of:  
                                                                                                                                                    2022                            2021 
                                                                                                                                                    $000                            $000 
Aggregate emoluments                                                                                      1,386                      1,333 
Aggregate gains made on the exercise of share options                                         –                           45 
                                                                                                                           1,386                      1,378 
Detailed remuneration disclosures are provided in the Directors’ Remuneration Report. 
Notes to the Parent Company Financial Statements 
continued 

13 Explanation of transition to FRS 101  
As stated in note 1, these are the Company’s ﬁrst ﬁnancial statements prepared in accordance with 
FRS 101. The accounting policies set out in note 1 and 2 have been applied in preparing the ﬁnancial 
statements for the year ended 31 December 2022, the comparative information presented in these 
ﬁnancial statements for the year ended 31 December 2021 and in the preparation of an opening FRS 
101 balance sheet at 1 January 2021 (the Company’s date of transition). 
In preparing its FRS 101 balance sheet, the Company has adjusted amounts reported previously in 
ﬁnancial statements prepared in accordance with its old basis of accounting (FRS 102).  
The Company has granted Share Options to employees and directors of the Orchard Therapeutics 
plc Group with various vesting schedules which are capable of being exercised as they vest in 
monthly tranches over a period of three to four years from the grant date.   
The fair value of the employee services received in exchange for the grant of the options is 
recognised as an expense in the subsidiary’s proﬁt and loss account, with a corresponding capital 
contribution from the Company. Under FRS 102, the Group measured the awards granted to 
employees based on the fair value on the date of grant and recognised a compensation expense, in 
the employing entity’s proﬁt and loss account, on a straight-line basis over the vesting period.  
Under FRS 101, each tranche is accounted for as a separate share-based payment. Consequently, 
each instalment would be separately measured and attributed to expense over the related vesting 
period. The Company has determined and adjusted the fair value, and associated share-based 
payment expense recognised, for all options with monthly vesting which remain outstanding from the 
date of transition. 
For equity-based awards made to employees of the Group, the expense is recognised by the 
Company as a capital contribution made to the employing subsidiary and is recorded as an increase 
in the cost of investment in subsidiaries. For equity-base awards made to Non-executive Directors, 
the associated expense is recognised in the Company’s proﬁt and loss account. 
The cumulative impact of this change on the date of transition, being 1 January 2021 was a reduction 
to cost of investments in subsidiaries, prior to impairment, of $45.1 million, and a corresponding 
reduction in impairment of investments in subsidiaries of $45.1 million. For the year ended 
31 December 2021, the Company has recognised on transition a reduction in additions to investment 
in subsidiaries of $7.7 million, and a corresponding reduction in impairment charge for the year of 
$7.7 million.  
 
176 Orchard Therapeutics plc 
Notes to the Parent Company Financial Statements 
continued

13 Explanation of transition to FRS 101 continued 
RECONCILIATION OF PROFIT AND LOSS 
                                                                                                                                                                                        2021 
                                                                                                                                                                                        $000 
Loss after tax for the year ended 31 December 2021 
As previously reported under FRS 102                                                                                       (437,351) 
Reduction in share-based payment expense                                                                                  1,164 
Reduction in impairment charge in investments in subsidiaries                                                      7,665 
Restated under FRS 101                                                                                                            (428,520) 
RECONCILIATION OF EQUITY  
                                                                                           Effect of                                                Effect of                       
                                                                                     transition to                                          transition to                       
                                                                   FRS 102          FRS 101        FRS 101    FRS 102        FRS 101        FRS 101 
                                                                          2020                2020              2020          2021              2021              2021 
                                                                          $000                $000              $000          $000              $000              $000 
Equity  
Share capital                                      12,497                   –        12,497    16,243                 –        16,243 
Share premium                                339,435                   –      339,435  486,382                 –      486,382 
Share-based payment reserve        115,062        (47,439)       67,623  143,794       (56,271)       87,523 
Other comprehensive income                  83                   –               83        (137)                –           (137) 
Retained earnings                            (38,383)        47,439          9,056 (475,735)       56,271    (419,464) 
Shareholders’ equity                     428,694                   –      428,694  170,547                 –      170,547 
There were no transition effects on the previously disclosed values for assets and liabilities. 
 
Orchard Therapeutics plc 177
Notes to the Parent Company Financial Statements 
continued 

Perivan.com 
265432

 
UNITED STATES 
SECURITIES AND EXCHANGE COMMISSION 
Washington, D.C. 20549 
 
FORM 10-K 
 
 (Mark One) 
☒
ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 
1934 
For the fiscal year ended December 31, 2022
OR 
☐
TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT 
OF 1934 FOR THE TRANSITION PERIOD FROM                      TO                     
Commission File Number 001-38722
 
ORCHARD THERAPEUTICS PLC 
(Exact name of Registrant as specified in its Charter) 
 
 
England and Wales
Not Applicable
(State or other jurisdiction of
incorporation or organization)
(I.R.S. Employer
Identification No.)
245 Hammersmith Road
London W6 8PW
United Kingdom
(Address of principal executive offices)
Registrant’s telephone number, including area code: +44 (0) 203 808-8286
 
Securities registered pursuant to Section 12(b) of the Act:
Title of each class
Trading Symbol(s)
Name of each exchange on which registered
American Depositary Shares, each representing 
one ordinary share, nominal value £0.10 per 
share
ORTX
The Nasdaq Capital Market
Securities registered pursuant to Section 12(g) of the Act: None
Indicate by check mark if the Registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☐ NO ☒
Indicate by check mark if the Registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act.  YES ☐ NO ☒
Indicate by check mark whether the Registrant: (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities 
Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the Registrant was required to file such reports), and 
(2) has been subject to such filing requirements for the past 90 days.  YES ☒ NO ☐
Indicate by check mark whether the Registrant has submitted electronically every Interactive Data File required to be submitted pursuant to 
Rule 405 of Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the Registrant was 
required to submit such files).  YES ☒ NO ☐
Indicate by check mark whether the Registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, smaller reporting 
company, or an emerging growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting 
company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer
☐
 Accelerated filer
☐
Non-accelerated filer
☒
 Smaller reporting company
☒
Emerging growth company
☐
If an emerging growth company, indicate by check mark if the Registrant has elected not to use the extended transition period for 
complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.  ☐
Indicate by check mark whether the Registrant has filed a report on and attestation to its management’s assessment of the effectiveness of 
its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public 
accounting firm that prepared or issued its audit report.  ☐
If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant 
included in the filing reflect the correction of an error to previously issued financial statements. ☐
Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based 
compensation received by any of the registrant’s executive oﬃcers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act).  YES ☐ NO ☒
As of the last business day of the Registrant’s most recently completed second fiscal quarter, the aggregate market value of the Registrant’s 
ordinary shares, nominal value £0.10 per share, held by non-affiliates was approximately $74 million, based on the last sale price of the 
Company's American Depositary Shares at the close of business on June 30, 2022. 
As of March 10, 2023, the Registrant had 183,984,499 ordinary shares, nominal value £0.10 per share, outstanding, which if all held in 
ADS form would be represented by 18,398,449 American Depositary Shares, each representing ten ordinary shares.  

DOCUMENTS INCORPORATED BY REFERENCE
Portions of the Registrant’s definitive proxy statement for its 2023 Annual General Meeting are incorporated by reference into Part III of 
this Annual Report on Form 10-K where indicated.

Summary of the Material Risks Associated with Our Business 
Our business is subject to numerous risks and uncertainties that you should be aware of in evaluating our business. These risks 
include, but are not limited to, the following:
•
We have incurred net losses since inception. We expect to incur net losses for the foreseeable future and may never 
achieve or maintain profitability.
•
We will need additional funding, which may not be available on acceptable terms or at all.
•
Our gene therapy product candidates are based on a novel technology, which makes it difficult to predict the time 
and cost of product candidate development and of subsequently obtaining regulatory approval.
•
The results from our clinical trials for any of our product candidates may not be sufficiently robust to support 
marketing approval or the submission of marketing approval. Before we submit our product candidates for 
marketing approval, the U.S. Food and Drug Administration or the European Medicines Agency may require us to 
conduct additional clinical trials or evaluate patients for an additional follow-up period.
•
Interim data and ad hoc analyses are preliminary in nature. Success in pre-clinical studies or early clinical trials may 
not be indicative of results obtained in later trials.
•
Gene therapies are novel, complex and difficult to manufacture. We have limited manufacturing experience, and we 
rely on third-party manufacturers that are often our single source of supply. 
•
Libmeldy™, Strimvelis® and our product candidates and the process for administering Libmeldy, Strimvelis and our 
product candidates may cause serious or undesirable side effects or adverse events. 
•
We may find it difficult to enroll patients in our clinical trials, which could delay or prevent us from proceeding with 
clinical trials of our product candidates.
•
We may be unable to establish effective sales and marketing capabilities, which would negatively impact our 
revenue. 
•
If the size and value of the market opportunities for our commercial products or product candidates are smaller than 
our estimates, or if we have difficulty in finding patients that meet eligibility requirements for Libmeldy or any of 
our product candidates, if approved, our product revenues may be adversely affected. 
•
We face significant competition in our industry and there can be no assurance that our commercial products or our 
product candidates, if approved, will achieve acceptance in the market. 
•
We may experience disruptions in the development of our product candidates as the result of the COVID-19 
pandemic. 
•
We may be unable to protect our intellectual property rights throughout the world.
•
We may become subject to claims that we are infringing certain third-party patents.
•
We have in the past, and in the future we may, enter into collaborations with third parties to develop or 
commercialize product candidates. These collaborations may not be successful.
•
The market price of our ADSs may be highly volatile and may fluctuate due to factors beyond our control.
The summary risk factors described above should be read together with the text of the full risk factors below, in the section 
entitled “Risk Factors” in Part I, Item 1.A. and the other information set forth in this Annual Report on Form 10-K, including 
our consolidated financial statements and the related notes, as well as in other documents that we file with the U.S. Securities 
and Exchange Commission. The risks summarized above or described in full below are not the only risks that we face. 
Additional risks and uncertainties not precisely known to us, or that we currently deem to be immaterial may also materially 
adversely affect our business, financial condition, results of operations and future growth prospects.

i
Table of Contents
Page
PART I
4
Item 1.
Business
36
Item 1A.
Risk Factors
95
Item 1B.
Unresolved Staff Comments
95
Item 2.
Properties
95
Item 3.
Legal Proceedings
96
Item 4.
Mine Safety Disclosures
96
PART II
97
Item 5.
Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of 
Equity Securities
97
Item 6.
Reserved
97
Item 7.
Management’s Discussion and Analysis of Financial Condition and Results of Operations
98
Item 7A.
Quantitative and Qualitative Disclosures About Market Risk
109
Item 8.
Financial Statements and Supplementary Data
110
Item 9.
Changes in and Disagreements with Accountants on Accounting and Financial Disclosure
110
Item 9A.
Controls and Procedures
110
Item 9B.
Other Information
111
Item 9C
Disclosure Regarding Foreign Jurisdiction that Prevents Inspections
118
PART III
119
Item 10.
Directors, Executive Officers and Corporate Governance
119
Item 11.
Executive Compensation
119
Item 12.
Security Ownership of Certain Beneficial Owners and Management and Related Stockholder 
Matters
119
Item 13.
Certain Relationships and Related Transactions, and Director Independence
119
Item 14.
Principal Accounting Fees and Services
119
PART IV
120
Item 15.
Exhibits, Financial Statement Schedules
120
Item 16
Form 10-K Summary
123

2
SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K, or Annual Report, contains express or implied forward-looking statements within the 
meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, 
as amended, that involve substantial risks and uncertainties. In some cases, forward-looking statements may be identified by 
the words “may,” “might,” “will,” “could,” “would,” “should,” “expect,” “intend,” “plan,” “objective,” “anticipate,” 
“believe,” “estimate,” “predict,” “potential,” “continue,” “ongoing,” or the negative of these terms, or other comparable 
terminology intended to identify statements about the future. These statements involve known and unknown risks, 
uncertainties and other important factors that may cause our actual results, levels of activity, performance or achievements to 
be materially different from the information expressed or implied by these forward-looking statements. The forward-looking 
statements and opinions contained in this Annual Report are based upon information available to our management as of the 
date of this Annual Report, and while we believe such information forms a reasonable basis for such statements, such 
information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an 
exhaustive inquiry into, or review of, all potentially available relevant information. Forward-looking statements contained in 
this Annual Report include, but are not limited to, statements about: 
•
the timing, progress and results of clinical trials and pre-clinical studies for our programs and product 
candidates, including statements regarding the timing of initiation and completion of trials or studies and related 
preparatory work and the period during which the results of the trials or studies will become available; 
•
the timing, scope and likelihood of regulatory submissions, filings and approvals, including our expectations 
and timing to prepare and submit a biologics license application, or BLA, for OTL-200 in mid-2023;
•
our ability to develop and advance product candidates into, and successfully complete, clinical trials; 
•
our expectations regarding the market opportunity for and size of the patient populations for Libmeldy (OTL-
200) and our product candidates, if approved for commercial use; 
•
the implementation of our business model and our strategic plans for our business, commercial products, 
product candidates and technology; 
•
our plans and ability to build out our commercial infrastructure and successfully identify eligible patients for 
Libmeldy in Europe and our product candidates, if approved for commercial use;
•
our commercialization, marketing and manufacturing capabilities and strategy; 
•
the pricing and reimbursement of Libmeldy and any of our product candidates, if approved, including 
reimbursement for patients treated in a country where they are not a resident; 
•
the adequacy, scalability and commercial viability of our manufacturing capacity, methods and processes, 
including those of our manufacturing partners, and our plans for future development; 
•
the rate and degree of market acceptance and clinical utility of our commercial products and product candidates 
and gene therapy in general; 
•
our ability to establish or maintain collaborations or strategic relationships or obtain additional funding; 
•
the impact of the COVID-19 global pandemic on our business operations;
•
our competitive position; 
•
the scope of protection we and our licensors are able to establish and maintain for intellectual property rights 
covering our commercial products and product candidates; 
•
developments and projections relating to our competitors and our industry; 
•
our estimates regarding expenses, future revenue, capital requirements and needs for additional financing; 
•
the impact of laws and regulations; 
•
our ability to attract and retain qualified employees and key personnel;
•
our ability to contract with third-party suppliers, clinical sites and manufacturers and their ability to perform 
adequately; 

3
•
our projected financial condition, including the sufficiency of our cash, cash equivalents and investments to 
fund operations in future periods and future liquidity, working capital and capital requirements; and 
•
other risks and uncertainties, including those listed under the caption “Item 1A. Risk Factors.” 
You should refer to the section titled “Item 1A. Risk Factors” for a discussion of important factors that may cause our actual 
results to differ materially from those expressed or implied by our forward-looking statements. As a result of these factors, 
we cannot be assured that the forward-looking statements in this Annual Report will prove to be accurate. Furthermore, if our 
forward-looking statements prove to be inaccurate, the inaccuracy may be material. In light of the significant uncertainties in 
these forward-looking statements, these statements should not be regarded as a representation or warranty by us or any other 
person that we will achieve our objectives and plans in any specified time frame, or at all. We undertake no obligation to 
publicly update any forward-looking statements, whether as a result of new information, future events or otherwise, except as 
required by law. 
You should read this Annual Report and the documents that we reference in this Annual Report and have filed as exhibits to 
this Annual Report completely and with the understanding that our actual future results may be materially different from 
what we expect. We qualify all of our forward-looking statements by these cautionary statements. 

4
PART I
Item 1. Business. 
We are a global gene therapy company dedicated to transforming the lives of people affected by rare diseases through the 
development of innovative, potentially curative gene therapies. Our ex vivo autologous hematopoietic stem cell, or HSC, gene 
therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct the underlying cause of 
disease in a single administration. We seek to achieve this outcome by utilizing a lentiviral vector to introduce a functional 
copy of a missing or faulty gene into the patient’s own, or autologous, HSCs through an ex vivo process, resulting in a gene-
modified cellular drug product that can then be administered to the patient at the bedside. 
To date, over 170 patients have been treated with our current and former product candidates across seven different diseases, 
with follow-up periods of more than 11 years following a single administration. We believe the data observed across these 
development programs, in combination with our expertise in the development, manufacturing and commercialization of gene 
and cell therapies, position us to provide potentially curative therapies to people suffering from a broad range of diseases. 
We are currently focusing our ex vivo autologous HSC gene therapy approach on severe neurometabolic diseases and early 
research programs. Our lead program is OTL-200, which was approved in the European Union, the United Kingdom, Iceland, 
Liechtenstein and Norway under the brand name Libmeldy for eligible patients with early-onset metachromatic 
leukodystrophy, or MLD. Pending the outcome of the multidisciplinary pre-BLA meeting scheduled for the second quarter of 
2023, we anticipate a potential BLA submission in mid-2023.
Our portfolio includes a commercial-stage product and research and development-stage product candidates. We believe our 
approach of using lentiviral vectors to genetically modify HSCs has wide-ranging applicability to a large number of 
indications. The ability of HSCs to differentiate into multiple cell types allows us to deliver gene-modified cells to multiple 
physiological systems, including the central nervous system, immune system and red blood cell and platelet lineage, thereby 
potentially enabling the correction of a wide range of diseases. By leveraging the innate self-renewing capability of HSCs 
that are engrafted in the bone marrow as well as the ability of lentiviral vectors to achieve stable integration of a modified 
gene into the chromosomes of HSCs, our gene therapies have the potential to provide a durable effect following a single 
administration. 
The diseases we target affect patients around the world, requiring an infrastructure to deliver gene therapies globally. In order 
to meet anticipated demand for our pipeline of approved products and product candidates still in development, we are 
utilizing our existing network of contract development and manufacturing organizations, or CDMOs, to manufacture 
lentiviral vectors and drug product. In addition, we have established process development capabilities in London, UK, and 
are leveraging technologies that will allow us to deliver our gene therapies globally. 
Cryopreservation of our gene-modified HSCs is a key component of our commercialization strategy to deliver potentially 
curative gene therapies to patients worldwide, facilitating both local treatment and local or cross-border product 
reimbursement. We developed a cryopreserved formulation of Libmeldy (OTL-200) and are collecting supportive clinical 
data from patients treated with cryopreserved formulations to support the analytical comparability to the fresh cell 
formulations used in our registrational clinical trials. The registrational trials for all our earlier stage product candidates are 
expected to be conducted using a cryopreserved formulation. 
With the exception of OTL-105, our product candidate for the potential treatment of hereditary angioedema, or HAE, which 
we are pursuing in partnership with Pharming Group N.V., we have global commercial rights to all our clinical product 
candidates and plan to commercialize our gene therapies in key markets worldwide, including in Europe and the U.S. 
initially, subject to obtaining the necessary marketing approvals for these jurisdictions. We are focused on deploying a 
commercial infrastructure to deliver Libmeldy and our product candidates, if approved, to patients and are focused on 
working closely with all relevant stakeholders, including patients, caregivers, specialist physicians and payors, to ensure the 
widest possible post-approval access for our product candidates. In addition, we may rely on third parties to assist with 
regulatory submissions, disease awareness, patient identification and reimbursement in countries where local expertise is 
required or where we do not have a direct presence. 

5
As we continue to develop our portfolio, we believe that the experience of our management team and our extensive academic 
relationships are key strategic strengths. Our management team has extensive experience in rare diseases and in the 
manufacturing, pre-clinical and clinical development and commercialization of gene and cell therapies. In addition, we 
partner with leading academic institutions around the world, which are pioneers in ex vivo autologous HSC-based gene 
therapy. We plan to leverage our internal expertise combined with our relationships with leading academic institutions to 
transition our lead clinical-stage product candidates to commercialization and continue to expand our portfolio of ex vivo 
autologous HSC gene therapy products. 
Our ex vivo autologous HSC gene therapy approach 
Our ex vivo autologous HSC gene therapy approach seeks to transform a patient’s autologous HSCs into a gene-modified 
cellular drug product to treat the patient’s disease. HSCs are self-renewing cells that are capable of differentiating into all 
types of blood cells, including white blood cells, red blood cells, platelets and tissue resident macrophages, which include the 
microglia of the central nervous system. HSCs can be obtained directly from the bone marrow, which requires administration 
of a general anesthetic, or from the patient’s peripheral blood with the use of mobilizing agents, which are agents that can 
move HSCs from the bone marrow into the peripheral blood for easier collection. The HSCs collected are then manufactured 
to insert a functional copy of the missing or faulty gene. By delivering gene-modified HSCs back to patients, we seek to take 
advantage of the self-renewing capability of HSCs to enable a durable effect following a single administration, as has been 
seen in our commercial and development programs. Since these cells are recognized by the body as the patient’s own cells, 
the risks associated with using donor cells may be reduced. In addition, the ability of HSCs to differentiate into multiple 
different cell types has the potential to enable the delivery of gene-modified cells to different physiological systems and allow 
the correction of a broad range of different diseases. 
Clinical validation already exists for hematopoietic stem cell transplantation, or HSCT, an approach of treating a patient with 
a genetic disease with HSCs contributed by a healthy donor individual, thereby using HSCs that contain a functioning copy 
of the gene of interest. However, this approach has significant limitations, including difficulties in finding appropriate 
genetically matched donors and the risk of graft-versus-host disease, transplant-related rejection and mortality from these and 
other complications, and is therefore typically only offered on a limited basis. Furthermore, genetically modified cells can be 
used to express enzyme activity at supra-physiological levels, which we believe has the potential to overcome the limitations 
of HSCT (where enzyme expression is generally limited to normal levels) to treat some neurometabolic disorders and 
improve the metabolic correction in neuronal cells before irreversible degeneration occurs. Our approach is intended to 
address these significant limitations of HSCT. 
In a pre-clinical study conducted by one of our scientific advisors and published in Proceedings of the National Academy of 
Sciences of the United States of America, or PNAS, a sub population of gene-modified HSCs has evidenced the potential to 
cross the blood-brain barrier, engraft in the brain as microglia and express genes and proteins within the central nervous 
system, one of the important physiological systems targeted by our HSC gene therapy approach. As published in PNAS, 
images taken during the study show a cross-section of the brain of a mouse that was infused intravenously with HSCs, which 
had been genetically modified using a lentiviral vector carrying green fluorescent protein, or GFP. The GFP expression 
observed throughout the brain illustrates the potential of gene-modified HSCs to cross the blood-brain barrier, engraft in the 
brain and express the functional protein throughout the brain, thereby potentially addressing a range of diseases that affect the 
central nervous system. Libmeldy (OTL-200), for instance, leverages this same mechanism of action to deliver gene-
modified HSCs that can cross the blood-brain barrier and deliver a therapeutic gene that can prevent neuronal degeneration. 
The study demonstrated widespread distribution and expression of GFP in the brain of a mouse model following intravenous 
administration of HSCs transduced with GFP encoding vector.
With respect to Libmeldy (OTL-200) and each of our product candidates, our ex vivo gene therapy approach utilizes a self-
inactivating, or SIN, lentiviral vector to introduce a functional copy of the missing or faulty gene into the patient’s autologous 
HSCs through an ex vivo process called transduction, resulting in a cellular drug product that can then be re-introduced into 
the patient. Unlike some other viral vectors, such as adeno-associated viral, or AAV, vectors, lentiviral vectors integrate into 
the chromosomes of patients’ HSCs. We believe this allows us to achieve stable integration of the functional gene into the 
HSCs and can lead to durable expression of the target protein by the gene-modified HSCs and their progeny after a single 
administration of gene therapy. In contrast, because AAV vectors rarely integrate into the genome, the transgene is not passed 
on to all progeny when the cell divides, resulting in rapid dilution and loss of the transgene among frequently dividing cells 
such as HSCs. Regarding immunogenicity, because in vivo delivery of AAV places the vector into direct contact with the 
immune system and most individuals harbor some type of pre-existing immunity, including neutralizing antibodies, to one or 
more types of AAV vector, the incoming vector can be completely inactivated by the patient’s immune system. Furthermore, 
there have been reports that certain high dose applications of AAV have resulted in acute and severe innate immune 
responses that have proved lethal. With ex vivo delivery, however, the vector is not introduced directly into the body and 

6
vector elements are washed away in the laboratory such that there is little to no vector element left to present to the immune 
system. Our HSC gene therapies and product candidates are all manufactured ex vivo. 
Strimvelis for adenosine deaminase severe combined immunodeficiency, or ADA-SCID, is the only gammaretroviral vector-
based gene therapy in our portfolio. In March 2022, we announced that we would discontinue our investment in and seek 
alternatives for Strimvelis.
The image below illustrates the steps in our approach to transform a patient’s autologous HSCs ex vivo into therapeutic 
product. 
Initial clinical trials conducted using our product candidates utilized a fresh product formulation, resulting in a limited drug 
product shelf life. We market Libmeldy (OTL-200) and plan to market our current and any future product candidates, if 
approved, in a cryopreserved product formulation, which is designed to extend the drug product shelf life and enable the 
shipment of the drug product to specialized treatment centers, allowing patients to receive treatment closer to their home 
while leveraging more centralized manufacturing. Cryopreservation also allows us to conduct a number of quality control 
tests on the genetically modified HSCs prior to introducing them into the patient. 
In addition, certain of our clinical-stage product candidates have been evaluated in registrational trials using drug product 
derived from HSCs extracted from the patients’ bone marrow. To optimize our potential product label and the number of 
patients that we may be able to treat, as part of any BLA or MAA submission for such product candidates, we plan to 
demonstrate comparability between drug product manufactured using HSCs derived from the patients’ peripheral blood and 
drug product manufactured using HSCs derived from the patients’ bone marrow. In cases where clinical trials were 
conducted using vector and/or drug product manufactured at academic centers, we plan to demonstrate comparability 
between vector and/or drug product manufactured by our third party commercial CDMOs with vector and drug product 
manufactured at such academic centers. 
We are currently focused on employing our ex vivo autologous HSC gene therapy approach in two therapeutic disease areas: 
neurodegenerative and immunological disorders. We also have a program focused on beta thalassemia, or TDT, a blood 
disorder, but new investments in this program are currently limited. Data from clinical trials suggest that ex vivo autologous 
HSC gene therapy has the potential to provide generally well-tolerated, sustainable and improved outcomes over existing 
standards of care for diseases in these areas. We believe that we can apply our approach beyond our current target indications 
to treat an even broader range of diseases. 
Our strategy 
We are building a leading, global, fully-integrated gene therapy company focused on transforming the lives of people 
affected by severe diseases. To achieve this, we are pursuing the following strategies:
•
Continue our commercialization efforts for Libmeldy (OTL-200) for treatment of eligible patients with early-
onset MLD in Europe and expand geographically into new markets as regulatory approvals are obtained
•
Advance our clinical-stage product candidates towards marketing approvals, including a potential BLA 
submission for OTL-200 in the U.S. in mid-2023

7
•
Leverage the power of our therapeutic approach to investigate the potential of HSC gene therapy in larger 
indications 
•
Invest in new technologies and innovations to continue to improve our manufacturing processes for lentiviral 
vector and drug product and reduce costs of goods manufactured
•
Establish end-to-end process development, manufacturing and supply chain capabilities, initially through third 
parties and internally over time
•
Establish a patient-centric, global commercial infrastructure, including with third parties in certain regions 
where we do not have a direct presence     
•
Execute a business development strategy to leverage our HSC gene therapy approach, expand geographically, 
accelerate time-to-market or attract disease-area expertise to optimize the value of our portfolio of product 
candidates or expand into new indications
Our pipeline 
Our pipeline spans multiple therapeutic areas where the disease burden on children, families and caregivers is immense and 
current treatment options are limited or do not exist. 
•
Our programs focused on neurodegenerative disorders consist of our commercial program approved in Europe, 
Libmeldy (OTL-200) for MLD, two clinical proof of concept-stage programs, OTL-203 for MPS-I and OTL-201 for 
mucopolysaccharidosis type IIIA, or MPS-IIIA, and one pre-clinical program, OTL-204 for frontotemporal 
dementia with progranulin mutations, or GRN-FTD. 
•
Our programs in immunological disorders consist of two pre-clinical programs, OTL-104 for Crohn’s disease with 
mutations in the nucleotide-binding oligomerization domain-containing protein 2, or NOD2-CD, and OTL-105 for 
HAE. 
o
In July 2021, we entered into a collaboration with Pharming Group N.V., or Pharming, pursuant to which 
we granted Pharming worldwide rights to OTL-105. Under our agreement with Pharming, we will lead the 
completion of IND-enabling activities of OTL-105 and oversee its manufacturing during pre-clinical and 
clinical development, which will be funded by Pharming. Pharming will be responsible for clinical 
development, regulatory filings and commercialization of OTL-105, if approved, including associated 
costs.
o
We also have a commercial product approved in Europe, Strimvelis for ADA-SCID, an advanced 
registrational clinical program, OTL-103 for Wiskott Aldrich syndrome, or WAS, and one clinical proof of 
concept-stage program, OTL-102 for X-linked chronic granulomatous disease, or X-CGD. However, in 
March 2022, we announced that we would discontinue our investment in and seek alternatives for these 
programs.
The nature of our autologous gene therapy product candidates precludes the conduct of Phase 1 safety studies in healthy 
volunteers. Moreover, considering the indications our product candidates are intended to treat, which are often fatal without 
treatment and which are rare indications with high unmet medical need, we believe our clinical programs will generally be 
eligible to proceed to registration based on a single pivotal study given the bioethical considerations regarding the conduct of 
randomized, double-blind and placebo-controlled clinical trials with gene therapies for such indications. For purposes of this 
Annual Report, we refer to an exploratory study, which is sometimes referred to as a Phase 1 or Phase 1/2 clinical trial, as a 
proof of concept trial, and a confirmatory efficacy and safety study to support submission of a potential marketing application 
with the applicable regulatory authorities, which is sometimes referred to as a Phase 2/3 or Phase 3 clinical trial or a pivotal 
trial, as a registrational trial. 
Neurodegenerative Disorders
Gene therapy for treatment of MLD 
Disease overview 
MLD is a rare and life-threatening inherited disease of the body’s metabolic system occurring in approximately one in every 
100,000 live births in most regions of the world. Higher incidence rates are reported in geographies of higher consanguinity, 
such as Turkey and the Middle East. MLD is caused by a mutation in the arylsulfatase-A gene, or ARSA, that results in the 
accumulation of sulfatides in the brain and other areas of the body, including the liver, gallbladder, kidneys, and/or spleen. 
Over time, the nervous system is damaged, leading to neurological problems such as motor, behavioral and cognitive 

8
regression, severe spasticity and seizures. Patients with MLD gradually lose the ability to move, talk, swallow, eat and see. In 
its late infantile form, mortality at five years from onset is estimated at 50% and 44% at 10 years for juvenile patients.
Limitations of current therapies 
Prior to the approval of Libmeldy (OTL-200) in Europe, there were no effective treatments or approved therapies for MLD. 
Palliative care options involve medications for seizures and pain, antibiotics and sedatives, on a case-by-case basis, as well as 
physiotherapy, hydrotherapy and tube feeding or gastrostomy when patients can no longer eat without assistance. Palliative 
care addresses the symptoms of MLD but does not slow or reverse the progression of the underlying disease. HSCT has 
limited and variable efficacy in arresting disease progression and, as a result, HSCT is not considered to be a standard of care 
for this disease. MLD patients, their caregivers and families, and the healthcare system have faced significant burdens given 
the severity of the disease and the lack of effective treatments. 
Our solution, Libmeldy (OTL-200) for treatment of MLD
OTL-200 is designed as a one-time therapy that aims to correct the underlying genetic cause of MLD, offering eligible 
patients the potential for long-term positive effects on cognitive development and maintenance of motor function at ages at 
which untreated patients show severe motor and cognitive impairments. With OTL-200, a patient’s own HSCs are selected, 
and functional copies of the ARSA gene are inserted into the genome of the HSCs using a lentiviral vector before these 
genetically modified cells are infused back into the patient. The ability of the gene-corrected HSCs to migrate across the 
blood-brain barrier into the brain, engraft, and express the functional enzyme has the potential to persistently correct the 
underlying disease with a single treatment. 
We obtained worldwide rights to this program through our asset purchase and license agreement with Glaxo Group Limited 
and GlaxoSmithKline Intellectual Property Development LTD, or, together, GSK. The clinical trials for this program have 
been conducted under a GSK-sponsored clinical trial authorization, which was transferred to us during the third quarter of 
2018. 
Libmeldy approval in Europe as Orphan Drug
In December 2020, the European Commission granted full, or standard, marketing authorization for Libmeldy (OTL-200) 
(autologous CD34+ cell enriched population that contains hematopoietic stem and progenitor cells transduced ex vivo using a 
lentiviral vector encoding the human arylsulfatase-A (ARSA) gene) for the treatment of early-onset MLD characterized by 
biallelic mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with (i) late infantile 
or early juvenile forms, without clinical manifestations of the disease, or (ii) the early juvenile form, with early clinical 
manifestations of the disease, who still have the ability to walk independently and before the onset of cognitive decline.
Libmeldy has received orphan drug designation from the EMA for the treatment of MLD and orphan drug status was 
maintained at the time of approval. We are continuing to follow patients in the clinical development program for up to 15 
years as a post-marketing commitment, and data will be presented to regulators at agreed time points in order to further 
characterize the long-term efficacy and safety of Libmeldy, particularly in the early symptomatic early juvenile population. 
Data Supporting the Clinical Profile of Libmeldy 
The European Commission (EC) approval is supported by clinical studies of Libmeldy in both pre- and early- symptomatic, 
early-onset MLD patients. Early-onset MLD encompasses the disease variants traditionally referred to as late infantile, or LI, 
and early juvenile, or EJ.
Clinical efficacy supporting EC approval was based on the integrated analysis of results from 29 patients with early-onset 
MLD who were all treated with Libmeldy:
•
20 patients were treated in a clinical study (median follow-up of 4 years); 9 patients were treated in expanded access 
programs (median follow-up of 1.5 years) 
•
16 patients had a diagnosis of LI MLD; 13 had a diagnosis of EJ MLD
•
At the time of treatment, 20 patients were deemed pre-symptomatic; 9 were deemed early-symptomatic
Clinical safety was evaluated in 35 patients with early-onset MLD:
•
29 patients from the efficacy analysis supporting EC approval (described above)
•
6 additional patients treated in another clinical study of Libmeldy

9
Co-primary endpoints
The co-primary endpoints of the integrated efficacy analysis were Gross Motor Function Measure, or GMFM, total score and 
ARSA activity, both evaluated at two years post-treatment. Results of this analysis indicate that a single-dose intravenous 
administration of Libmeldy is effective in modifying the disease course of early-onset MLD in most patients.
Pre-symptomatic LI and EJ patients treated with Libmeldy experienced significantly less deterioration in motor function at 
two years and three years post-treatment, as measured by GMFM total score, compared to age and disease subtype-matched 
untreated patients (p≤0.008). The mean difference between treated pre-symptomatic LI patients and age-matched untreated 
LI patients was 71.0% at year 2 and 79.8% at year 3. Similarly, the mean difference between treated pre-symptomatic EJ 
patients and age-matched untreated EJ patients was 52.4% at year 2 and 74.9% at year 3. Although not statistically 
significant, a clear difference in GMFM total score was also noted between treated early-symptomatic EJ patients and age-
matched untreated EJ patients (28.7% at year 2; p=0.350 and 43.9% at year 3; p=0.054).
A statistically significant increase in ARSA activity in peripheral blood mononuclear cells was observed at 2 years post-
treatment compared to pre-treatment in both pre-symptomatic patients (20.0-fold increase; p<0.001) and early-symptomatic 
patients (4.2-fold increase; p=0.004).
At the time of the integrated data analysis, all treated LI patients were alive with a follow-up post-treatment of up to 7.5 years 
and 10 out of 13 treated EJ patients were alive with a follow-up post-treatment of up to 6.5 years. No treatment-related 
mortality has been reported in patients treated with Libmeldy.
Key secondary endpoints
For EJ patients who were early-symptomatic when treated with Libmeldy, meaningful effects on motor development were 
demonstrated when these patients were treated before entering the rapidly progressive phase of the disease (IQ≥85 and Gross 
Motor Function Classification, or GMFC, ≤1). By 4 years post-disease onset, an estimated 62.5% of treated, early-
symptomatic EJ MLD patients survived and maintained locomotion and ability to sit without support compared with 26.3% 
of untreated early-symptomatic EJ MLD patients, representing a delay in disease progression following treatment with 
Libmeldy.
A secondary efficacy endpoint that measured cognitive and language abilities as quantified by Intelligence 
Quotient/Development Quotient, or IQ/DQ, found in the treated LI subgroup, 12 out of 15 assessed patients had a fairly 
constant IQ/DQ, within the normal range (IQ/DQ score of 100 +/- SD of 15) throughout follow-up. All but two of these 
patients (i.e., one pre-symptomatic and one early-symptomatic) remained above the threshold of severe mental disability 
(IQ/DQ>55) at chronological ages at which all 14 untreated comparator LI patients showed evidence of severe cognitive 
impairment, which is defined as IQ/DQ below 55 and close to zero. Of the 10 surviving EJ patients, all 4 pre-symptomatic 
patients and 4 out of 6 early-symptomatic patients showed normal IQ/DQ throughout follow-up. In contrast, 11 out of 12 
untreated EJ patients showed evidence of severe cognitive impairment during follow-up.
Clinical trial with cryopreserved drug formulation
The cryopreserved formulation of OTL-200 is being studied in a clinical trial of pediatric patients with pre-symptomatic LI, 
or pre- to early-symptomatic EJ in Milan, Italy.
The primary goal of this clinical trial is to assess the safety and efficacy of a cryopreserved formulation of OTL-200 in early-
onset MLD patients, as measured by improvement in gross motor function and ARSA activity levels in the patients’ blood 
cells as well as overall survival. Secondary goals for this clinical trial include assessment of cognitive function through IQ. 
Ten patients were treated in this trial between April 2017 and April 2020. Data, which included six of these ten patients, was 
presented at WORLD Symposium in 2021. The median duration of follow up was 0.87 years as of November 2019. 
Administration was generally well tolerated in all patients, and for those with enough follow-up post-treatment, preliminary 
evidence of engraftment and restoration of ARSA activity in peripheral blood to supraphysiological levels and in cerebral 
spinal fluid, or CSF, to normal levels has been shown. The short-term safety profile was comparable between patients treated 
with the fresh formulation.
Data Supporting Safety Profile of Libmeldy
The safety of Libmeldy was evaluated in 35 patients with MLD. 
The median duration of follow-up in the integrated safety data set, which included 29 patients treated with the fresh 
(investigational) formulation was 4.51 years. Three patients died and a total of 26 patients remained in the follow-up phase. 
The median duration of follow-up in the 6 patients treated with the cryopreserved (commercial) formulation was 0.87 years.

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All treated LI patients were alive with a follow-up post-treatment of up to 7.5 years, and 10 out of 13 treated EJ patients were 
alive with a follow-up post-treatment of up to 6.5 years. No treatment-related mortality has been reported in patients treated 
with Libmeldy.
The most common adverse reaction attributed to Libmeldy was presence of anti-ARSA antibodies, or AAA. Five events of 
AAA were observed in four out of 35 patients and were related to treatment. Antibody titers were generally low and resolved 
either spontaneously or after a short course of rituximab. In all patients with positive AAA test results, no negative effects 
were observed in the post-treatment ARSA activity of peripheral blood or bone marrow cellular sub populations nor in the 
ARSA activity within the cerebrospinal fluid. No impact on the clinical efficacy or safety outcomes were observed.in any of 
the subjects who reported AAA. In addition to the risk associated with the gene therapy, treatment with Libmeldy is preceded 
by other medical interventions, namely bone marrow harvest or peripheral blood mobilization and apheresis, followed by 
myeloablative conditioning, which carry their own risks. During the clinical studies, the safety profiles of these interventions 
were consistent with their known safety and tolerability.
A total of 39 patients have been treated as part of the clinical development program between April 2010 and April 2020. An 
integrated data analysis comparing 39 treated patients to a natural history study cohort was presented at WORLD Symposium 
in 2023. Consistent with previously published results (Fumagalli et al Lancet 2022), these results combining the original 29 
subjects with the 10 treated patients from the study evaluating the cryopreserved formulation, with longer follow-up (median 
6.15 years, max 11.03 years), show a continued favorable benefit-risk profile for arsa-cel in pre-symptomatic LI and EJ and 
early-symptomatic EJ MLD. Arsa-cel was generally well tolerated with no treatment-related SAEs or treatment-related 
deaths.
For more details, please see the Summary of Product Characteristics, or SmPC, for Libmeldy.
OTL-200 development in the U.S.
OTL-200 has received orphan drug designation for the treatment of MLD as well as Rare Pediatric Disease designation. In 
late 2020, the FDA cleared our IND application for OTL-200 in the U.S., and in January 2021, FDA granted regenerative 
medicine advanced therapy, or RMAT, designation for OTL-200. Based on feedback received from the FDA, we are 
preparing for a BLA filing for OTL-200 in pre-symptomatic, early-onset MLD patients, expected in mid-2023, using data 
from existing OTL-200 patients. This approach and timeline are subject to the successful completion of activities remaining 
in advance of a pre-BLA meeting with the FDA, scheduled for the second quarter of 2023.
Gene therapy for treatment of MPS-IH
Disease overview 
Mucopolysaccharidosis type I is a lysosomal storage disease caused by a deficiency of the lysosomal enzyme alpha-L-
iduronidase, or IDUA. Inherited deficiency of IDUA is responsible for MPS-I. Without treatment, clinical manifestations of 
this severe disease include skeletal abnormalities with severe orthopedic manifestations, hepatosplenomegaly, 
neurodevelopmental decline, sight and hearing disturbances, cardiovascular and respiratory problems leading to death in 
early childhood. IDUA deficiency can result in a wide range of clinical severity, with three major recognized clinical entities: 
(1) Hurler, or MPS-IH, (2) Scheie, or MPS-IS (3) and Hurler-Scheie, or MPS-IH/S, syndromes. MPS-IH is the most severe 
form of MPS-I.
The median age of diagnosis for MPS-IH is 12 months, and most affected children are diagnosed before 18 months of age. 
Infants affected by MPS-IH may appear normal at birth, but progress to develop symptoms such as kyphosis of the spine, and 
inguinal or umbilical hernias in the first six months, developing the characteristic somatic phenotype over the first few years 
of life. 
The approximate incidence of MPS-I is of one in 100,000 live births. Approximately 60 percent of children born with MPS-I 
have MPS-IH.
Limitations of current therapies 
Allogeneic-HSCT, or allo-HSCT, which is commonly accompanied by pre- and peri-transplant enzyme replacement therapy, 
or ERT, from diagnosis to engraftment, has been established as the standard of care for MPS-IH patients with preserved 
cognition. The recommendation of allo-HSCT as the standard of care for MPS-IH patients is endorsed by the European 
Society for Blood and Marrow Transplantation and the American Society for Transplantation and Cellular Therapy.
Despite its established position in treatment algorithms, allogeneic-HSCT can result in alloreactive complications, including 
and graft versus host disease or death, particularly when the degree of matching between graft donor and recipient is poor. 
Additionally, there remains a significant disease burden in those treated, even if treated early in life, including severely 

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debilitating cognitive, neurological, growth, orthopedic, cardiac, respiratory and ophthalmic manifestations, all of which are 
reported during long-term post-HSCT follow-up. 
Our solution, OTL-203 for treatment of MPS-IH
Ex vivo autologous HSC gene therapy strategies aimed at correcting the genetic defect in patients could represent a 
significant improvement for the treatment of MPS-I, notably MPS-IH, the most severe and prevalent phenotype with the 
highest unmet medical need, when compared to current treatments.  
OTL-203 is a single administration, gene therapy product candidate consisting of autologous CD34+ enriched HSPCs, 
derived from mobilized peripheral blood, genetically modified ex vivo with the lentiviral vector encoding for the IDUA 
complementary DNA, or cDNA. It is being developed as a cryopreserved formulation. Ex vivo autologous gene therapies, 
such as OTL-203, are designed to correct the genetic defect in patients’ own HSCs and their progeny by addition of 
functional cDNA. The OTL-203 mechanism of action, or MOA, addresses the disease pathophysiology by restoring 
enzymatic IDUA expression in peripheral and central body compartments as well as restoring microglia homeostasis in the 
central nervous system, or CNS, to confer neuroprotective effects against the neurotoxic effects of glycosaminoglycan, or 
GAG, accumulation in affected cells. 
The achievement of long-term sustained correction of the manifestations of MPS-IH occurs via local secretion of functional 
IDUA enzyme, which facilitates the efficient clearance of GAGs. This MoA is based on the local release of IDUA enzyme 
from genetically corrected cells containing functional copies of the IDUAgene into the extracellular space, which is in turn 
taken up by neighboring cells in a process referred to as “cross-correction.” Animal models have shown that genetically 
modified cells are able to cross the blood brain barrier and can provide cross-correction within the CNS. Engraftment of these 
cells within the CNS gives rise to monocyte-derived microglia-like cells that secrete the functional IDUA enzyme, which is 
taken up by neuronal and glial cells via cross-correction. 
One way in which OTL-203 differs from allo-HSCT is the ability of the transduced autologous cells to produce 
supraphysiological levels of IDUA enzyme in peripheral compartments and increased IDUA levels in central compartments 
in both non-clinical and clinical settings. This difference may be important because multivariate analyses have consistently 
identified higher post-HSCT IDUA levels as predictors of outcomes with lower residual disease burden in multiple organ 
systems, including skeletal, ophthalmic, cardiac, auditory and respiratory. It is therefore hypothesized that the presence of 
supraphysiological levels of IDUA enzyme in peripheral compartments may help overcome the limitations of allo-HSCT by 
enhancing the cross-correction process, by enabling presence of greater quantities of available enzyme in difficult-to-reach 
protected (i.e., brain) or avascular compartments (i.e., eye and joint tissue) and better enable clearance of GAGs in hard-to-
reach tissues. 
In addition, OTL-203 has the potential to overcome safety issues associated with the current standard of care. Compared to 
allogeneic transplantation, which is the current standard of care for MPS-IH treatment, the autologous nature of OTL-203 is 
associated with a significantly reduced transplant-related morbidity and mortality and avoidance of graft versus host (both 
acute and chronic) and immune mediated graft rejection.
We have obtained worldwide development and commercialization rights to OTL-203 from Telethon Foundation and San 
Raffaele Hospital.
OTL-203 has received orphan drug and PRIME designation from the EMA as well as orphan drug designation and rare 
pediatric disease designation from the FDA for the treatment of MPS-I. 
Ongoing clinical trials
OTL-203 is currently being investigated in an ongoing, academic-sponsored clinical trial at the San Raffaele Hospital in 
Milan, Italy to establish proof of concept. The study is a prospective, single dose, single center, non-randomized, open label 
study involving a single administration of OTL-203 in eight patients with a confirmed diagnosis of MPS-IH. The study is 
fully enrolled using a cryopreserved formulation of OTL-203. 
The patients evaluated in this trial include pediatric MPS-IH patients from 14 to 34 months of age at the time of treatment 
and will be followed for at least five years post-treatment in the context of the proof of concept study and then continue to be 
evaluated in a long-term follow-up study. 
In September 2022, we announced  the presentation of the interim clinical results from the ongoing academic-sponsored 
clinical trial at the San Raffaele Hospital. For this presentation’s last follow up of all patients (range: 24 and 36 months), 
interim data supporting clinical proof-of-concept illustrated that treatment with OTL-203 was generally well-tolerated with a 
safety profile consistent with the selected conditioning regimen. IDUA antibodies present prior to gene therapy as a result of 

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ERT were not seen in any patient within three months following treatment. In addition, ERT was discontinued at least three 
weeks prior to any patient receiving gene therapy treatment, and no patients had re-started ERT post-treatment.
In December 2022 we received IND clearance of OTL-203 from the FDA, which allows us to initiate a global registrational 
study in MPS-IH. We plan to initiate the study, which will include centers across the US and Europe, in the second half of 
2023.  
The study will be a multi-center, randomized, active controlled clinical trial designed to evaluate the efficacy and safety of 
OTL-203 in patients with MPS-IH compared to standard of care with allogeneic hematopoietic stem cell transplant. A total of 
40 patients with a confirmed diagnosis of MPS-IH who meet the study inclusion criteria will be randomized 1:1 to receive 
either OTL-203 or allogeneic HSCT. The study is powered to demonstrate superiority of OTL-203 over allo-HSCT.
Gene therapy for treatment of MPS-IIIA 
Disease overviews
MPS-IIIA, also known as Sanfilippo syndrome type A, is a life-threatening metabolic disease that causes accumulation of 
glycosaminoglycan in cells, tissues and organs, particularly in the brain. Within the first years after birth, MPS-IIIA and 
MPS-IIIB patients begin to experience progressive neurodevelopmental delay and decline, including speech delay and 
eventual loss of language, behavioral disturbances and potentially severe dementia. Ultimately, most patients with MPS-IIIA 
progress to a vegetative state. Life expectancy for patients with MPS-IIIA is between 10 to 25 years. 
The incidence of MPS-IIIA is currently estimated to be one in 100,000 live births per year. 
Limitations of current therapies 
Currently, there are no effective treatments or approved therapies for MPS-IIIA. Palliative care options involve medications 
for seizures and pain, antibiotics and sedatives, on a case-by-case basis, as well as physiotherapy, hydrotherapy and tube 
feeding or gastrostomy when patients can no longer eat without assistance. Palliative care addresses the symptoms of MPS-
IIIA but does not slow or reverse the progression of the underlying disease. Systemic ERT is not an approved treatment 
option and HSCT is not considered to be an effective treatment option for these diseases. The severity of symptoms and lack 
of an effective treatment option to manage these symptoms is a significant burden to MPS-IIIA patients, their caregivers and 
families and healthcare systems. 
Our solutions, OTL-201 for treatment of MPS-IIIA
We are developing OTL-201 as an ex vivo autologous HSC gene therapy for treatment of patients with MPS-IIIA. We 
believe pre-clinical studies in mice have shown that ex vivo autologous gene therapy has the potential to address the 
neurological manifestations of MPS-IIIA. We have obtained worldwide development and commercialization rights to OTL-
201 from The University of Manchester. 
OTL-201 has received orphan drug designation from the EMA and FDA for the treatment of MPS-IIIA and has received rare 
pediatric disease designation from the FDA. 
Proof of concept trial in MPS-IIIA 
We are supporting a proof-of-concept trial for the treatment of MPS-IIIA, which started enrollment in January 2020. The 
trial, which is being conducted by the Royal Manchester Children’s Hospital and sponsored by the Manchester University 
NHS Foundation Trust, completed enrollment in 2021 with the fifth patient treated in September 2021. 
Early clinical findings, including the first neurocognitive results, from the proof-of-concept trial were presented at the 
American Society of Hematology (ASH) Annual Meeting in December 2022 and at the WORLD Symposium in February 
2023. The data, which encompassed follow-up ranging from 9 to 24 months, showed robust, prompt, sustained, multi-lineage 
engraftment of genetically modified cells. Supraphysiological levels of SGSH enzyme were seen in leukocytes, plasma and 
CSF and rapid and reduction of substrate (glycosaminoglycans, GAGs) observed in all compartments. 
Early neurocognitive outcomes also indicated that since receiving OTL-201, four out of five patients showed gain of 
cognitive skills in line with development in healthy children. The oldest patient at last follow up has maintained this normal 
cognitive development since treatment, despite reaching a chronological age where cognition is observed to decline in natural 
history patients, showing improvement from this comparator. Three additional patients are currently within the normal 
development quotient (DQ) range at 9 to 18 months post-treatment but require longer follow-up to assess outcomes.
Treatment with OTL-201 was generally well-tolerated in the initial study population. Of the six serious adverse events 
(SAEs) reported to date, four were determined to be due to conditioning or leukapheresis and one was related to background 

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disease. One patient had delayed platelet engraftment until day 52 post-treatment, likely due to Cytomegalovirus infection 
around the time of infusion.
Research program in FTD 
Disease overview 
Frontotemporal Dementia, or FTD, is the second most common cause of dementia after Alzheimer Disease in people under 
the age of 65. FTD is due to the atrophy of the frontal and temporal lobes of the brain. The disease manifests with progressive 
changes in behavior and personality, starting with symptoms such as decline in social and personal interactions, depression, 
apathy, emotional blunting, disinhibition and language disorders, and then progressing to general cognitive impairment at a 
later stage. In ~5% of patients, FTD is caused by mutations in one copy (haploinsufficiency) of the gene that codes for 
progranulin, or GRN. GRN is a neurotrophic, anti-inflammatory factor that is produced and secreted among others by 
specialized cells in the brain called microglia cells. GRN produced by microglia cells can be taken up by neighboring 
neurons, helping them to be healthy and functional. Since GRN-FTD patients’ cells do not produce enough GRN, brain 
inflammation develops with time and neurons become progressively dysfunctional until they eventually die, leading to brain 
atrophy and the aforementioned symptoms. 
We believe there are currently up to 2,500 people affected by GRN-FTD in Europe and the U.S., with approximately 800 
new cases per year.
Limitations of current therapies 
There are no treatments available for FTD and death occurs six to nine years after onset.
Our solution, OTL-204 for treatment of FTD
OTL-204 is an ex vivo autologous HSC gene therapy being developed to replace the defective microglia cells in the brain of 
GRN-FTD patients with genetically modified microglia cells that produce and secrete a corrective amount of GRN. These 
cells develop naturally from HSCs, which are collected from the patient and modified by using a viral vector that brings a 
functional copy of the GRN gene. When they are infused in the patient, the genetically modified HSCs naturally reach the 
brain and become resident microglia cells. OTL-204 is being developed in partnership with Professor Alessandra Biffi at the 
University of Padua in Italy. As part of the collaboration, we initiated a sponsored research agreement with the University of 
Padua and obtained an exclusive option with Boston Children’s Hospital to develop and exclusively license the program.
Pre-clinical development of OTL-204
Preliminary in vitro data obtained in 2020 have demonstrated that human cell lines and mouse HSCs can be efficiently 
transduced to produce GRN. GRN is then secreted in the culture medium and can be taken up by other types of cells that do 
not produce GRN themselves.
Preliminary in vivo data from the pre-clinical proof-of-concept study showed that murine GRN-/- HSPCs, transduced with an 
LV expressing progranulin under the control of a novel promoter, are able to engraft and repopulate the brain myeloid 
compartment of FTD mice and to locally deliver the GRN enzyme.
Immunological Disorders 
Research program in NOD2-Crohn’s Disease 
Disease overview 
Crohn’s Disease, or CD, is a form of Inflammatory Bowel Disease, or IBD, a condition affecting the gastrointestinal tract 
caused by an uncontrolled and chronic inflammatory process directed against intestinal bacteria. Mutations in a number of 
genes are known to confer susceptibility to the risk of CD, and among these the NOD2 gene (nucleotide-binding 
oligomerization domain-containing protein 2) is known to be the most common genetic factor, with 20-40% of Crohn’s 
patients carrying mutations causing defective NOD2 activity.  NOD2 encodes a cell receptor which controls bacterial 
elimination by innate immune cells such as macrophages through recognition of bacterial peptide (MDP) and induction of a 
pro-inflammatory immune response. NOD2 deficiency results in an impaired detection and clearance of bacteria penetrating 
the gut during gastrointestinal infection, creating an unchecked and relapsing inflammation within the intestinal tissues 
characterized by intestinal granuloma formation. This leads to recurrent clinical symptoms of chronic abdominal pain, 
diarrhea, weight loss, fatigue, malnutrition and for some patients, more severe intestinal damage requiring surgical resection. 
NOD2-CD patients typically present with more severe symptoms and are reported to be more refractory to existing therapies.

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The incidence of CD is high compared to our other indications, with estimates of 100 to 200 patients per million in Europe 
and North America.  Epidemiological studies suggest NOD2 genetic variants causing functional defects are associated with 7 
to 10% of all cases of CD, with up to 200,000 patients in the U.S. and Europe with two NOD2 mutated alleles.
Limitations of current therapies 
Current clinical management for Crohn’s disease includes use of immune-suppressive medications, biological agents such as 
anti-TNF, steroids and surgical resection. There is currently no cure for Crohn's disease, and long-term, effective treatment 
options are limited. Several clinical trials have evaluated autologous HSCT in Crohn’s disease, although with limited success. 
There remains a need for therapeutic modalities that target underlying causes of Crohn’s disease to achieve effective 
amelioration of symptoms and disease remission.
Our solution, OTL-104 for treatment of NOD2-CD
We are developing OTL-104 to evaluate its therapeutic efficacy as an ex vivo autologous HSC gene therapy to treat patients 
with NOD2-CD through a single administration. As the pathogenesis of NOD2-CD is associated with the function of cells of 
the hematopoietic system, ex vivo autologous HSC gene therapy may therefore be used to restore NOD2 function to immune 
cells such as tissue resident macrophages within the gastrointestinal tract. Our OTL-104 program is being designed to 
introduce the NOD2 gene into cells of the hematopoietic system by lentiviral transduction of a patient’s own blood or bone 
marrow derived HSCs, and the gene-modified cells can then be infused back into the patient. Clinical observations in the 
allogeneic transplant setting, where HSCT has resulted in the clinical reversion of Crohn’s Disease and other monogenic 
forms of IBD, supports the scientific rationale and mode of action of OTL-104. We own patent applications in the United 
States and other jurisdictions and all other intellectual property rights associated with the OTL-104 program. 
Pre-clinical development of OTL-104
OTL-104 pre-clinical work has shown that restoration of NOD2 gene expression in murine and human stem cells can rescue 
a defective myeloid immune response to MDP. NOD2 defective inflammatory functions in primary human myeloid cells can 
be restored by both lentiviral and gene editing approaches. The OTL-104 lentiviral vector is designed to express NOD2 under 
the chimeric CathepsinG/cFES promoter to deliver myeloid directed transgene expression. Pre-clinical studies to evaluate the 
safety of this approach show that NOD2-LV gene modification of human CD34+stem cells and murine lineage negative stem 
cells does not affect HSC engraftment or immune subset development and differentiation following transplantation into NSG 
or NOD2-KO mice, respectively. Transplantation of NOD2-LV gene modified murine stem cells further demonstrates that 
HSC derived cells can efficiently migrate and reconstitute the myeloid cell compartments of intestinal tissue, restoring a 
normal biodistribution of NOD2 expression within the gut.
Pre-clinical proof-of-concept studies include in vivo colitis disease modeling and a non-interventional clinical research study 
using NOD2-genetically defined patients with Crohn’s Disease. We have generated in vivo evidence that defective monocyte 
functions in NOD2-KO mice can be corrected by OTL-104 gene therapy, restoring NOD2-dependent systemic cytokine 
responses and innate immune cell mobilization. In vitro, myeloid cells differentiated from CD34+ cells obtained from 
peripheral blood of genetically characterized NOD2 deficient CD patients, are refractory to MDP stimulation and unable to 
generate a normal cytokine response profile. LV transduction of NOD2-deficient patient cells restores MDP-induced 
cytokine responses to levels comparable to those observed in monocytes derived from CD34+ cells from healthy donors, 
correcting a NOD2-defective phenotype. Orchard’s OTL-104 program is currently under development towards IND-/ CTA- 
enabling toxicology / biodistribution studies.
Other programs
In March 2022, we announced that we would discontinue our investment in and seek alternatives for Strimvelis, OTL-103 for 
treatment of WAS and OTL-102 for treatment of X-CGD.
Future applications of our ex vivo autologous HSC gene therapy approach 
We believe that our versatile ex vivo autologous HSC gene therapy approach has the potential to deliver promising gene 
therapies to patients across a broad range of diseases. Although our near-term focus is on delivering our commercial and 
clinical-stage gene therapies to patients suffering from several rare diseases described above, we believe we can leverage our 
significant research and development experience and partnerships with academic institutions to identify other diseases in our 
target areas, including neurodegenerative, immunological and blood disorders, where ex vivo gene therapy may have a 
comparably higher probability of success as compared to other approaches our mid- to long-term strategy is to leverage our 
HSC gene therapy approach in additional larger indications, seeking development partnerships as the programs advance 

15
towards the clinic. One partnership already established in 2021 is our collaboration with Pharming on OTL-105, as 
referenced above.
Our regulatory strategy 
The nature of our autologous gene therapy product candidates precludes the conduct of Phase 1 safety studies in healthy 
volunteers. Moreover, considering the indications our product candidates are intended to treat, which are often fatal without 
treatment and which are rare indications with high unmet medical need, we believe our clinical programs will generally be 
eligible to proceed to registration based on a single pivotal study given the bioethical considerations regarding the conduct of 
randomized, double-blind and placebo-controlled clinical trials with gene therapies for such indications. Both the FDA and 
EMA provide expedited pathways for the development of drug product candidates for the treatment of rare diseases, 
particularly life-threatening diseases with high unmet medical need. Such drug product candidates may be eligible to proceed 
to registration following one or more clinical trials in a limited patient population, following review of the trial’s design, 
endpoints and clinical data by the applicable regulatory agencies. These determinations are based on the applicable regulatory 
agency’s scientific judgment and these determinations may differ in the United States and the European Union. 
In some cases applicable regulatory agency may require us to perform analytical studies or conduct additional clinical trials 
to support analytical comparability of drug product, for example by demonstrating comparability of drug product 
manufactured using HSCs derived from a patient’s mobilized peripheral blood and drug product manufactured using HSCs 
derived from a patient’s bone marrow and/or comparability of drug product that has been cryopreserved and fresh drug 
product. For the purposes of this Annual Report we refer to these clinical trials as supportive clinical trials. In addition, 
certain of our product candidates may be evaluated in clinical trials for which clinical data is not intended to be pooled with 
data from our registrational trials for the purposes of a regulatory submission but will be submitted to the applicable 
regulatory agencies for informational purposes. For the purposes of this Annual Report we refer to these trials as additional 
clinical trials. In addition, in some cases patients may be ineligible for participation in our clinical trials and may receive 
treatment under a compassionate use program or an expanded access program. We expect that the available safety and 
efficacy results from all these trials would be included in any regulatory submission we may submit, and the applicable 
regulatory agency with respect to each clinical program will make a determination as to whether the available data is 
sufficient to support a regulatory submission. 
Manufacturing 
The diseases we are targeting affect patients across the world. Therefore, we are implementing plans to enhance our 
partnerships with CDMOs and leverage technologies that will allow us to deliver our gene therapies globally. 
Global supply network with experienced CDMOs 
We currently partner with a network of experienced CDMOs, including AGC Biologics S.p.A. (formerly MolMed S.p.A.) 
and Oxford BioMedica, for the supply of our vectors and drug products, including Libmeldy. We have established 
relationships with commercial CDMO partners with the resources and capacity to meet our clinical and existing and expected 
initial commercial needs. Our CDMO partners also provide us with access to their state-of-the art manufacturing 
technologies. 
Manufacturing efficiencies and scalability 
We are investing in human capital and advancing manufacturing technologies for HSC-based autologous ex vivo gene 
therapies. We have licensed lentiviral vector stable cell line technologies from GSK, completed transduction enhancer 
screening processes, established a vector process development lab at a Catapult Network facility in the UK, and are in the 
process of building cell therapy and analytical development capabilities at our London, UK global headquarters. We seek to 
enhance our product and process understanding while actively exploring and developing innovative technologies for vector 
and drug product manufacturing to improve the efficiency and scalability of manufacturing processes with an ultimate goal to 
reliably manufacture high quality products for rare diseases and larger indications at lower cost. For example, we have 
identified and validated several transduction enhancing compounds in order to facilitate lentiviral vector entry into HSCs, 
showing a greater than 50% reduction in vector requirements. We continue to invest in our people to support the 
commercialization and life cycle management of our pipeline products. 
Cryopreservation of our gene therapy programs 
Cryopreservation of gene-modified cells is a key component of our strategy to deliver innovative, potentially curative gene 
therapies to patients worldwide. We have developed cryopreserved formulations of our OTL-200 program and expect to 
demonstrate comparability of our cryopreserved formulations to earlier manufactured fresh formulations in support of future 

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submissions for marketing approval in the United States and Europe. Our programs in OTL-203 and OTL-201 have already 
started or will start with cryopreserved formulations. We plan to establish cryopreserved product formulations as the standard 
for all of our future gene therapy candidates. 
In the cryopreservation process, a patient’s gene-modified HSCs are frozen at extremely low temperatures and then stored to 
allow quality control testing and release to be performed before introducing the gene-modified cells back into the patient. Our 
cryopreserved formulations are expected to have shelf-lives of months to years, enabling us to potentially distribute our 
products and product candidates from a few centralized manufacturing facilities to geographically dispersed treatment sites. 
Our ability to ultimately distribute our product candidates globally will facilitate access of the therapies to patients and reduce 
the logistical burden on patients and their families. 
Commercial operations
We have launched Libmeldy (OTL-200) for the treatment of early-onset MLD following receipt of full, or standard, 
marketing approval from the European Commission in December 2020. We have secured agreements with several major 
European markets, including the U.K., Italy, Germany and Sweden, to enable access and reimbursement for all eligible 
patients with MLD. In addition, we have secured the renewal of the early access program in France, under which the 
Company receives reimbursement for the treatment of any eligible patient with MLD. We have recognized revenue from 
commercial treatments from markets with reimbursement agreements, early access mechanisms, treatment abroad programs 
and European cross-border (S2) pathways. Subject to approval of OTL-200 by the FDA, we also plan to put in place 
commercial operations and treatment centers in the U.S. 
We are building our commercial capabilities by employing individuals with broad experience in quality assurance and 
compliance, medical education, marketing, supply chain, sales, public policy, patient services, market access and product 
reimbursement. We will need to expand these capabilities as we continue to implement appropriate quality systems, 
compliance policies, systems and procedures, as well as internal systems and infrastructure in order to support our supply 
chain, qualify and train additional treatment centers, establish patient-focused programs, educate healthcare professionals, 
and secure reimbursement. The timing and conduct of these commercial activities will be dependent upon regulatory 
approvals and on agreements we have made or may make in the future with strategic collaborators. 
As part of the commercialization process, we are engaged in discussions with stakeholders across the healthcare system, 
including public and private payors, patient advocates and organizations, and healthcare providers, to drive more timely 
patient identification through education, newborn screening, and diagnostic initiatives and to explore new payment models 
that we hope will enable broader patient access. We have initiated over a dozen newborn screening studies in Europe, the 
Middle East and the U.S., six of which are actively screening. To date, there have been three genetically confirmed cases of 
MLD after screening of approximately 96,000 newborns globally. One of these cases has been assessed clinically and 
referred for treatment with Libmeldy with the other two more recently identified patients pending clinical assessment.
We are engaging with European country- and regional-level payment authorities to negotiate further reimbursement and 
access for Libmeldy.
Intellectual property and barriers to entry 
Our commercial success depends, in part, upon our ability to protect commercially important and proprietary aspects of our 
business, defend and enforce our intellectual property rights, preserve the confidentiality of our know-how and trade secrets, 
and operate without infringing, misappropriating and otherwise violating valid and enforceable intellectual property rights of 
others. In particular, we strive to protect the proprietary aspects of our business and to develop barriers to entry that we 
believe are important to the development and commercialization of our gene therapies. For example, where appropriate, we 
develop, or acquire exclusive rights to, clinical data, patents, know-how and trade secrets associated with each of our 
products and product candidates. However, we do not own any patents or patent applications that cover Libmeldy or any of 
our lead product candidates. We cannot guarantee that patents will issue from any of existing patent applications or from any 
patent applications that we or our licensors may file in the future, nor can we guarantee that any patents that may issue in the 
future from such patent applications will be commercially useful in protecting our products and product candidates. In 
addition, we plan to rely on regulatory protection based on orphan drug exclusivities, data exclusivities and market 
exclusivities. See “—Government regulation” for additional information. 
We currently rely primarily on know-how and trade secret protection for aspects of our proprietary technologies that we or 
our licensors believe are not amenable to or appropriate for patent protection, including, for example, clinical data and 
production information for Libmeldy, Strimvelis and each of our product candidates. Nonetheless, know-how and trade 
secrets can be difficult to protect. Although we take steps to protect our know-how, trade secrets and other proprietary 
information, including restricting access to our premises and our confidential information, as well as entering into agreements 
with our employees, consultants, advisors and potential collaborators, third parties may independently develop the same or 

17
similar know-how, trade secrets or proprietary information or may otherwise gain access to such know-how, trade secrets and 
other proprietary information or such know-how, trade secrets or other proprietary information may otherwise become 
known. Moreover, we cannot guarantee that our confidentiality agreements will provide meaningful protection or that they 
will not be breached, and we may not have an adequate remedy for any such breach. As a result, we may be unable to 
meaningfully protect our know-how, trade secrets and other proprietary information. 
In addition, with regard to patent protection, the scope of coverage being sought in a patent application may be reduced 
significantly before a patent is issued, and even after issuance the scope of coverage may be challenged. As a result, we 
cannot guarantee that any of our product candidates will be protectable or remain protected by enforceable patents. We 
cannot predict whether the patent applications we are currently pursuing will issue as patents in any particular jurisdiction or 
whether the claims of any issued patents will provide sufficient proprietary protection from competitors. Any patents that we 
hold may be challenged, circumvented or invalidated by third parties. 
With regards to OTL-200 and as discussed in detail in “—License agreements”, we have exclusive, worldwide, sublicensable 
licenses pursuant to our asset purchase and license agreement with GSK, or the GSK Agreement, and the R&D Agreement to 
anonymized patient-level data arising from the clinical trials of OTL-200 and know-how, including other clinical data and 
production information relating to OTL-200.
The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most 
countries in which we are seeking patent protection for our product candidates, the patent term is 20 years from the earliest 
date of filing a non-provisional patent application. In the United States, the term of a patent may be lengthened by a patent 
term adjustment to accommodate for administrative delays caused at the U.S. Patent and Trademark Office, or USPTO, or 
may be shortened if another patent has a terminal disclaimer with an earlier expiration date. Furthermore, in the United 
States, the term of a patent covering an FDA-approved drug may be eligible for a patent term extension under the Hatch-
Waxman Amendments as compensation for the loss of patent term during the FDA regulatory review process. The period of 
extension may be up to five years beyond the expiration of the patent but cannot extend the remaining term of a patent 
beyond a total of 14 years from the date of product approval. Only one patent among those eligible for an extension may be 
extended. Similar provisions are available in Europe and in certain other jurisdictions to extend the term of a patent that 
covers an approved drug. In the future, if we obtain any additional issued U.S. patents covering one of our present or future 
product candidates, and if such product candidate receives FDA approval, we expect to apply for a patent term extension, if 
available, to extend the term of the patent covering such approved product candidate. We also expect to seek patent term 
extensions in any jurisdictions where they are available, but there is no guarantee that the applicable authorities, including the 
FDA, will agree with our assessment of whether such an extension should be granted, and even if granted, they may disagree 
with our assessment of the appropriate length of such an extension. 
License agreements 
GSK asset purchase and license agreement 
In April 2018, we entered into the GSK Agreement, pursuant to which GSK transferred its portfolio of approved and 
investigational rare disease gene therapies to us, which included Strimvelis and OTL-200 for MLD, among other programs. 
GSK also simultaneously novated to us their R&D Agreement with Telethon-OSR.
Under the GSK Agreement, we are subject to certain diligence obligations to develop and advance certain of the acquired 
product candidates. For example, we were required to use best endeavors to file an MAA for OTL-200 for MLD in either 
Europe or a BLA for MLD in the United States and to subsequently use commercially reasonable efforts to file an MAA or 
BLA, as applicable, in the other jurisdiction and to market, sell and promote OTL-200 in such jurisdictions. In December 
2020, we received full, or standard, marketing authorization for Libmeldy in the European Union as well as the United 
Kingdom, Iceland, Liechtenstein and Norway.
We are also required to use commercially reasonable efforts to obtain a priority review voucher, or PRV, from the FDA for 
certain programs, including OTL-200, and to transfer the first such PRV to GSK. GSK also has an option to acquire at a 
defined price any PRVs granted to us thereafter for certain programs. In the event that GSK does not exercise this option with 
respect to any PRV, we may sell the PRV to a third party and must share any proceeds in excess of a specified sale price 
equally with GSK. 
Under the GSK Agreement we are also obligated to pay non-refundable royalties and milestone payments in relation to the 
gene therapy programs acquired. For example, for Libmeldy, we pay a tiered royalty rate at percentages from the mid-teens 
to the low twenties. These royalties owed to GSK are in addition to any royalties owed to other third parties under various 
license agreements for the GSK programs. In aggregate, we may pay up to £90.0 million in milestone payments upon 
achievement of certain sales milestones. Our royalty obligations with respect to OTL-200 may be deferred for a certain 

18
period in the interest of prioritizing available capital to develop each product. Our royalty obligations are subject to reduction 
on a product-by-product basis in the event of market control by biosimilars and will expire in April 2048. 
We may terminate our development or commercialization activities of any of the programs under the GSK Agreement upon 
the occurrence of a serious adverse event, or SAE, if we believe such program poses a safety risk to patients and in certain 
additional situations. GSK may require us to grant a third party a non-exclusive license under the intellectual property we 
have acquired from GSK under the GSK Agreement if we materially breach our obligations to use best endeavors or 
commercially reasonable efforts, as applicable, to develop and commercialize the acquired programs and fail to develop and 
implement a mutually agreeable plan to cure such material breach within a specified time period. The foregoing hypothetical 
license would only continue until such time as we cured our material breach, and we would be required to pay GSK all 
amounts we received from the third party in connection with such license. 
Telethon-OSR research and development collaboration and license agreement 
In April 2018, in connection with our entering into the GSK Agreement, we entered into a deed of novation with GSK, 
Telethon Foundation and San Raffaele Hospital, together referred to as Telethon-OSR, pursuant to which we acquired and 
assumed all of GSK’s rights and obligations under the R&D Agreement with Telethon-OSR for the research, development 
and commercialization of ex vivo HSC gene therapies for certain programs, including OTL-200 and Strimvelis.
Pursuant to the R&D Agreement, Telethon-OSR granted to GSK an exclusive, worldwide, sublicensable license under certain 
intellectual property rights to develop and commercialize ex vivo gene therapy products for the treatment of ADA-SCID. In 
addition, Telethon-OSR had granted to GSK an exclusive option for an exclusive, sublicensable, worldwide license under 
certain intellectual property rights to develop and commercialize certain vectors and gene therapy products from disease-
specific development programs for the treatment of certain other diseases, including MLD. At the time we entered into the 
novation agreement, GSK had completed development, launched and commercialized Strimvelis for ADA-SCID in the 
European Union, and had exercised its exclusive option to obtain exclusive licenses from Telethon-OSR to certain programs, 
including MLD. We acquired Strimvelis and GSK’s exclusive licenses relating to the ADA-SCID and MLD programs, 
among others, pursuant to the GSK Agreement and the deed of novation. 
Under the R&D Agreement, Telethon-OSR is required to use commercially reasonable efforts to conduct each of the 
collaboration programs in accordance with development plans approved by a joint steering committee. With respect to those 
programs in relation to which our option has been exercised, we are required to use commercially reasonable efforts to 
develop, obtain regulatory approval, launch and promote in both the European Union and the United States all licensed 
products and to commercialize and manufacture such products at levels sufficient to meet commercial demands. We are 
required to use best efforts to renew the European Union marketing authorization for Strimvelis to enable patients to be 
treated at the San Raffaele hospital from all referring centers globally, as permitted by applicable law. We are responsible for 
the costs and activities associated with the continued development of Strimvelis and each program for which an option under 
the R&D Agreement is exercised. 
As consideration for the licenses and options granted under the R&D Agreement, we are required to make payments to 
Telethon-OSR upon achievement of certain product development milestones. We are obligated to pay up to an aggregate of 
€31.0 million in connection with product development milestones with respect to those programs for which we have 
exercised an option under this agreement, including OTL-200. Additionally, we are required to pay to Telethon-OSR a tiered 
mid-single to low-double digit royalty percentage on net annual sales of licensed products on a country-by-country basis, as 
well as a low double-digit percentage of sublicense income received from any certain third party sublicensees of the 
collaboration programs. Our royalty obligation expires on a licensed product-by-licensed product and country-by-country 
basis upon the latest to occur of the expiration of the last valid claim under the licensed patent rights in such country, the 10th 
anniversary of the first commercial sale of such licensed product in such country, and the expiration of any applicable 
regulatory exclusivity in such country, provided that our royalty obligation will terminate immediately in the event 
significant generic or biosimilar competition to a licensed product achieves a certain threshold percentage of the market 
share. 
Unless terminated earlier, the R&D Agreement will expire (i) on a product-by-product and country-by-country basis upon the 
expiration of all payment obligations with respect to such product in such country, (ii) in its entirety upon the expiration of all 
payment obligations with respect to the last product in all countries in the world, and (iii) on a program-by-program basis 
when no vector or gene therapy product is being researched, developed or commercialized. Either we or Telethon-OSR may 
terminate the R&D Agreement in its entirety or on a program-by-program basis if the other party commits a material breach 
and fails to cure such breach within a certain period of time. Additionally, either we or Telethon-OSR may terminate 
involvement in a collaboration program for compelling safety reasons, and either we or Telethon-OSR may terminate the 
R&D Agreement if the other party becomes insolvent. We may also terminate the R&D Agreement either in its entirety or on 
a program-by-program basis for any reason upon notice to Telethon-OSR. 

19
Oxford BioMedica license and development agreement 
In November 2016, we entered into a license and development agreement, or the Oxford Development Agreement, with 
Oxford BioMedica (UK) Limited, or Oxford BioMedica, for the development of gene therapies for ADA-SCID, MPS-IIIA 
and certain other diseases that we may request be included under the Oxford Development Agreement, such other diseases 
referred to as Subsequent Indications. The Oxford Development Agreement was amended on multiple occasions and most 
recently in April 2020.
Pursuant to the Oxford Development Agreement, Oxford BioMedica granted us an exclusive, worldwide license under 
certain intellectual property rights for the purposes of research, development and commercialization of ex vivo gene therapy 
products for the treatment of ADA-SCID, MPS-IIIA and Subsequent Indications, except that such license is non-exclusive to 
the extent the treatment of a Subsequent Indication is the subject of a certain previous license granted by Oxford BioMedica. 
Oxford BioMedica also granted us a non-exclusive, worldwide license under certain intellectual property rights for the 
purposes of research, development, commercialization and manufacture of ex vivo gene therapy products for the treatment of 
certain diseases other than ADA-SCID, MPS-IIIA and Subsequent Indications. Under the Oxford Development Agreement, 
Oxford BioMedica is required to use commercially reasonable efforts to perform the activities set forth in a collaboration 
plan approved by a joint steering committee, and we are responsible for certain costs of the activities set forth in such 
collaboration plan. 
As consideration for the licenses granted under the agreement, we issued 588,220 of our ordinary shares to Oxford 
BioMedica. We are also obligated to issue additional equity upon the achievement of certain milestones, pursuant to which 
we issued 150,826 ordinary shares upon the achievement of the first milestone in November 2017 and 150,826 ordinary 
shares were issued upon the achievement of further milestones in August 2018. In April 2020, the fifth milestone was 
deemed to have been met upon execution of the amended agreement in April 2020, and the Company issued another 75,413 
ordinary shares to Oxford BioMedica. Additionally, we are obligated to pay low single-digit percentage royalties on net sales 
of licensed products until January 31, 2039. The foregoing royalties are reduced by a mid-double digit percentage in the case 
of compassionate use of a licensed product in a country until the first commercial sale following marketing authorization in 
such country. We are also required to pay a set monthly fee to Oxford BioMedica in the event we use a certain Oxford 
BioMedica system for generating stable cell lines. 
Unless terminated earlier, the Oxford Development Agreement will expire when no further payments are due to Oxford 
BioMedica. We may terminate the performance of the collaboration plan upon notice to Oxford BioMedica, and either party 
may terminate the performance of the collaboration plan or the Oxford Development Agreement if the other party commits a 
material breach that is not cured within a certain period of time. Either party may also terminate the Oxford Development 
Agreement in the event the other party becomes insolvent. 
Telethon-OSR license agreement
In May 2019, we entered into a license agreement with Telethon-OSR under which Telethon-OSR granted us an exclusive 
worldwide license for the research, development, manufacture and commercialization of ex vivo autologous HSC lentiviral 
based gene therapy products for the treatment of MPS-I, including MPS IH. Under the terms of the agreement, Telethon-OSR 
is entitled to receive an upfront payment, and we may be required to make milestone payments if certain development, 
regulatory and commercial milestones are achieved. Additionally, we will be required to pay Telethon-OSR a tiered mid-
single to low-double digit royalty percentage on annual net sales of licensed products.
Competition
The biotechnology and pharmaceutical industries are characterized by intense and rapidly changing competition to develop 
new technologies and proprietary products. While we believe that our portfolio of product candidates and scientific expertise 
in gene therapy provides us with competitive advantages, we face potential competition from many different sources. 
We face competition not only from gene therapy companies, but also from companies that are developing novel, non-gene 
therapy approaches or improving existing treatment approaches. Depending on how successful these efforts are, it is possible 
they may increase the barriers to adoption and success for our product candidates, if approved. 
We are currently aware of the following competitive approaches among our products and clinical programs: 
•
MLD: To our knowledge, beyond Libmeldy in Europe, there is currently no other effective treatment option for 
patients with MLD. HSCT, for example, has demonstrated limited efficacy in halting disease progression and is 
therefore not considered a standard of care for this disease. A number of alternative approaches to HSCT are 
under investigation. For instance, Homology Medicines is at the pre-clinical stage of developing an in vivo 
AAV gene therapy for MLD delivered intravenously, Passage Bio has a pre-clinical development program for 
MLD, and Affinia has a pre-clinical program for in vivo AAV gene therapy for MLD through lumbar puncture 

20
(LP) administration. We are also aware that Takeda is investigating an ERT for MLD with a biweekly 
intrathecal infusion, and Denali Therapeutics is at the pre-clinical stage of developing a recombinant ARSA 
enzyme engineered to cross the blood-brain barrier.
•
MPS-I: The current standard of care for MPS-IH patients is HSCT before the age of 30 months. We are aware 
that REGENXBIO is developing an AAV-based gene therapy, which is in Phase I trials and to be delivered 
intracisternally. bluebird bio and Immusoft have both reported that they are developing ex vivo cell therapies in 
the pre-clinical stage. For MPS-I patients that are not suitable candidates for HSCT because they lack a suitable 
donor, were diagnosed later in life, or have a less severe subtype of MPS-I, the current standard of care for the 
treatment of MPS-I involves regular intravenous injections of laronidase (Aldurazyme), an ERT 
commercialized by BioMarin and Sanofi Genzyme. A formulation of laronidase for intrathecal administration is 
currently under evaluation. JCR Pharmaceuticals is developing an ERT, which is in Phase I trials. Denali 
Therapeutics has an ERT program in the discovery stage.
•
MPS-IIIA: There are currently no effective disease modifying treatment options for patients with MPS-IIIA. 
We are aware of three gene therapy candidates in clinical development. Lysogene is developing an AAV gene 
therapy product administered through intracerebral injections and regained global commercial rights after its 
collaboration with Sarepta Therapeutics terminated in July 2022; Abeona Therapeutics has been developing an 
AAV gene therapy product administered intravenously, which was licensed to Ultragenyx in May 2022 for 
further clinical development; and Esteve is developing an AAV gene therapy administered through 
intracerebroventricular injection. Amicus Therapeutics is at the pre-clinical stage of developing an AAV gene 
therapy for MPS-IIIA. JCR Pharmaceuticals and Denali Therapeutics each have a pre-clinical stage ERT 
program for MPS-IIIA.
•
GRN-FTD: There are no approved disease modifying treatments for GRN-FTD. Each of Prevail Therapeutics 
(now owned by Eli Lilly & Company) and Passage Bio is developing in early-stage clinical trials an AAV gene 
therapy to be delivered intra-cisterna magna. Alector is developing a monoclonal antibody designed to increase 
levels of GRN in the brain in late-stage clinical trials, and Denali Therapeutics is developing a modified protein 
designed to penetrate across the blood-brain barrier at the pre-clinical stage in collaboration with Takeda.
•
NOD2-Crohn’s: There are no approved treatment options specifically for the NOD-2 form of Crohn’s disease, 
and many patients with Crohn’s disease have uncontrolled symptoms despite treatment with standard of care, 
including multiple anti-inflammatory biologics and surgical interventions. We are not aware of any other 
treatments in development specifically for the NOD-2 form of Crohn’s disease. 
Many of our potential competitors, alone or with their strategic partners, have substantially greater financial, technical and 
other resources than we do, such as larger research and development, clinical, marketing and manufacturing organizations. 
Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being 
concentrated among a smaller number of competitors. Our commercial opportunity could be reduced or eliminated if 
competitors develop and commercialize products that are safer, more effective, have fewer or less severe side effects, are 
more convenient or are less expensive than any products that we may develop. Competitors also may obtain FDA, EMA or 
other regulatory approval for their products more rapidly than we may obtain approval for ours, which could result in our 
competitors establishing a strong market position before we are able to enter the market. Additionally, technologies 
developed by our competitors may render our potential product candidates uneconomical or obsolete, and we may not be 
successful in marketing our product candidates against competitors. 
Government regulation 
In the United States, biological products, including gene therapy products, are subject to regulation under the Federal Food, 
Drug, and Cosmetic Act, or FD&C Act, and the Public Health Service Act, or PHS Act, and other federal, state, local and 
foreign statutes and regulations. Both the FD&C Act and the PHS Act and their corresponding regulations govern, among 
other things, the research, development, clinical trial, testing, manufacturing, safety, efficacy, labeling, packaging, storage, 
record keeping, distribution, reporting, advertising and other promotional practices involving biological products. Each 
clinical trial protocol for a gene therapy product must be reviewed by the FDA. FDA approval must be obtained before the 
marketing of biological products. The process of obtaining regulatory approvals and the subsequent compliance with 
appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial 
resources and we may not be able to obtain the required regulatory approvals. 
Ethical, social and legal concerns about gene therapy, genetic testing and genetic research could result in additional laws and 
regulations restricting or prohibiting the processes we may use. Federal and state legislatures, agencies, congressional 
committees and foreign governments have expressed interest in further regulating biotechnology. More restrictive laws and 

21
regulations or interpretations of existing laws or regulations, or claims that our products are unsafe or pose a hazard, could 
prevent us from commercializing any products. New government requirements may be established that could delay or 
prevent regulatory approval of our product candidates under development. It is impossible to predict whether legislative 
changes will be enacted, regulations, policies or guidance changed, or interpretations by agencies or courts changed, or what 
the impact of such changes, if any, may be. 
U.S. biological products development process 
The process required by the FDA before a biological product may be marketed in the United States generally involves the 
following: 
•
completion of nonclinical laboratory tests and animal studies according to good laboratory practices, or GLPs, 
unless justified, and applicable requirements for the humane use of laboratory animals or other applicable 
regulations; 
•
submission to the FDA of an application for an investigational new drug application, or IND, which must 
become effective before human clinical trials may begin; 
•
approval of the protocol and related documentation by an independent institutional review board, or IRB, or 
ethics committee at each clinical trial site before each study may be initiated; 
•
performance of adequate and well-controlled human clinical trials according to the FDA’s regulations 
commonly referred to as good clinical practices, or GCPs, and any additional requirements for the protection of 
human research subjects and their health information, to establish the safety and efficacy of the proposed 
biological product for its intended use; 
•
submission to the FDA of a biologics license application, or BLA, for marketing approval that includes 
sufficient evidence of establishing the safety, purity, and potency of the proposed biological product for its 
intended indication, including from results of nonclinical testing and clinical trials; 
•
satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the biological 
product is produced to assess compliance with current good manufacturing practice, or cGMP, to assure that the 
facilities, methods and controls are adequate to preserve the biological product’s identity, strength, quality and 
purity and, if applicable, the FDA’s current good tissue practices, or CGTPs, for the use of human cellular and 
tissue products; 
•
potential FDA audit of the nonclinical study and clinical trial sites that generated the data in support of the BLA 
in accordance with any applicable expedited programs or designations; 
•
review of the product candidate by an FDA advisory committee, where appropriate or if applicable;
•
payment of user fees for FDA review of the BLA (unless a fee waiver applies); and 
•
FDA review and approval, or licensure, of the BLA. 
Before testing any biological product candidate, including a gene therapy product, in humans, the product candidate enters 
the pre-clinical testing stage. Pre-clinical tests, also referred to as nonclinical studies, include laboratory evaluations of 
product biological characteristics, chemistry, toxicity and formulation, as well as animal studies to assess the potential safety 
and activity of the product candidate. The conduct of the pre-clinical tests must comply with federal regulations and 
requirements including GLPs. 
An IND is an exemption from the FD&C Act that allows an unapproved product candidate to be shipped in interstate 
commerce for use in an investigational clinical trial and a request for FDA authorization to administer such investigational 
product to humans. Such authorization must be secured prior to interstate shipment and administration of any product 
candidate that is not the subject of an approved BLA. In support of a request for an IND, applicants must submit a protocol 
for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND. In addition, 
the results of the pre-clinical tests, together with manufacturing information, analytical data, any available clinical data or 
literature and plans for clinical trials, among other things, must be submitted to the FDA as part of an IND. The FDA requires 
a 30-day waiting period after the filing of each IND before clinical trials may begin. This waiting period is designed to allow 
the FDA to review the IND to determine whether human research subjects will be exposed to unreasonable health risks. At 
any time during this 30-day period the FDA may raise concerns or questions about the conduct of the trials as outlined in the 
IND and impose a clinical hold or partial clinical hold. In this case, the IND sponsor and the FDA must resolve any 
outstanding concerns before clinical trials can begin. 

22
Following commencement of a clinical trial, the FDA may also place a clinical hold or partial clinical hold on that trial. A 
clinical hold is an order issued by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing 
investigation. A partial clinical hold is a delay or suspension of only part of the clinical work requested under the IND. No 
more than 30 days after imposition of a clinical hold or partial clinical hold, the FDA will provide the sponsor a written 
explanation of the basis for the hold. Following issuance of a clinical hold or partial clinical hold, an investigation may only 
resume after the FDA has notified the sponsor that the investigation may proceed. 
A sponsor may choose, but is not required, to conduct a foreign clinical trial under an IND. When a foreign clinical trial is 
conducted under an IND, all FDA IND requirements must be met unless waived. When a foreign clinical trial is not 
conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in 
order to use the study as support for an IND or application for marketing approval or licensing. In particular, such studies 
must be conducted in accordance with GCP, including review and approval by an independent ethics committee, or IEC, and 
informed consent from subjects. The FDA must be able to validate the data through an onsite inspection, if deemed necessary 
by the FDA. 
An IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial 
before it commences at that institution, and the IRB must conduct continuing review and re-approve the study at least 
annually. The IRB must review and approve, among other things, the study protocol and informed consent information to be 
provided to study subjects. An IRB must operate in compliance with FDA regulations. An IRB can suspend or terminate 
approval of a clinical trial at its institution, or an institution it represents, if the clinical trial is not being conducted in 
accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to 
patients. 
Some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety 
monitoring board or committee, or DSMB. This group provides authorization as to whether or not a trial may move forward 
at designated check points based on access that only the group maintains to available data from the study. 
In addition to the submission of an IND to the FDA before initiation of a clinical trial in the United States, certain human 
clinical trials involving recombinant or synthetic nucleic acid molecules are subject to oversight of institutional biosafety 
committees, or IBCs, as set forth in the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid 
Molecules, or NIH Guidelines. Under the NIH Guidelines, recombinant and synthetic nucleic acids are defined as: (i) 
molecules that are constructed by joining nucleic acid molecules and that can replicate in a living cell (i.e., recombinant 
nucleic acids); (ii) nucleic acid molecules that are chemically or by other means synthesized or amplified, including those that 
are chemically or otherwise modified but can base pair with naturally occurring nucleic acid molecules (i.e., synthetic nucleic 
acids); or (iii) molecules that result from the replication of those described in (i) or (ii). Specifically, under the NIH 
Guidelines, supervision of human gene transfer trials includes evaluation and assessment by an IBC, a local institutional 
committee that reviews and oversees research utilizing recombinant or synthetic nucleic acid molecules at that institution. 
The IBC assesses the safety of the research and identifies any potential risk to public health or the environment, and such 
review may result in some delay before initiation of a clinical trial. While the NIH Guidelines are not mandatory unless the 
research in question is being conducted at or sponsored by institutions receiving NIH funding of recombinant or synthetic 
nucleic acid molecule research, many companies and other institutions not otherwise subject to the NIH Guidelines 
voluntarily follow them.
Information about clinical trials must be submitted within specific time frames to the NIH for public dissemination on its 
ClinicalTrials.gov website. 
Clinical trials typically are conducted in three sequential phases that may overlap or be combined: 
•
Phase 1. The biological product is initially introduced into healthy human subjects and tested for safety. In the 
case of some products for severe or life-threatening diseases, especially when the product may be too inherently 
toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients. 
•
Phase 2. The biological product is evaluated in a limited patient population to identify possible adverse effects 
and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases and to 
determine dosage tolerance, optimal dosage and dosing schedule. 
•
Phase 3. Clinical trials are undertaken to further evaluate dosage, clinical efficacy, potency, and safety in an 
expanded patient population at geographically dispersed clinical trial sites. These clinical trials are intended to 
establish the overall risk/benefit ratio of the product and provide an adequate basis for approval and product 
labeling. 
Post-approval clinical trials, sometimes referred to as Phase 4 clinical trials, may be conducted after initial marketing 
approval. These clinical trials are used to gain additional experience from the treatment of patients in the intended therapeutic 

23
indication, particularly for long-term safety follow-up. The FDA generally recommends that sponsors of human gene therapy 
products integrating vectors such as gammaretroviral and lentiviral vectors and transposon elements observe subjects for 
potential gene therapy-related delayed adverse events for a 15-year period, including a minimum of five years of annual 
examinations followed by ten years of annual queries, either in person or by questionnaire, of study subjects. 
Both the FDA and the EMA provide expedited pathways for the development of drug product candidates for treatment of rare 
diseases, particularly life-threatening diseases with high unmet medical need. Such drug product candidates may be eligible 
to proceed to registration following a single clinical trial in a limited patient population, sometimes referred to as a Phase 1/2 
trial, but which may be deemed a pivotal or registrational trial following review of the trial’s design and primary endpoints 
by the applicable regulatory agencies. Determination of the requirements to be deemed a pivotal or registrational trial is 
subject to the applicable regulatory authority’s scientific judgment and these requirements may differ in the U.S. and the 
European Union. 
During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical 
activities, clinical data, and clinical trial investigators. Annual progress reports detailing the results of the clinical trials must 
be submitted to the FDA. Written IND safety reports must be promptly submitted to the FDA, the NIH and the investigators 
for serious and unexpected adverse events, any findings from other studies, tests in laboratory animals or in vitro testing that 
suggest a significant risk for human subjects, or any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 
calendar days after the sponsor determines that the information qualifies for reporting. The sponsor also must notify the FDA 
of any unexpected fatal or life-threatening suspected adverse reaction within seven calendar days after the sponsor’s initial 
receipt of the information. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any 
specified period, if at all. The FDA or the sponsor, acting on its own or based on a recommendation from the sponsor’s data 
safety monitoring board may suspend a clinical trial at any time on various grounds, including a finding that the research 
subjects or patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or terminate approval of 
a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the 
biological product has been associated with unexpected serious harm to patients. 
Human gene therapy products are a new category of therapeutics. Because this is a relatively new and expanding area of 
novel therapeutic interventions, there can be no assurance as to the length of the study period, the number of patients the 
FDA will require to be enrolled in the studies in order to establish the safety, purity and potency of human gene therapy 
products, or that the data generated in these studies will be acceptable to the FDA to support marketing approval. 
Concurrent with clinical trials, companies usually complete additional animal studies and also must develop additional 
information about the physical characteristics of the biological product as well as finalize a process for manufacturing the 
product in commercial quantities in accordance with cGMP requirements. To help reduce the risk of the introduction of 
adventitious agents with use of biological products, the PHS Act emphasizes the importance of manufacturing control for 
products whose attributes cannot be precisely defined. The manufacturing process must be capable of consistently producing 
quality batches of the product candidate and, among other things, the sponsor must develop methods for testing the identity, 
strength, quality, potency and purity of the final biological product. Additionally, appropriate packaging must be selected and 
tested and stability studies must be conducted to demonstrate that the biological product candidate does not undergo 
unacceptable deterioration over its shelf life. 
U.S. review and approval processes 
After the completion of clinical trials of a biological product, FDA approval of a BLA must be obtained before commercial 
marketing of the biological product. The BLA must include results of product development, laboratory and animal studies, 
human studies, information on the manufacture and composition of the product, proposed labeling and other relevant 
information. The testing and approval processes require substantial time and effort and there can be no assurance that the 
FDA will accept the BLA for filing and, even if filed, that any approval will be granted on a timely basis, if at all. 

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Within 60 days following submission of the application, the FDA reviews a BLA submitted to determine if it is substantially 
complete before the FDA accepts it for filing. The FDA may refuse to file any BLA that it deems incomplete or not properly 
reviewable at the time of submission and may request additional information. In this event, the BLA must be resubmitted 
with the additional information. The resubmitted application also is subject to review before the FDA accepts it for filing. In 
most cases, the submission of a BLA is subject to a substantial application user fee, although the fee may be waived under 
certain circumstances. Under the performance goals and policies implemented by the FDA under the Prescription Drug User 
Fee Act, or PDUFA, for original BLAs, the FDA targets ten months from the filing date in which to complete its initial 
review of a standard application and respond to the applicant, and six months from the filing date for an application with 
priority review. The FDA does not always meet its PDUFA goal dates, and the review process is often significantly extended 
by FDA requests for additional information or clarification. This review typically takes twelve months from the date the BLA 
is submitted to the FDA because the FDA has approximately two months to make a ‘‘filing’’ decision. The review process 
and the PDUFA goal date may be extended, for example, by three months if the BLA sponsor submits a major new clinical 
study report, a major re-analysis of a previously submitted study or other major amendment at any time during the review 
cycle. 
Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the BLA. The FDA reviews the 
BLA to determine, among other things, whether the proposed product is safe, pure and potent, for its intended use, and 
whether the product is being manufactured in accordance with cGMP to ensure the continued safety, purity and potency of 
such product. The FDA may refer applications for novel biological products or biological products that present difficult or 
novel questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for 
review, evaluation and a recommendation as to whether the application should be approved and under what conditions. The 
FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when 
making decisions. During the biological product approval process, the FDA also will determine whether a Risk Evaluation 
and Mitigation Strategy, or REMS, is necessary to assure the safe use of the biological product. If the FDA concludes a 
REMS is needed, the sponsor of the BLA must submit a proposed REMS; the FDA will not approve the BLA without a 
REMS, if required. 
Before approving a BLA, the FDA typically will inspect the facilities at which the product is manufactured. The FDA will 
not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP 
requirements and adequate to assure consistent production of the product within required specifications. For a gene therapy 
product, the FDA also will not approve the product if the manufacturer is not in compliance with the CGTPs. These are FDA 
regulations that govern the methods used in, and the facilities and controls used for, the manufacture of human cells, tissues, 
and cellular and tissue-based products, or HCT/Ps, which are human cells or tissue intended for implantation, transplant, 
infusion, or transfer into a human recipient. The primary intent of the CGTP requirements is to ensure that cell and tissue-
based products are manufactured in a manner designed to prevent the introduction, transmission and spread of communicable 
disease. FDA regulations also require tissue establishments to register and list their HCT/Ps with the FDA and, when 
applicable, to evaluate donors through appropriate screening and testing. Additionally, before approving a BLA, the FDA 
will typically inspect one or more clinical sites to assure that the clinical trials were conducted in compliance with IND study 
requirements and GCP requirements. During the COVID-19 pandemic, restrictions preventing the conduct or completion of 
facility or clinical site inspections have led to FDA deferred action on marketing applications or the issuance of complete 
response letters. To assure cGMP, CGTP and GCP compliance, an applicant must incur significant expenditure of time, 
money and effort in the areas of training, record keeping, production and quality control. 
Under the Pediatric Research Equity Act, or PREA, a BLA or supplement to a BLA for a novel product (e.g., new active 
ingredient, new indication, etc.) must contain data to assess the safety and effectiveness of the biological product for the 
claimed indications in all relevant pediatric subpopulations and to support dosing and administration for each pediatric 
subpopulation for which the product is safe and effective. The FDA may grant deferrals for submission of data or full or 
partial waivers. Unless otherwise required by regulation, PREA does not apply to any biological product for an indication for 
which orphan designation has been granted. 
Notwithstanding the submission of relevant data and information, the FDA may ultimately decide that the BLA does not 
satisfy its regulatory criteria for approval and deny approval. Data obtained from clinical trials are not always conclusive and 
the FDA may interpret data differently than we interpret the same data. If the FDA decides not to approve the BLA in its 
present form, the FDA will issue a complete response letter that usually describes all of the specific deficiencies in the BLA 
identified by the FDA. The deficiencies identified may be minor, for example, requiring labeling changes, or major, for 
example, requiring additional clinical trials. Additionally, the complete response letter may include recommended actions 
that the applicant might take to place the application in a condition for approval. If a complete response letter is issued, the 
applicant may either resubmit the BLA, addressing all of the deficiencies identified in the letter, or withdraw the application. 

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If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the 
indications for use may otherwise be limited, including to subpopulations of patients, which could restrict the commercial 
value of the product. Further, the FDA may require that certain contraindications, warnings precautions or interactions be 
included in the product labeling. The FDA may impose restrictions and conditions on product distribution, prescribing, or 
dispensing in the form of a REMS, or otherwise limit the scope of any approval. In addition, the FDA may require post-
marketing clinical trials, sometimes referred to as Phase 4 clinical trials, designed to further assess a biological product’s 
safety and effectiveness, and testing and surveillance programs to monitor the safety of approved products that have been 
commercialized. 
Orphan drug designation 
Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare 
disease or condition, which is generally a disease or condition that affects fewer than 200,000 individuals in the United 
States, or more than 200,000 individuals in the United States and for which there is no reasonable expectation that the cost of 
developing and making a drug or biological product available in the United States for this type of disease or condition will be 
recovered from sales of the product. Orphan product designation must be requested before submitting a BLA. After the FDA 
grants orphan product designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by 
the FDA. Orphan product designation does not convey any advantage in or shorten the duration of the regulatory review and 
approval process. 
Orphan drug designation entitles a party to financial incentives such as opportunities for grant funding towards clinical trial 
costs, tax advantages and user-fee waivers. If a product that has orphan designation subsequently receives the first FDA 
approval for the disease or condition for which it has such designation, the product is entitled to orphan product exclusivity, 
which means that the FDA may not approve any other applications to market the same drug or biological product for the 
same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product with 
orphan exclusivity. Competitors, however, may receive approval of different products for the indication for which the orphan 
product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product 
has exclusivity. Orphan product exclusivity also could block the approval of one of our products for seven years if a 
competitor obtains approval of the same biological product for the same use or indication, and we are unable to demonstrate 
that our product is clinically superior to the previously approved drug for the same use or indication. If a drug or biological 
product designated as an orphan product receives marketing approval for an indication broader than what is designated, it 
may not be entitled to orphan product exclusivity. Orphan drug status in the European Union has similar, but not identical, 
benefits.
Rare Pediatric Disease Designation and Priority Review Vouchers 
Under the FD&C Act, the FDA incentivizes the development of drugs and biological products that meet the definition of a 
“rare pediatric disease,” defined to mean a serious or life-threatening disease in which the serious of life-threatening 
manifestations primarily affect individuals aged from birth to 18 years and the disease affects fewer than 200,000 individuals 
in the United States or affects more than 200,000 in the United States and for which there is no reasonable expectation that 
the cost of developing and making in the United States a drug or biological product for such disease or condition will be 
received from sales in the United States of such drug or biological product. The sponsor of a product candidate for a rare 
pediatric disease may be eligible for a voucher that can be used to obtain a priority review for a subsequent human drug or 
biological product application after the date of approval of the rare pediatric disease drug or biological product, referred to as 
a priority review voucher, or PRV. A sponsor may request rare pediatric disease designation from the FDA prior to the 
submission of its BLA. A rare pediatric disease designation does not guarantee that a sponsor will receive a PRV upon 
approval of its BLA. Moreover, a sponsor who chooses not to submit a rare pediatric disease designation request may 
nonetheless receive a PRV upon approval of their marketing application if they request such a voucher in their original 
marketing application and meet all of the eligibility criteria. If a PRV is received, it may be sold or transferred an unlimited 
number of times. Congress has extended the PRV program through September 30, 2024, with the potential for PRVs to be 
granted through September 30, 2026.
Expedited development and review programs 
The FDA has various programs, including Fast Track designation, breakthrough therapy designation, accelerated approval 
and priority review, that are intended to expedite or simplify the process for the development and FDA review of drugs and 
biologics that are intended for the treatment of serious or life-threatening diseases or conditions. These programs do not 
change the standards for approval but may help expedite the development or approval process. To be eligible for fast track 
designation, new drugs and biological products must be intended to treat a serious or life-threatening condition and 
demonstrate the potential to address unmet medical needs for the condition. Fast Track designation applies to the 

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combination of the product and the specific indication for which it is being studied. The sponsor of a new drug or biologic 
may request the FDA to designate the drug or biologic as a Fast Track product at any time during the clinical development of 
the product. One benefit of fast track designation, for example, is that the FDA may consider for review sections of the 
marketing application for a product that has received Fast Track designation on a rolling basis before the complete 
application is submitted. 
Under the FDA’s breakthrough therapy program, products intended to treat a serious or life-threatening disease or condition 
may be eligible for the benefits of the Fast Track program when preliminary clinical evidence demonstrates that such product 
may have substantial improvement on one or more clinically significant endpoints over existing therapies. Additionally, the 
FDA will seek to ensure the sponsor of a breakthrough therapy product receives timely advice and interactive 
communications to help the sponsor design and conduct a development program as efficiently as possible. 
Any product is eligible for priority review if it has the potential to provide safe and effective therapy where no satisfactory 
alternative therapy exists or a significant improvement in the treatment, diagnosis or prevention of a disease compared to 
marketed products. The FDA will attempt to direct additional resources to the evaluation of an application for a new drug or 
biological product designated for priority review in an effort to facilitate the review. Under priority review, the FDA’s goal is 
to review an application in six months once it is filed, compared to ten months for a standard review. 
Additionally, a product may be eligible for accelerated approval. Drug or biological products studied for their safety and 
effectiveness in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefit over existing 
treatments may receive accelerated approval, which means that they may be approved on the basis of adequate and well-
controlled clinical trials establishing that the product has an effect on a surrogate endpoint that is reasonably likely to predict 
a clinical benefit, or on the basis of an effect on an intermediate clinical endpoint other than survival or irreversible 
morbidity. As a condition of approval, the FDA may require that a sponsor of a drug or biological product receiving 
accelerated approval perform adequate and well-controlled post-marketing clinical trials. Under the Food and Drug Omnibus 
Reform Act of 2022, or FDORA, the FDA is permitted to require, as appropriate, that a post-approval confirmatory study or 
studies be underway prior to approval or within a specified time period after the date of accelerated approval was granted. 
FDORA also requires sponsors to send updates to the FDA every 180 days on the status of such studies, including progress 
toward enrollment targets, and the FDA must promptly post this information publicly. FDORA also gives the FDA increased 
authority to withdraw approval of a drug or biologic granted accelerated approval on an expedited basis if the sponsor fails to 
conduct such studies in a timely manner, send the necessary updates to the FDA, or if such post-approval studies fail to verify 
the drug’s predicted clinical benefit. Under FDORA, the FDA is empowered to take action, such as issuing fines, against 
companies that fail to conduct with due diligence any post-approval confirmatory study or submit timely reports to the 
agency on their progress. In addition, for products being considered for accelerated approval, the FDA generally requires, 
unless otherwise informed by the agency, that all advertising and promotional materials intended for dissemination or 
publication within 120 days of marketing approval be submitted to the agency for review during the pre-approval review 
period. 
RMAT designation 
As part of the 21st Century Cures Act, enacted in December 2016, Congress amended the FD&C Act to facilitate an efficient 
development program for, and expedite review of RMAT, which include cell and gene therapies, therapeutic tissue 
engineering products, human cell and tissue products, and combination products using any such therapies or products. RMAT 
do not include those HCT/Ps regulated solely under section 361 of the PHS Act and 21 CFR Part 1271. This program is 
intended to facilitate efficient development and expedite review of regenerative medicine therapies, which are intended to 
treat, modify, reverse, or cure a serious or life-threatening disease or condition and qualify for RMAT designation. A drug 
sponsor may request that FDA designate a drug as a RMAT concurrently with or at any time after submission of an IND. 
FDA has 60 calendar days to determine whether the drug meets the criteria, including whether there is preliminary clinical 
evidence indicating that the drug has the potential to address unmet medical needs for a serious or life-threatening disease or 
condition. A BLA for a regenerative medicine therapy that has received RMAT designation may be eligible for priority 
review or accelerated approval through use of surrogate or intermediate endpoints reasonably likely to predict long-term 
clinical benefit, or reliance upon data obtained from a meaningful number of sites. Benefits of RMAT designation also 
include early interactions with FDA to discuss any potential surrogate or intermediate endpoint to be used to support 
accelerated approval. A regenerative medicine therapy with RMAT designation that is granted accelerated approval and is 
subject to post-approval requirements may fulfill such requirements through the submission of clinical evidence from clinical 
trials, patient registries, or other sources of real world evidence, such as electronic health records; the collection of larger 
confirmatory data sets; or post-approval monitoring of all patients treated with such therapy prior to its approval. Like some 
of FDA’s other expedited development programs, RMAT designation does not change the standards for approval but may 
help expedite the development or approval process. 

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Post-approval requirements 
Maintaining substantial compliance with applicable federal, state, and local statutes and regulations requires the expenditure 
of substantial time and financial resources. Rigorous and extensive FDA regulation of biological products continues after 
approval, particularly with respect to cGMP. We currently rely, and may continue to rely, on third parties for the production 
of clinical and commercial quantities of any products that we may commercialize. Manufacturers of our products are required 
to comply with applicable requirements in the cGMP regulations, including quality control and quality assurance and 
maintenance of records and documentation. Other post-approval requirements applicable to biological products, include 
reporting of cGMP deviations that may affect the identity, potency, purity and overall safety of a distributed product, record-
keeping requirements, reporting of adverse effects, reporting updated safety and efficacy information, and complying with 
electronic record and signature requirements. After a BLA is approved, the product also may be subject to official lot release. 
As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it 
is released for distribution. If the product is subject to official release by the FDA, the manufacturer submits samples of each 
lot of product to the FDA together with a release protocol showing a summary of the history of manufacture of the lot and the 
results of all of the manufacturer’s tests performed on the lot. The FDA also may perform certain confirmatory tests on lots of 
some products, such as viral vaccines, before releasing the lots for distribution by the manufacturer. In addition, the FDA 
conducts laboratory research related to the regulatory standards on the safety, purity, potency, and effectiveness of biological 
products. 
We also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer 
advertising, the prohibition on promoting products for uses or in patient populations that are not described in the product’s 
approved labeling (known as “off-label use”), industry-sponsored scientific and educational activities, and promotional 
activities involving the internet. Discovery of previously unknown problems or the failure to comply with the applicable 
regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from the market 
as well as possible civil or criminal sanctions. Failure to comply with the applicable U.S. requirements at any time during the 
product development process, approval process or after approval, may subject an applicant or manufacturer to administrative 
or judicial civil or criminal sanctions and adverse publicity. FDA sanctions could include refusal to approve pending 
applications, withdrawal of an approval, clinical holds, warning or untitled letters, product recalls, product seizures, total or 
partial suspension of production or distribution, injunctions, fines, refusals of government contracts, mandated corrective 
advertising or communications with doctors or other stakeholders, debarment, restitution, disgorgement of profits, or civil or 
criminal penalties. Any agency or judicial enforcement action could have a material adverse effect on us. 
Biological product manufacturers and other entities involved in the manufacture and distribution of approved biological 
products and those supplying products, ingredients and components of them, are required to register their establishments with 
the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state 
agencies for compliance with cGMP and other laws. Accordingly, manufacturers must continue to expend time, money, and 
effort in the area of production and quality control to maintain cGMP compliance. Discovery of problems with a product after 
approval may result in restrictions on a product, manufacturer, or holder of an approved BLA, including withdrawal of the 
product from the market. In addition, changes to the manufacturing process or facility generally require prior FDA approval 
before being implemented and other types of changes to the approved product, such as adding new indications and additional 
labeling claims, are also subject to further FDA review and approval. 
U.S. patent term restoration and marketing exclusivity 
Depending upon the timing, duration and specifics of the FDA approval of the use of our product candidates, some of our 
U.S. patents may be eligible for limited patent term extension under the Hatch-Waxman Amendments. The Hatch-Waxman 
Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product 
development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a 
patent beyond a total of 14 years from the product’s approval date. The patent term restoration period is generally one-half 
the time between the effective date of an IND and the submission date of a BLA plus the time between the submission date of 
a BLA and the approval of that application. Only one patent applicable to an approved biological product is eligible for the 
extension and the application for the extension must be submitted prior to the expiration of the patent. In addition, a patent 
can only be extended once and only for a single product. The USPTO, in consultation with the FDA, reviews and approves 
the application for any patent term extension or restoration. In the future, we may intend to apply for restoration of patent 
term for one of our patents, if and as applicable, to add patent life beyond its current expiration date, depending on the 
expected length of the clinical trials and other factors involved in the filing of the relevant BLA. 
A biological product can obtain pediatric market exclusivity in the United States. Pediatric exclusivity, if granted, adds six 
months to existing exclusivity periods. This six-month exclusivity, which runs from the end of other exclusivity protection, 
may be granted based on the voluntary completion of a pediatric study in accordance with an FDA-issued “Written Request” 
for such a study. 

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The ACA, signed into law on March 23, 2010, includes a subtitle called the Biologics Price Competition and Innovation Act 
of 2009 which created an abbreviated approval pathway for biological products shown to be similar to, or interchangeable 
with, an FDA-licensed reference biological product. This amendment to the PHS Act attempts to minimize duplicative 
testing. Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and 
the reference product in terms of safety, purity, and potency, can be shown through analytical studies, animal studies, and a 
clinical trial or trials. Interchangeability requires that a product is biosimilar to the reference product and the product must 
demonstrate that it can be expected to produce the same clinical results as the reference product and, for products 
administered multiple times, the biologic and the reference biologic may be switched after one has been previously 
administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic. 
A reference biological product is granted four- and 12-year exclusivity periods from the time of first licensure of the product. 
FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until 
four years after the date of first licensure of the reference product, and FDA will not approve an application for a biosimilar 
or interchangeable product based on the reference biological product until twelve years after the date of first licensure of the 
reference product. “First licensure” typically means the initial date the particular product at issue was licensed in the United 
States. Date of first licensure does not include the date of licensure of (and a new period of exclusivity is not available for) a 
biological product if the licensure is for a supplement for the biological product or for a subsequent application by the same 
sponsor or manufacturer of the biological product (or licensor, predecessor in interest, or other related entity) for a change 
(not including a modification to the structure of the biological product) that results in a new indication, route of 
administration, dosing schedule, dosage form, delivery system, delivery device or strength, or for a modification to the 
structure of the biological product that does not result in a change in safety, purity, or potency. Therefore, one must determine 
whether a new product includes a modification to the structure of a previously licensed product that results in a change in 
safety, purity, or potency to assess whether the licensure of the new product is a first licensure that triggers its own period of 
exclusivity. Whether a subsequent application, if approved, warrants exclusivity as the “first licensure” of a biological 
product is determined on a case-by-case basis with data submitted by the sponsor. 
Additional regulation 
In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including 
the Occupational Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, 
affect our business. These and other laws govern our use, handling and disposal of various biological, chemical and 
radioactive substances used in, and wastes generated by, our operations. If our operations result in contamination of the 
environment or expose individuals to hazardous substances, we could be liable for damages and governmental fines. We 
believe that we are in material compliance with applicable environmental laws and that continued compliance therewith will 
not have a material adverse effect on our business. We cannot predict, however, how changes in these laws may affect our 
future operations. 
U.S. Foreign Corrupt Practices Act 
The U.S. Foreign Corrupt Practices Act, to which we are subject, prohibits corporations and individuals from engaging in 
certain activities to obtain or retain business or to influence a person working in an official capacity. It is illegal to pay, offer 
to pay or authorize the payment of anything of value to any foreign government official, government staff member, political 
party or political candidate in an attempt to obtain or retain business or to otherwise influence a person working in an official 
capacity. 
Government regulation outside of the United States 
In addition to regulations in the United States, we are subject to a variety of regulations in other jurisdictions governing, 
among other things, research and development, clinical trials, testing, manufacturing, safety, efficacy, labeling, packaging, 
storage, record keeping, distribution, reporting, advertising and other promotional practices involving biological products as 
well as authorization and approval of our products. Because biologically sourced raw materials are subject to unique 
contamination risks, their use may be restricted in some countries. 
The requirements and process governing the conduct of clinical trials, product licensing, pricing and reimbursement vary 
from country to country. In all cases, the clinical trials must be conducted in accordance with GCP and the applicable 
regulatory requirements and the ethical principles that have their origin in the Declaration of Helsinki. If we fail to comply 
with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension of clinical trials, 
suspension or withdrawal of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal 
prosecution.
Clinical trials regulation

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Whether or not we obtain FDA approval for a product, we must obtain the requisite approvals from regulatory authorities in 
foreign countries prior to the commencement of clinical trials or marketing of the product in those countries. Certain 
countries outside of the United States have a similar process that requires the submission of a clinical trial application much 
like the IND prior to the commencement of human clinical trials. 
In April 2014, the EU adopted the new Clinical Trials Regulation (EU) No 536/2014, or Regulation, which replaced the 
Clinical Trials Directive 2001/20/EC, or Directive, on January 31, 2022. The transitory provisions of the new Regulation 
provide that, by January 31, 2025, all ongoing clinical trials must have transitioned to the new Regulation. The new 
Regulation overhauled the system of approvals for clinical trials in the EU. Specifically, the new Regulation, which is 
directly applicable in all Member States (meaning that no national implementing legislation in each EU Member State is 
required), aims at simplifying and streamlining the approval of clinical trials in the EU. The main characteristics of the 
regulation include: a streamlined application procedure via a single-entry point through the Clinical Trials Information 
System, or CTIS; a single set of documents to be prepared and submitted for the application as well as simplified reporting 
procedures for clinical trial sponsors; and a harmonized procedure for the assessment of applications for clinical trials, which 
is divided in two parts (Part I contains scientific and medicinal product documentation and Part II contains the national and 
patient-level documentation). Part I is assessed by a coordinated review by the competent authorities of all EU Member 
States in which an application for authorization of a clinical trial has been submitted (Member States concerned) of a draft 
report prepared by a Reference Member State. Part II is assessed separately by each Member State concerned. Strict 
deadlines have been established for the assessment of clinical trial applications. The role of the relevant ethics committees in 
the assessment procedure will continue to be governed by the national law of the concerned EU Member State. However, 
overall related timelines will be defined by the Clinical Trials Regulation.
Drug review and approval 
In the EU, medicinal products, including advanced therapy medicinal products, or ATMPs, are subject to extensive pre- and 
post-market regulation by regulatory authorities at both the EU and national levels. ATMPs comprise gene therapy products, 
somatic cell therapy products and tissue engineered products. Gene therapy products deliver genes into the body that lead to a 
therapeutic, prophylactic or diagnostic effect. Libmeldy is authorized as a gene therapy product in the EU, and we anticipate 
that our gene therapy development products would also be regulated as ATMPs in the EU. 
To obtain regulatory approval of an ATMP under EU regulatory systems, we must submit an MAA under the centralized 
procedure administered by the EMA. The application used to submit the BLA in the United States is similar to that required 
in the EU, with the exception of, among other things, certain specific requirements set out in Regulation (EC) No 1394/2007 
on advanced therapy medicinal products, or the ATMP Regulation, for example certain particulars to be contained in the 
summary of product characteristics. The centralized procedure provides for the grant of a single marketing authorization by 
the European Commission that is valid across all of the EU, and in the additional Member States of the European Economic 
Area (Iceland, Liechtenstein and Norway), or EEA. As provided for in the ATMP Regulation, the scientific evaluation of 
MAAs for ATMPs is primarily performed by a specialized scientific committee called the Committee for Advanced 
Therapies, or CAT. The CAT prepares a draft opinion on the quality, safety and efficacy of the ATMP which is the subject of 
the MAA, which is sent for final approval to the Committee for Medicinal Products for Human Use, or CHMP. The CHMP 
recommendation is then sent to the European Commission, which adopts a decision binding in all EU Member States. The 
maximum time frame for the evaluation of an MAA for an ATMP is 210 days from receipt of a valid MAA, excluding clock 
stops when additional information or written or oral explanation is to be provided by the applicant in response to questions 
asked by the CAT and/or CHMP. Clock stops may extend the time frame of evaluation of an MAA considerably beyond 210 
days. Where the CHMP gives a positive opinion, the EMA provides the opinion together with supporting documentation to 
the European Commission, who make the final decision to grant a marketing authorization, which is issued within 67 days of 
receipt of the EMA’s recommendation. Accelerated assessment may be granted by the CHMP in exceptional cases, when a 
medicinal product is of major public health interest, particularly from the viewpoint of therapeutic innovation. If the CHMP 
accepts such a request, the time frame of 210 days for assessment will be reduced to 150 days (excluding clock stops), but it 
is possible that the CHMP may revert to the standard time limit for the centralized procedure if it determines that the 
application is no longer appropriate to conduct an accelerated assessment.
Now that the UK (which comprises Great Britain and Northern Ireland) has left the EU, Great Britain is no longer covered by 
centralized marketing authorizations (under the Northern Ireland Protocol, centralized marketing authorizations continue to 
be recognized in Northern Ireland). All medicinal products with an existing centralized marketing authorization were 
automatically converted to Great Britain marketing authorizations on January 1, 2021. For a period of three years from 
January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or MHRA, the UK medicines regulator, could 
rely on a decision taken by the European Commission on the approval of a new marketing authorization in the centralized 
procedure, in order to more quickly grant a new Great Britain marketing authorization. A separate application will, however, 
still be required. On January 24, 2023, the  MHRA announced that a new international recognition framework will be put in 

30
place from January 1, 2024, which will have regard to decisions on the approval of marketing authorizations made by the 
European Medicines Agency and certain other regulators when determining an application for a new Great Britain marketing 
authorization.
Data and marketing exclusivity
The EU also provides opportunities for market exclusivity. Upon receiving a marketing authorization in the EU, innovative 
medicinal products generally receive eight years of data exclusivity and an additional two years of market exclusivity. If 
granted, data exclusivity prevents generic or biosimilar applicants from referencing the innovator’s pre-clinical and clinical 
trial data contained in the dossier of the reference product when applying for a generic or biosimilar marketing authorization 
during a period of eight years from the date on which the reference product was first authorized in the EU. During the 
additional two-year period of market exclusivity, a generic or biosimilar marketing authorization can be submitted, and the 
innovator’s data may be referenced, but no generic or biosimilar product can be marketed until the expiration of the market 
exclusivity period. The overall ten-year period will be extended to a maximum of eleven years if, during the first eight years 
of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications 
which, during the scientific evaluation prior to authorization, is held to bring a significant clinical benefit in comparison with 
existing therapies. Even if an innovative medicinal product gains the prescribed period of data exclusivity, another company 
may market another version of the product if such company obtained marketing authorization based on an MAA with a 
complete and independent data package of pharmaceutical tests, pre-clinical tests and clinical trials. There is, however, no 
guarantee that a product will be considered by the EU’s regulatory authorities to be an innovative medicinal product, and 
products may therefore not qualify for data exclusivity. 
Orphan designation and exclusivity
Products with an orphan designation in the EU can receive ten years of market exclusivity, during which time “no similar 
medicinal product” for the same indication may be placed on the market. A “similar medicinal product” is defined as a 
medicinal product containing a similar active substance or substances as contained in an authorized orphan medicinal 
product, and which is intended for the same therapeutic indication. An orphan medicinal product can also obtain an additional 
two years of market exclusivity in the EU where an agreed pediatric investigation plan for pediatric studies has been 
complied with. No extension to any supplementary protection certificate can be granted on the basis of pediatric studies for 
orphan indications. 
The criteria for designating an “orphan medicinal product” in the EU are similar in principle to those in the United States. 
Under Article 3 of Regulation (EC) 141/2000, a medicinal product may be designated as an orphan medicinal product if it 
meets the following criteria: (1) it is intended for the diagnosis, prevention or treatment of a life-threatening or chronically 
debilitating condition; and (2) either (i) the prevalence of such condition must not be more than five in 10,000 persons in the 
EU when the application is made, or (ii) without the benefits derived from orphan status, it must be unlikely that the 
marketing of the medicine would generate sufficient return in the EU to justify the investment needed for its development; 
and (3) there exists no satisfactory method of diagnosis, prevention or treatment of such condition authorized for marketing 
in the EU, or if such a method exists, the product will be of significant benefit to those affected by the condition, as defined 
in Regulation (EC) 847/2000. Orphan medicinal products are eligible for financial incentives such as reduction of fees or fee 
waivers and are, upon grant of a marketing authorization, entitled to ten years of market exclusivity for the approved 
therapeutic indication. The application for orphan designation must be submitted before the application for marketing 
authorization. The applicant will receive a fee reduction for the MAA if the orphan designation has been granted, but not if 
the designation is still pending at the time the marketing authorization is submitted. Orphan designation does not convey any 
advantage in, or shorten the duration of, the regulatory review and approval process. A marketing authorization may be 
granted to a “similar medicinal product” for the same orphan indication at any time if:
•
a second applicant can establish that its product, although similar, is safer, more effective or otherwise clinically 
superior; 
•
the marketing authorization holder of the authorized orphan product consents to a second orphan medicinal 
product application; or 
•
the marketing authorization holder of the authorized orphan product cannot supply enough orphan medicinal 
product. 
Since January 1, 2021, a separate process for orphan designation has applied in Great Britain. There is now no pre-marketing 
authorization orphan designation (as there is in the EU) in Great Britain and the application for orphan designation will be 
reviewed by the MHRA at the time of an MAA for a UK or Great Britain marketing authorization. The criteria for orphan 
designation are the same as in the EU, save that they apply to Great Britain only (e.g., there must be no satisfactory method 

31
of diagnosis, prevention or treatment of the condition concerned in Great Britain, as opposed to the EU, and the prevalence of 
the condition must not be more than five in 10,000 persons in Great Britain).
Pediatric development 
In the EU, companies developing a new medicinal product must agree upon a pediatric investigation plan, or PIP, with the 
EMA’s Pediatric Committee, or PDCO, and must conduct pediatric clinical trials in accordance with that PIP, unless a waiver 
applies, (e.g., because the relevant disease or condition occurs only in adults). The PIP sets out the timing and measures 
proposed to generate data to support a pediatric indication of the product for which a marketing authorization is being sought. 
The MAA for the product must include the results of pediatric clinical trials conducted in accordance with the PIP, unless a 
waiver applies, or a deferral has been granted by the PDCO of the obligation to implement some or all of the measures of the 
PIP until there are sufficient data to demonstrate the efficacy and safety of the product in adults, in which case the pediatric 
clinical trials must be completed at a later date. Products that are granted a marketing authorization with the results of the 
pediatric clinical trials conducted in accordance with the PIP are eligible for a six-month extension of the protection under a 
supplementary protection certificate, or SPC (provided an application for such extension is made at the same time as filing 
the SPC application for the product, or at any point up to 2 years before the SPC expires) even where the trial results are 
negative. In the case of orphan medicinal products, a two-year extension of the orphan market exclusivity may be available. 
This pediatric reward is subject to specific conditions and is not automatically available when data in compliance with the 
PIP are developed and submitted. 
PRIME Designation 
In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for 
which few or no therapies currently exist. The PRIority MEdicines, or PRIME, scheme is intended to encourage drug 
development in areas of unmet medical need and provides accelerated assessment of products representing substantial 
innovation, where the MAA will be made through the centralized procedure. Eligible products must target conditions for 
which there is an unmet medical need (there is no satisfactory method of diagnosis, prevention or treatment in the EU or, if 
there is, the new medicine will bring a major therapeutic advantage) and they must demonstrate the potential to address the 
unmet medical need by introducing new methods of therapy or improving existing ones. Products from small- and medium-
sized enterprises may qualify for earlier entry into the PRIME scheme than larger companies. Many benefits accrue to 
sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue 
with the EMA, frequent discussions on clinical trial designs and other development program elements, and accelerated MAA 
assessment once a dossier has been submitted. Importantly, a dedicated EMA contact and rapporteur from the CHMP or CAT 
are appointed early in the PRIME scheme facilitating increased understanding of the product at the EMA’s Committee level. 
A kick-off meeting initiates these relationships and includes a team of multidisciplinary experts at the EMA to provide 
guidance on the overall development and regulatory strategies. Where, during the course of development, a medicine no 
longer meets the eligibility criteria, support under the PRIME scheme may be withdrawn.
Post-approval controls 
Following approval, the holder of the marketing authorization is required to comply with a range of requirements applicable 
to the manufacturing, marketing, promotion and sale of the medicinal product. These include the following:
•
The holder of a marketing authorization must establish and maintain a pharmacovigilance system and appoint an 
individual qualified person for pharmacovigilance, who is responsible for oversight of that system. Key obligations 
include expedited reporting of suspected serious adverse reactions and submission of periodic safety update reports, 
or PSURs. 
•
All new MAAs must include a risk management plan, or RMP, describing the risk management system that the 
company will put in place and documenting measures to prevent or minimize the risks associated with the product. 
The regulatory authorities may also impose specific obligations as a condition of the marketing authorization. Such 
risk-minimization measures or post-authorization obligations may include additional safety monitoring, more 
frequent submission of PSURs, or the conduct of additional clinical trials or post-authorization safety studies. RMPs 
and PSURs are routinely available to third parties requesting access, subject to limited redactions. 
•
All advertising and promotional activities for the product must be consistent with the approved SmPC and therefore 
all off-label promotion is prohibited. Direct-to-consumer advertising of prescription medicines is also prohibited in 
the EU. Although general requirements for advertising and promotion of medicinal products are established under 
EU directives, the details are governed by regulations in each EU Member State and can differ from one country to 
another. 
The aforementioned EU rules are generally applicable in the EEA.

32
Brexit and the Regulatory Framework in the UK 
The UK left the EU (commonly referred to as “Brexit”) in January 2020. The UK and EU entered a trade and cooperation 
agreement, or TCA, which has been formally applicable since May 2021. The TCA includes specific provisions concerning 
pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal 
products and GMP documents issued, but does not provide for wholesale mutual recognition of UK and EU pharmaceutical 
regulations. At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal 
products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU 
regulatory framework continues to apply in Northern Ireland). Except in respect of the new EU Clinical Trials Regulation, 
the regulatory regime in Great Britain therefore largely aligns with current EU regulations. However, it is possible that these 
regimes will diverge more significantly in future now that Great Britain’s regulatory system is independent from the EU and 
the TCA does not provide for mutual recognition of UK and EU pharmaceutical legislation. However, notwithstanding that 
there is no wholesale recognition of EU pharmaceutical legislation under the TCA, under the new framework mentioned 
above which will be put in place by the MHRA from January 1, 2024, the MHRA has stated that it will take into account 
decisions on the approval of marketing authorizations from the EMA (and certain other regulators) when considering an 
application for a Great Britain marketing authorization.
Other healthcare laws and compliance requirements 
In the United States, our current and future operations are subject to regulation by various federal, state and local authorities 
in addition to the FDA, including but not limited to, the Centers for Medicare and Medicaid Services, or CMS, other 
divisions of the U.S. Department of Health and Human Services, or HHS (such as the Office of Inspector General, Office for 
Civil Rights and the Health Resources and Service Administration), the U.S. Department of Justice, or DOJ, and individual 
U.S. Attorney offices within the DOJ, and state and local governments. For example, our clinical research, sales, marketing 
and scientific/educational grant programs may have to comply with the anti-fraud and abuse provisions of the Social Security 
Act, the false claims laws, the privacy and security provisions of the federal Health Insurance Portability and Accountability 
Act of 1996, or HIPAA, and similar state laws, each as amended, as applicable:
•
the federal Anti-Kickback Statute, which prohibits, among other things, knowingly and willfully soliciting, 
receiving, offering or paying any remuneration (including any kickback, bribe, or rebate), directly or indirectly, 
overtly or covertly, in cash or in kind, to induce, or in return for, either the referral of an individual, or the 
purchase, lease, order, arrangement or recommendation of any good, facility, item or service for which payment 
may be made, in whole or in part, under a federal healthcare program, such as the Medicare and Medicaid 
programs; a person or entity does not need to have actual knowledge of the federal Anti-Kickback Statute or 
specific intent to violate it to have committed a violation. In addition, the government may assert that a claim 
including items or services resulting from a violation of the federal Anti-Kickback Statute constitutes a false or 
fraudulent claim for purposes of the federal False Claims Act or federal civil money penalties statute; 
•
the federal civil and criminal false claims laws and civil monetary penalty laws, including the False Claims Act, 
which prohibit, among other things, individuals or entities from knowingly presenting, or causing to be 
presented, false or fraudulent claims for payment to, or approval by Medicare, Medicaid, or other federal 
healthcare programs, knowingly making, using or causing to be made or used a false record or statement 
material to a false or fraudulent claim or an obligation to pay or transmit money to the federal government, or 
knowingly concealing or knowingly and improperly avoiding or decreasing or concealing an obligation to pay 
money to the federal government. Manufacturers can be held liable under the False Claims Act even when they 
do not submit claims directly to government payers if they are deemed to “cause” the submission of false or 
fraudulent claims. The False Claims Act also permits a private individual acting as a “whistle blower” to bring 
actions on behalf of the federal government alleging violations of the False Claims Act and to share in any 
monetary recovery; 
•
the anti-inducement law, which prohibits, among other things, the offering or giving of remuneration, which 
includes, without limitation, any transfer of items or services for free or for less than fair market value (with 
limited exceptions), to a Medicare or Medicaid beneficiary that the person knows or should know is likely to 
influence the beneficiary’s selection of a particular supplier of items or services reimbursable by a federal or 
state governmental program; 

33
•
HIPAA, which created new federal criminal statutes that prohibit knowingly and willfully executing, or 
attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or 
fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody 
or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and 
willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially 
false, fictitious, or fraudulent statements or representations in connection with the delivery of, or payment for, 
healthcare benefits, items or services relating to healthcare matters; similar to the federal Anti-Kickback Statute, 
a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to 
have committed a violation; 
•
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, and 
their respective implementing regulations, which impose requirements on certain covered healthcare providers, 
health plans, and healthcare clearinghouses as well as their respective business associates that perform services 
for them that involve the use, or disclosure of, individually identifiable health information, relating to the 
privacy, security and transmission of individually identifiable health information; 
•
the federal transparency requirements under the ACA, including the provision commonly referred to as the 
Physician Payments Sunshine Act, and its implementing regulations, which requires applicable manufacturers 
of drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or 
the Children’s Health Insurance Program to report annually to the U.S. Department of Health and Human 
Services, CMS, information related to payments or other transfers of value made to physicians (defined to 
include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as 
ownership and investment interests held by the physicians described above and their immediate family 
members. Effective January 1, 2022, these reporting obligations extend to include transfers of value made to 
certain non-physician providers such as physician assistants and nurse practitioners; 
•
federal government price reporting laws, which require us to calculate and report complex pricing metrics in an 
accurate and timely manner to government programs; and 
•
federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and 
activities that potentially harm consumers. 
Additionally, we are subject to state and foreign equivalents of each of the healthcare laws and regulations described above, 
among others, some of which may be broader in scope and may apply regardless of the payor. Many U.S. states have adopted 
laws similar to the federal Anti-Kickback Statute and False Claims Act, and may apply to our business practices, including, 
but not limited to, research, distribution, sales or marketing arrangements and claims involving healthcare items or services 
reimbursed by non-governmental payors, including private insurers. In addition, some states have passed laws that require 
pharmaceutical companies to comply with the April 2003 Office of Inspector General Compliance Program Guidance for 
Pharmaceutical Manufacturers and/or the Pharmaceutical Research and Manufacturers of America’s Code on Interactions 
with Healthcare Professionals. Several states also impose other marketing restrictions or require pharmaceutical companies to 
make marketing or price disclosures to the state. There are ambiguities as to what is required to comply with these state 
requirements and if we fail to comply with an applicable state law requirement, we could be subject to penalties. Finally, 
there are state and foreign laws governing the privacy and security of health information (e.g., the California Consumer 
Privacy Act), many of which differ from each other in significant ways and often are not preempted by HIPAA, thus 
complicating compliance efforts. 

34
We may also be subject to additional privacy restrictions. The collection, use, storage, disclosure, transfer, or other 
processing of personal data regarding individuals in the European Economic Area, or EEA, including personal health data, is 
subject to the General Data Protection Regulation 2016/679 (EU GDPR), which became effective in May 2018. Following 
Brexit and the expiration of the subsequent transition period on December 31, 2020, the EU GDPR has been brought into UK 
law as the “UK GDPR” which, along with the UK Data Protection Act 2018, governs the collection, use, storage, disclosure, 
transfer, or other processing of personal data regarding individuals in the UK. In the present document, references to 
“GDPR” are meant to include both the EU GDPR and the UK GDPR, unless specified. The GDPR is wide-ranging in scope 
and imposes numerous requirements on companies that process personal data. 
Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible 
that some of our business activities could be subject to challenge under one or more of such laws. 
Violations of fraud and abuse laws may be punishable by criminal and/or civil sanctions, including penalties, fines, 
imprisonment and/or exclusion or suspension from federal and state healthcare programs such as Medicare and Medicaid and 
debarment from contracting with the U.S. government. In addition, private individuals have the ability to bring actions on 
behalf of the U.S. government under the federal False Claims Act as well as under the false claims laws of several states. 
Law enforcement authorities are increasingly focused on enforcing fraud and abuse laws, and it is possible that some of our 
practices may be challenged under these laws. Efforts to ensure that our current and future business arrangements with third 
parties, and our business generally, will comply with applicable healthcare laws and regulations will involve substantial 
costs. If our operations, including our arrangements with physicians and other healthcare providers are found to be in 
violation of any of such laws or any other governmental regulations that apply to us, we may be subject to penalties, 
including, without limitation, administrative, civil and criminal penalties, damages, fines, disgorgement, contractual damages, 
reputational harm, diminished profits and future earnings, the curtailment or restructuring of our operations, exclusion from 
participation in federal and state healthcare programs (such as Medicare and Medicaid), and imprisonment, any of which 
could adversely affect our ability to operate our business and our financial results. In addition, our gene therapy programs for 
Strimvelis and Libmeldy were approved by the EMA in 2016 and 2020, respectively, and the approval and 
commercialization of Strimvelis and Libmeldy subjects us to foreign equivalents of the healthcare laws mentioned above, 
among other foreign laws. The approval and commercialization of any of our other gene therapies outside the United States 
will also likely subject us to foreign equivalents of the healthcare laws mentioned above, among other foreign laws. 
If any of the physicians or other healthcare providers or entities with whom we expect to do business are found to be not in 
compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusions 
from government funded healthcare programs, which may also adversely affect our business. 
The risk of our being found in violation of these laws is increased by the fact that many of these laws have not been fully 
interpreted by the regulatory authorities or the courts, and their provisions are open to a variety of interpretations. Any action 
against us for violation of these laws, even if we successfully defend against it, could cause us to incur significant legal 
expenses and divert our management’s attention from the operation of our business. The shifting compliance environment 
and the need to build and maintain a robust system to comply with multiple jurisdictions with different compliance and 
reporting requirements increases the possibility that a healthcare company may violate one or more of the requirements. 
Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and 
regulations will involve substantial cost. 
Healthcare reform
The United States and many foreign jurisdictions have enacted or proposed legislative and regulatory changes that affect the 
healthcare system and which could prevent or delay marketing approval of our potential products, restrict or regulate post-
approval activities and affect our ability to profitably sell products, if approved. 
In the United States, there have been and continue to be a number of legislative initiatives to contain healthcare costs. As one 
example, in March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education 
Reconciliation Act of 2010, or the ACA, was passed, which substantially changed the way health care is financed by both 
governmental and private insurers, and significantly impacted the U.S. pharmaceutical industry. Since its enactment, there 
have been numerous judicial, administrative, executive and legislative challenges to certain aspects of the ACA, as we expect 
there will be additional challenges and amendments to the ACA in the future. 
In Europe, delivery of healthcare is largely a matter of national law and policy. National governments and health service 
providers have different priorities and approaches to the delivery of health care and the pricing and reimbursement of 
products in that context. Budgetary constraints could affect our ability to profitably sell approved products in certain 
jurisdictions. 

35
We expect that healthcare reform measures may result in more rigorous coverage criteria and downward pressure on the price 
that we receive for approved products. There have been, and likely will continue to be, legislative and regulatory proposals at 
the foreign, federal and state levels directed at lowering the cost of healthcare. The implementation of cost containment 
measures or other healthcare reforms may prevent us from generating sufficient revenue, attaining profitability or 
commercializing additional products.
Coverage and reimbursement 
Significant uncertainty exists as to the coverage and reimbursement status of any gene therapies for which we obtain 
regulatory approval. In the United States and markets in other countries, sales of any gene therapies for which we receive 
regulatory approval for commercial sale will depend, in part, on the availability of coverage and reimbursement from payors. 
Payors include government authorities, managed care providers, private health insurers and other organizations. Patients who 
are prescribed treatments for their conditions and providers generally rely on these third-party payors to reimburse all or part 
of the associated healthcare. The process for determining whether a payor will provide coverage for a product may be 
separate from the process for setting the reimbursement rate that the payor will pay for the product. Payors may limit 
coverage to specific products on an approved list, or formulary, which might not include all of the FDA-approved products 
for a particular indication. A decision by a payor not to cover our gene therapies could reduce physician utilization of our 
products once approved and have a material adverse effect on our sales, results of operations and financial condition. 
Moreover, a payor’s decision to provide coverage for a product does not imply that an adequate reimbursement rate will be 
approved. Adequate third-party reimbursement may not be available to enable us to maintain price levels sufficient to realize 
an appropriate return on our investment in product development and manufacturing costs. 
The Inflation Reduction Act of 2022, or IRA, includes several provisions that may impact our business to varying degrees, 
including provisions that reduce the out-of-pocket cap for Medicare Part D beneficiaries to $2,000 starting in 2025; impose 
new manufacturer financial liability on certain drugs under Medicare Part D, allow the U.S. government to negotiate 
Medicare Part B and Part D price caps for certain high-cost drugs and biologics without generic or biosimilar competition, 
require companies to pay rebates to Medicare for certain drug prices that increase faster than inflation, and delay the rebate 
rule that would limit the fees that pharmacy benefit managers can charge. Further, under the IRA, orphan drugs are exempted 
from the Medicare drug price negotiation program, but only if they have one rare disease designation and for which the only 
approved indication is for that disease or condition.  If a product receives multiple rare disease designations or has multiple 
approved indications, it may not qualify for the orphan drug exemption. The effects of the IRA on our business and the 
healthcare industry in general is not yet known.
In addition, coverage and reimbursement for products can differ significantly from payor to payor. One payor’s decision to 
cover a particular medical product or service does not ensure that other payors will also provide coverage for the medical 
product or service, or will provide coverage at an adequate reimbursement rate. In the United States, the principal decisions 
about reimbursement for new medicines are typically made by the Centers for Medicare & Medicaid Services, or CMS, an 
agency within the U.S. Department of Health and Human Services. CMS decides whether and to what extent a new medicine 
will be covered and reimbursed under Medicare and private payors tend to follow CMS to a substantial degree.
Additionally, the coverage determination process will require us to provide scientific and clinical support for the use of our 
products to each payor separately and will be a time-consuming process. 
Payors are increasingly challenging the price and examining the medical necessity and cost-effectiveness of medical products 
and services, in addition to their safety and efficacy. In order to obtain and maintain coverage and reimbursement for any 
product, we may need to conduct expensive evidence generation studies in order to demonstrate the medical necessity and 
cost-effectiveness of such a product, in addition to the costs required to obtain regulatory approvals. If payors do not consider 
a product to be cost-effective compared to current standards of care, they may not cover the product as a benefit under their 
plans or, if they do, the level of payment may not be sufficient to allow a company to cover its costs or make a profit. 
Outside of the United States, the pricing of pharmaceutical products is subject to governmental control in many countries. For 
example, in the EU, pricing and reimbursement schemes vary widely from country to country. Some countries provide that 
products may be marketed only after a reimbursement price has been agreed with the government authority. Furthermore, 
some countries may require the completion of additional studies that compare the effectiveness and/or cost-effectiveness of a 
particular therapy to current standards of care as part of so-called health technology assessments, or HTAs, in order to obtain 
reimbursement or pricing approval. Additionally, there may be a need for activities to secure reimbursement for procedures 
associated with products administered in a hospital setting, such as Libmeldy, under the diagnosis-related group, or DRG, 
system, whereby a billing code may not exist or may be currently insufficient to cover the cost of the procedure. In other 
instances, countries may monitor and control product volumes and issue guidance to physicians to limit prescriptions in the 
form of treatment policies. Efforts to control prices and utilization of pharmaceutical products will likely continue as 
countries attempt to manage healthcare expenditures.

36
Employees and Human Capital Resources
As of December 31, 2022, we had 166 full-time employees. We have no collective bargaining agreements with our 
employees, and we have not experienced any work stoppages. We consider our relationship with our employees to be 
positive. We monitor employee engagement through an annual survey and develop a prioritized action plan on an annual 
basis to address any areas in need of attention. Our human capital objectives include, as applicable, identifying, recruiting, 
developing, retaining, and incentivizing our existing and prospective employees, as well as optimizing the overall employee 
experience. The principal purposes of our incentive plans are to attract, retain and motivate our employees. The granting of 
share-based compensation awards is designed to reward selected employees for long-term shareholder value creation and our 
cash-based performance bonus awards reward the achievement of annual performance goals. The health and safety of our 
employees, customers and communities are of primary concern. During the COVID-19 pandemic, we have taken significant 
steps to protect our workforce, including, but not limited to, implementing a hybrid work model and social distancing 
protocols consistent with guidelines issued by federal, state and local laws. 
Corporate Information
We were originally incorporated under the laws of England and Wales in August 2018 as Orchard Rx Limited (now known 
as Orchard Therapeutics plc) to become a holding company for Orchard Therapeutics (Europe) Limited (previously known as 
Orchard Therapeutics Limited). Orchard Rx Limited subsequently re-registered as a public limited company and its name 
was changed from Orchard Rx Limited to Orchard Therapeutics plc in October 2018. Orchard Therapeutics (Europe) Limited 
was originally incorporated under the laws of England and Wales in September 2015 as Newincco 1387 Limited and 
subsequently changed its name to Orchard Therapeutics Limited in November 2015 and to Orchard Therapeutics (Europe) 
Limited in October 2018. Our registered office is located at 245 Hammersmith Road, London W6 8PW, United Kingdom, 
and our telephone number is +44 (0) 203 808 8286. Our website address is www.orchard-tx.com. We do not incorporate the 
information on or accessible through our website into this Annual Report, and you should not consider any information on, or 
that can be accessed through, our website as part of this Annual Report. We make available free of charge through our 
website our Annual Reports on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and amendments 
to these reports filed or furnished pursuant to Section 13(a) or 15(d) of the Securities Exchange Act of 1934, as amended, as 
soon as reasonably practicable after we electronically file or furnish such materials to the U.S. Securities and Exchange 
Commission.
Item 1A. Risk Factors. 

37
Our business faces significant risks. This section of the Annual Report highlights some of the risks that may affect our future 
operating results. You should carefully consider the risks described below, as well as in our consolidated financial 
statements and the related notes included elsewhere in this Annual Report and in our other SEC filings. The occurrence of 
any of the events or developments described below could harm our business, financial condition, results of operations and 
prospects. This Annual Report also contains forward-looking statements that involve risks and uncertainties. Our results 
could materially differ from those anticipated in forward-looking statements as a result of certain factors, including the risks 
described below and elsewhere in this Annual Report and our other SEC filings. See “Special Note Regarding Forward-
Looking Statements” above. 
Risks related to our financial position and need for additional capital
We have incurred net losses since inception. We expect to incur net losses for the foreseeable future and may never 
achieve or maintain profitability.
Since inception, we have incurred net losses. We incurred net losses of $150.7 million and $144.6 million for the twelve 
months ended December 31, 2022 and 2021, respectively. We historically have financed our operations primarily through 
private placements of our convertible preferred shares, through sales of our ADSs in our initial public offering and follow-on 
offering, and through private placements of our ordinary shares. We have devoted substantially all of our efforts to research 
and development, including clinical and pre-clinical development and arranging the manufacturing of our product candidates, 
establishing a commercial infrastructure to support the commercialization of Libmeldy in the European Union, building a 
global commercial infrastructure to support commercialization of Libmeldy (OTL-200) and our product candidates if such 
product candidates are approved, as well as to building our team. Absent the realization of sufficient revenue from product 
sales of Libmeldy and from sales of our current or future product candidates, if approved, we may never attain profitability.
We expect to continue to incur significant expenses and operating losses for the foreseeable future, particularly if, and as, we: 
•
seek marketing approvals for our product candidates that successfully complete clinical trials or meet primary 
endpoints, if any;
•
market and sell Libmeldy in Europe and grow our commercial infrastructure for the commercialization (or 
anticipated commercialization) of any product candidates that we may submit for and obtain marketing approval 
anywhere in the world;
•
continue the development of our product candidates; 
•
continue our ongoing clinical trials and any required regulatory updates for certain de-prioritized programs; 
•
conduct investigational new drug application, or IND, or clinical trial application, or CTA, enabling studies for 
our pre-clinical programs;
•
initiate additional clinical trials and pre-clinical studies for our other product candidates or future product 
candidates, including new research programs in genetic subsets of frontotemporal dementia, or FTD, and Crohn’s 
disease;
•
seek to identify and develop, acquire or in-license additional product candidates or technologies;
•
develop the necessary processes, controls and manufacturing data to obtain marketing approval for our product 
candidates, to support technology and process innovation, and to support manufacturing of product to 
commercial scale;
•
establish partnerships with contract development and manufacturing organizations, or CDMOs;
•
develop and implement plans to establish and operate our own in-house manufacturing operations and facility in 
the long-term; 
•
hire and retain personnel, such as non-clinical, clinical, pharmacovigilance, quality, regulatory affairs, process 
development and control, manufacturing, supply chain, legal, compliance, medical affairs, finance, general and 
administrative, commercial and scientific personnel; 
•
encounter delays or setbacks in the pre-clinical testing, enrollment or conduct of our clinical trials for our product 
candidates, encounter delays in regulatory review timelines, or experience high levels of absenteeism due to the 
COVID-19 pandemic;
•
develop, maintain, expand and protect our intellectual property portfolio; and

38
•
comply with our obligations as a public company.
Since receiving marketing authorization, only a limited number of patients have been treated with Libmeldy. There is no 
assurance that revenue from sales of Libmeldy alone will be sufficient for us to become profitable. To become and remain 
profitable, we must develop and eventually commercialize product candidates with greater market potential. This will require 
us to be successful in a range of challenging activities, and our expenses will increase as we seek to complete necessary pre-
clinical studies and clinical trials of our product candidates, and manufacture, market and sell Libmeldy or any future product 
candidates for which we may obtain marketing approval, if any, and satisfy any post-marketing requirements. We may never 
succeed in any or all of these activities and, even if we do, we may never generate revenue that is significant or large enough 
to achieve profitability. If we do achieve profitability, we may not be able to sustain or increase profitability on a quarterly or 
annual basis. Our failure to become and remain profitable would decrease the value of our company and could impair our 
ability to raise capital, maintain our research and development efforts, expand our business or continue our operations.
We have only generated limited sales revenue to date, and we may never be profitable. 
Our ability to generate revenue from product sales and achieve profitability depends on our ability, alone or with 
collaborative partners, to successfully develop and commercialize products. Although we have generated revenue from the 
sale of Libmeldy and Strimvelis in Europe, we will not achieve profitability unless and until we complete the development 
of, and obtain the regulatory approvals necessary to commercialize, additional product candidates. Our ability to generate 
future revenue from product sales depends heavily on our and or our collaborators’ success in:
•
completing research and pre-clinical development of our product candidates and identifying attractive new gene 
therapy product candidates;
•
conducting and fully enrolling clinical trials in the development of our product candidates, including maintaining 
or reaching target enrollment levels and collecting the necessary follow-up data; 
•
seeking and obtaining regulatory and marketing approvals for product candidates for which we complete 
registrational clinical trials that achieve their primary endpoints;
•
successfully commercializing Libmeldy in Europe and other product candidates for which we obtain regulatory 
and marketing approval by expanding our existing sales force, marketing and distribution infrastructure or, 
alternatively, collaborating with a commercialization partner;
•
maintaining marketing authorization and related post-marketing commitments for regulatory compliance for 
Libmeldy and Strimvelis in the European Union;
•
qualifying for, and maintaining, adequate coverage and reimbursement by government and payors for Libmeldy 
and Strimvelis and any product candidate for which we obtain marketing approval;
•
establishing and maintaining supply and manufacturing processes and relationships with third parties that can 
provide adequate, in both amount and quality, products and services to support clinical development of our 
product candidates and the market demand for Libmeldy and Strimvelis, if sales are resumed, and any of our 
product candidates for which we obtain marketing approval;
•
obtaining market acceptance of Libmeldy and our product candidates, if approved, as viable treatment options 
with acceptable safety profiles;
•
addressing any competing technological and market developments;
•
the impact of geopolitical instability and the ongoing COVID-19 pandemic, including the emergence of new 
variants;
•
implementing additional internal systems and infrastructure, as needed, including robust quality systems and 
manufacturing capabilities;
•
negotiating favorable terms in any collaboration, licensing or other arrangements into which we may enter and 
performing our obligations under such arrangements;
•
maintaining, protecting and expanding our portfolio of intellectual property rights, including patents, trade 
secrets and know-how; and
•
attracting, hiring and retaining qualified personnel.
We expect that we will continue to incur significant costs associated with commercializing Libmeldy in Europe and any other 
products for which we obtain marketing approval. Our expenses could increase beyond expectations if the FDA,  the EMA or 

39
other regulatory authorities require us to perform clinical or other studies in addition to those that we currently anticipate or if 
we encounter delays or clinical holds in the development of our product candidates. Even if we generate more significant 
revenue from sales of Libmeldy in Europe and generate revenue from the sale of any other approved products, we may not 
become profitable and may need to obtain additional funding to continue operations.
We may not receive any additional amounts under the Securities Purchase Agreement, dated March 6, 2023.
As previously disclosed, on March 6, 2023, we announced a private placement pursuant to which the Company agreed to sell 
ordinary shares, non-voting ordinary shares and warrants. If certain conditions are met and all warrants are exercised, the 
Company could receive a total of $188 million pursuant to the private placement. In accordance with the Securities Purchase 
Agreement (the “SPA”), the Company received $34 million at the initial closing on March 10, 2023. However, the Company 
may not receive any additional amounts under the SPA. 
As described below, the second closing is contingent and could be delayed or never happen, and certain of the contingencies 
are not entirely without the Company’s control. In addition, the warrants sold under the SPA do not obligate the purchasers to 
exercise them, and even if they are exercised they are exercisable at a lower price if FDA approval of OTL-200 is delayed 
beyond 2024.
The investors in the private placement agreed to purchase additional ordinary shares, non-voting ordinary shares and warrants 
at a pre-agreed price at a second closing for an aggregate total of $34 million. The second closing is subject to the Company’s 
public announcement of our intention to submit a BLA application with the FDA following receipt of minutes from the 
Company’s pre-BLA meeting with the FDA, which is currently scheduled for the second quarter of 2023. The second closing 
is also subject to shareholder approval for authority under U.K. law to allot the shares issuable upon exercise of the warrants 
and to disapply pre-emption rights in respect of such authority.
The second closing has not yet occurred, and it may never occur. The minutes from our pre-BLA meeting with the FDA may 
advise us not to submit a BLA application without making certain changes or performing additional work. We could also 
decide that as a result of the pre-BLA meeting additional work is necessary or appropriate before submitting a BLA 
application. If either of these things were to occur, the second closing would be delayed and may not occur. 
The second closing could also be delayed or never occur if the Company fails to receive the necessary shareholder approvals. 
Although we have agreed to hold a shareholder meeting no later than 120 days following the initial closing, the required 
shareholder votes could fail or we could fail to receive the quorum necessary to hold the vote. Under U.K. law, the proposal 
asking shareholders to disapply pre-emption rights is considered a special resolution requiring the affirmative vote of 75% of 
votes cast by shareholders present (in person or by proxy) at the meeting and entitled to vote. Under the SPA, we have agreed 
to continue seeking shareholder approval if the necessary votes fail for a period of time, but we may never receive the 
required shareholder vote.
The purchasers of warrants are not obligated to exercise the warrants, so we may not receive any additional proceeds from 
their exercise. The warrants will become exercisable during the 30 days following the Company's announcement of receipt of 
marketing approval of its BLA with respect to OTL-200; provided, that exercise of any warrant is conditioned on the receipt 
of shareholder approval (as described above). If the Company does not announce receipt of marketing approval of its BLA or 
does not receive the necessary shareholder approval, the warrants will expire on March 10, 2026. In addition, the exercise 
price of the warrants is lower if OTL-200 is approved by the FDA after 2024, so any proceeds we receive from their exercise 
could be lower than the total amount possible as of today. The exercise price of the warrants is $1.10 per ordinary share if 
OTL-200 is approved by the FDA in 2024 and $0.95 per ordinary share if approval comes after 2024. 
We will need additional funding, which may not be available on acceptable terms, or at all. Failure to obtain this 
necessary capital when needed may force us to delay, limit or terminate our product development efforts or other 
operations.
Our operations have consumed a substantial amount of cash since our inception, and we recorded negative cash flows from 
operating activities during the twelve months ended December 31, 2022, primarily due to our net loss of $150.7 million for 
that period. We expect to continue to incur substantial expenses in connection with our ongoing activities, which may 
increase over time, particularly as we (i) continue to commercialize Libmeldy in Europe, (ii) continue the research and 
development of, initiate further clinical trials of and seek marketing approval for, our product candidates and (iii) continue to 
enhance and optimize our vector technology and manufacturing processes. In addition, we expect to incur significant 
expenses related to product sales, post-marketing regulatory commitments, medical affairs, marketing, manufacturing, 
distribution and quality systems to support Libmeldy and any other products for which we obtain marketing approval. 
Furthermore, we will continue to incur costs associated with operating as a public company, including with respect to the 
system and process evaluations and testing of our internal controls and financial reporting. Accordingly, we will need to 
obtain substantial additional funding in connection with our continuing operations. If we are unable to raise capital when 

40
needed or on reasonable terms, or at all, we would be forced to delay, reduce or eliminate certain of our ongoing activities, 
such as research and development programs and commercialization efforts. 
Our future capital requirements will depend on many factors, including:
•
the success of our commercialization efforts and market acceptance of Libmeldy in Europe;
•
the cost and our ability to maintain the commercial infrastructure and manufacturing capabilities to support 
Libmeldy in Europe and any other products for which we obtain marketing approval, including costs relating to 
quality systems, regulatory affairs, compliance, product sales, medical affairs, commercial marketing, 
manufacturing and distribution;
•
qualifying for, and maintaining, adequate coverage and reimbursement by government and payors on a timely 
basis for Libmeldy and any other products for which we obtain marketing approval;
•
the costs of preparing and submitting marketing approvals for any of our product candidates that successfully 
complete clinical trials, and the costs of maintaining marketing authorization and related post-marketing 
commitments for regulatory compliance for any products for which we obtain marketing approval;
•
the scope, progress, results and costs of drug discovery, laboratory testing, pre-clinical development and clinical 
trials for our product candidates or future product candidates, including the need to conduct long-term follow-up 
for up to 15 years for our development programs and additional clinical trials to support marketing approvals for 
our product candidates;
•
our ability to enroll clinical trials in a timely manner and to quickly resolve any delays or clinical holds that may 
be imposed on our development programs; 
•
the costs associated with our manufacturing process development and evaluation of third-party manufacturers 
and suppliers; 
•
the costs, timing and outcome of regulatory review of our product candidates;
•
revenue, if any, received from commercial sales of Libmeldy and any other products for which we may obtain 
marketing approval, including amounts reimbursed by government and third-party payors;
•
the costs of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual 
property rights and defending intellectual property-related claims;
•
the terms of our current and any future license agreements and collaborations; and
•
the extent to which we acquire or in-license other product candidates, technologies and intellectual property.
Identifying potential product candidates and conducting pre-clinical testing and clinical trials, as well as preparing for the 
potential commercialization of these product candidates, is a time-consuming, expensive and uncertain process that takes 
years to complete. We may never generate the necessary data or results required to obtain marketing approval and achieve 
product sales for any products other than Libmeldy and Strimvelis. In addition, Libmeldy and any other products for which 
we obtain and maintain marketing approval may not achieve commercial success. Any product revenue from our product 
candidates, if any, will be derived from or based on sales of products that may not be commercially available for many years, 
if at all. Accordingly, we will need to continue to rely on additional financing to achieve our business objectives. Adequate 
additional financing may not be available to us on acceptable terms, or at all.
Raising additional capital may cause dilution to our existing shareholders, restrict our operations or cause us to 
relinquish valuable rights.
We may seek to raise capital through a combination of public and private equity offerings, debt financings, strategic 
partnerships and alliances and licensing arrangements. To the extent that we raise capital through the sale of equity, 
convertible debt securities or other equity-based derivative securities, ownership percentages of all our shareholders may be 
diluted and the terms may include liquidation or other preferences that adversely affect their rights as shareholders. Any 
additional indebtedness we incur would result in additional increased fixed payment obligations and could involve restrictive 
covenants, such as limitations on our ability to incur additional debt, limitations on our ability to acquire or license 
intellectual property rights and other operating restrictions that could adversely impact our ability to conduct our business. 
Furthermore, the issuance of additional securities, whether equity or debt, by us, or the possibility of such issuance, may 
cause the market price of our ADSs to decline and existing shareholders may not agree with our financing plans or the terms 
of such financings. If we raise funds through strategic partnerships, alliances or licensing arrangements with third parties, we 
may have to relinquish valuable rights to our technologies, or our product candidates, or grant licenses on terms unfavorable 

41
to us. Adequate financing may not be available to us on acceptable terms, or at all. In the past several years, global credit and 
financial markets have experienced volatility, instability and disruptions, including as a result of the COVID-19 pandemic, 
geopolitical instability and other macroeconomic factors. The significant volatility in public equity markets and the 
disruptions to the U.S. and global economies may make it more difficult to raise capital through sales of our ADSs on 
favorable terms, or at all.
Our limited operating history may make it difficult to evaluate the success of our business to date and to assess our future 
viability.
We were incorporated in August 2018 to become a holding company for Orchard Therapeutics (Europe) Limited, which was 
founded in 2015, and its subsidiaries. Our operations to date have been limited to corporate organization, recruiting key 
personnel, business planning, raising capital, acquiring certain of our product candidate portfolios and rights to our 
technology, identifying potential product candidates, undertaking pre-clinical studies and planning and supporting clinical 
trials of our product candidates, establishing research and development and manufacturing capabilities, establishing a quality 
management system, establishing a commercial infrastructure to support the commercialization of Strimvelis in the European 
Union and building a global commercial infrastructure to support commercialization of Libmeldy. Consequently, any 
predictions about our future success or viability may not be as accurate as they might be if we had a longer operating history. 
In addition, as a new business, we may encounter unforeseen expenses, difficulties, complications, delays and other known 
and unknown factors and setbacks.
Unfavorable market and global economic conditions could adversely affect our business, financial condition or results of 
operations.
As widely reported, global credit and financial markets have experienced extreme volatility and disruptions in the past 
several years, including severely diminished liquidity and credit availability, declines in consumer confidence, declines in 
economic growth, and uncertainty about economic stability, including most recently in connection with the ongoing COVID-
19 pandemic, current macroeconomic conditions, currency exchange rates, and volatile financial markets. There can be no 
assurance that further deterioration in credit and financial markets and confidence in economic conditions will not occur. Our 
general business strategy may be adversely affected by any such economic downturn, volatile business environment or 
continued unpredictable and unstable market conditions. If the current equity and credit markets deteriorate, or do not 
improve, it may make any necessary debt or equity financing more difficult, more costly, and more dilutive. Furthermore, our 
stock price may decline due in part to the volatility of the stock market and the general economic downturn. 
Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect on 
our growth strategy, financial performance and stock price and could require us to delay, scale back or discontinue the 
development and commercialization of one or more of our product candidates or delay our pursuit of potential in-licenses or 
acquisitions. In addition, there is a risk that one or more of our current service providers, manufacturers and other partners 
may not survive these difficult economic times, which could directly affect our ability to attain our operating goals on 
schedule and on budget. 
Volatility among foreign currencies could impact our results of operations. As an example, we had net realized and 
unrealized losses on foreign currency transactions of $24.4 million during the twelve months ended December 31, 2022, 
compared to net realized and unrealized losses of $1.2 million during the twelve months ended December 31, 2021. 
Unrealized gains and losses are driven primarily by entities that have a functional currency other than the U.S. Dollar that 
have intercompany balances denominated in U.S. Dollar. 
 
Risks related to the discovery, development and regulatory approval of our product candidates
 
Our gene therapy product candidates are based on a novel technology, which makes it difficult to predict the time and cost 
of product candidate development and of subsequently obtaining regulatory approval.
We have concentrated our research and development efforts on our autologous ex vivo gene therapy approach, and our future 
success depends on our successful development of commercially viable gene therapy products. There can be no assurance 
that we will not experience problems or delays in developing new products and that such problems or delays will not cause 
unanticipated costs or that any such development problems can be solved. Although we have established a commercial 
infrastructure for the production of Strimvelis in the European Union and we are building a global commercial infrastructure 
to support commercialization of Libmeldy, we may experience delays in establishing a sustainable, reproducible and scalable 
manufacturing capability with commercial CDMO partners, which may prevent us from commercializing our product 
candidates for which we obtain marketing approval on a timely or profitable basis, if at all. 
In addition, the clinical trial requirements of the FDA, EMA and other foreign regulatory authorities and the criteria these 
regulators use to determine the safety and efficacy of a product candidate can vary substantially, for example, based upon the 

42
type, complexity, novelty and intended use and market of such product candidates. The regulatory approval process for novel 
product candidates such as ours can be more expensive and take longer than the process for other, better known or more 
extensively studied product candidates. To date, only a limited number of gene therapies have received marketing 
authorization from the FDA or EMA. We have limited experience in preparing, submitting and maintaining regulatory 
submissions. It is difficult to determine how long it will take or how much it will cost to obtain regulatory approvals for our 
product candidates in the United States, Europe or in other jurisdictions, or how long it will take to commercialize Libmeldy 
in Europe or any other product candidates for which we obtain marketing approval. Approvals by the EMA may not be 
indicative of what the FDA may require for approval, and vice versa.
The results from our clinical trials for OTL-200 for MLD and for any of our other product candidates may not be 
sufficiently robust to support marketing approval or the submission of marketing approval. Before we submit our product 
candidates for marketing approval, the FDA or the EMA may require us to conduct additional clinical trials or evaluate 
patients for an additional follow-up period.
The results from our clinical trials may not be sufficiently robust to support the approval of or submission of marketing 
approval for our product candidates, including by the FDA for OTL-200. The FDA and EMA normally require two 
registrational trials to approve a drug or biologic product, and therefore either the FDA or EMA might require that we 
conduct additional clinical trials of our product candidates prior to a BLA or MAA submission, respectively. The FDA and 
EMA typically do not consider a single registrational clinical trial to be adequate to serve as sufficient evidence to support a 
marketing authorization unless, among other things, (i) the trial is well-controlled and demonstrates a clinically meaningful 
effect on mortality, irreversible morbidity, or prevention of a disease with a potentially serious outcome and (ii) a 
confirmatory study would be practically or ethically impossible. 
Due to the nature of the indications our product candidates are designed to treat, and the limited number of patients with these 
conditions, a placebo-controlled and blinded study is not always practicable for ethical and other reasons. Accordingly, in 
some cases our registrational programs rely on natural history models to demonstrate clinical efficacy. While the FDA 
recognizes the potential for natural history models to alleviate the need for placebo arms in trials for drugs that target very 
rare diseases, where trial recruitment can be especially challenging, the FDA has found the use of natural history data as a 
historical comparator to be unsuitable for adequate and well-controlled trials in many circumstances. The FDA generally 
finds trials using historical controls to be credible only when the observed effect is large in comparison to variability in 
disease course. It is possible the FDA will not consider our comparisons to natural history data and, where available, 
historical transplant data or intra-subject comparison between before gene therapy and after gene therapy, to provide 
clinically meaningful results. Additionally, even though OTL-200 for MLD has achieved the primary endpoints in its 
ongoing registrational clinical trial, the FDA has not yet approved the clinical meaningfulness of the trial results and their 
sufficiency to support a marketing authorization. 
For example, although the FDA cleared our IND application for OTL-200 in 2020 and we received Regenerative Medicine 
Advanced Therapy, or RMAT, designation in 2021, there can be no guarantee we will be successful in resolving open matters 
to the FDA’s satisfaction before our intended BLA submission. We continue to engage with the FDA as we seek to address 
its recommendations and identify expeditious paths to market for our product candidates.
It is possible that the FDA or EMA may recommend or require us to conduct further studies, analyses or registrational trials 
with respect to our product candidates, possibly involving a larger sample size or a different clinical trial design. The FDA or 
EMA may also require that we conduct a longer follow-up period of patients treated with our product candidates prior to 
accepting a BLA or MAA submission, as applicable. 
In addition, data obtained from pre-clinical and clinical activities are subject to varying interpretations, which may delay, 
limit or prevent regulatory approval. There can be no assurance that the FDA, EMA or other foreign regulatory bodies will 
find the efficacy endpoints in our registrational trials or any efficacy endpoint we propose in future registrational trials to be 
sufficiently validated and clinically meaningful, or that our product candidates will achieve the pre-specified endpoints in 
current or future registrational trials to a degree of statistical significance, and with acceptable safety profiles. The FDA may 
further refer any future BLA submission to an advisory committee for review, evaluation and recommendation as to whether 
the application should be approved. This review may add to the time for approval, and although the FDA is not bound by the 
recommendation of an advisory committee, objections or concerns expressed by the advisory committee may cause the FDA 
to delay or deny approval. We also may experience regulatory delays or rejections as a result of many factors, including 
serious adverse events, or SAEs, involving our product candidates, changes in regulatory policy or changes in requirements 

43
during the period of our product candidate development. Any such delays could materially and adversely affect our business, 
financial condition, results of operations and prospects.
We expect that the FDA and EMA will assess the totality of the safety and efficacy data from our product candidates in 
reviewing any future BLA or MAA submissions. Based on this assessment, the FDA or EMA may require that we conduct 
additional pre-clinical studies or clinical trials prior to submitting or approving a BLA or MAA for our target indications.
It is possible that the FDA or EMA may not consider the results of our clinical trials, including reliance on foreign clinical 
data, to be sufficient for approval of our product candidates. If the FDA or EMA require additional trials, we would incur 
increased costs and delays in the marketing approval process, which may require us to expend more resources than we have 
available. In addition, it is possible that the FDA and EMA may have divergent opinions on the elements necessary for a 
successful BLA and MAA submission, respectively, which may cause us to alter our development, regulatory or 
commercialization strategies.
Regulatory requirements governing gene and cell therapy products have evolved and may continue to change in the 
future. Such requirements may lengthen the regulatory review process, require us to perform additional studies, and 
increase our development costs or may force us to delay, limit or terminate certain of our programs.
Regulatory requirements governing gene and cell therapy products have evolved and may continue to change in the future. 
The FDA has established the Office of Therapeutic Products within its Center for Biologics Evaluation and Research, or 
CBER, to consolidate the review of gene therapy and related products, and has established the Cellular, Tissue and Gene 
Therapies Advisory Committee to advise CBER in its review when called upon. The NIH has refocused the NIH 
Recombinant DNA Advisory Committee and changed its name to the Novel and Exceptional Technology and Research 
Advisory Committee, or NExTRAC. NExTRAC is a federal advisory committee that provides recommendations to the NIH 
Director and a public forum for the discussion of the scientific, safety, and ethical issues associated with emerging 
biotechnologies, which include, but are not restricted to, technologies surrounding advances in recombinant or synthetic 
nucleic acid research such as human gene transfer. These regulatory review committees and advisory groups and any new 
guidelines they promulgate may lengthen the regulatory review process, require us to perform additional studies, increase our 
development costs, lead to changes in regulatory positions and interpretations, delay or prevent approval and 
commercialization of these product candidates or lead to significant post-approval limitations or restrictions. 
The FDA and EMA have each expressed interest in further regulating biotechnology, including gene therapy and genetic 
testing. For example, the EMA advocates a risk-based approach to the development of a gene therapy product. Agencies at 
both the federal and state level in the United States, as well as U.S. congressional committees and other governments or 
governing agencies, have also expressed interest in further regulating the biotechnology industry. Such action may delay or 
prevent commercialization of some or all of our product candidates. Adverse events in clinical trials of gene therapy products 
conducted by others may cause the FDA or other oversight bodies to change the requirements for approval of any of our 
product candidates, which could require additional pre-clinical studies or clinical trials to support the marketing approval of 
our product candidates or which could make our product candidates unable to successfully obtain approval. Similarly, the 
European Commission may issue new guidelines concerning the development and marketing authorization for gene therapies 
and require that we comply with these new guidelines, which could require additional pre-clinical studies or clinical trials to 
support the marketing approval of our product candidates or which could make our product candidates unable to successfully 
obtain approval.
As we advance our product candidates, we are required to consult with these regulatory and advisory groups and comply with 
applicable guidelines. If we fail to do so, we may be required to delay or discontinue development of certain of our product 
candidates. These additional processes may result in a review and approval process that is longer than we otherwise would 
have expected. Delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a 
potential product to market could decrease our ability to generate sufficient product revenue, and our business, financial 
condition, results of operations and prospects might be materially and adversely affected.
The FDA and EMA have released a series of final guidance documents and a draft guidance document for consultation, 
which among other topics, included various aspects of gene therapy product development, review and approval, including 
aspects relating to clinical and manufacturing issues related to gene therapy products. We cannot be certain whether future 
guidance will be issued and be relevant to, or have an impact on, our gene therapy programs or the duration or expense of any 
applicable regulatory development and review processes.

44
Libmeldy, Strimvelis and our product candidates and the process for administering Libmeldy, Strimvelis and our product 
candidates may cause serious or undesirable side effects or adverse events or have other properties that could delay or 
prevent regulatory approval, limit commercial potential or result in significant negative consequences for our company. 
Following treatment with our gene therapies, patients may experience changes in their health, including illnesses, injuries, 
discomforts or a fatal outcome. It is possible that as we test our product candidates in larger, longer and more extensive 
clinical programs, or as use of our product candidates becomes more widespread if they receive regulatory approval, 
illnesses, injuries, discomforts and other adverse events that were observed in previous clinical trials, as well as conditions 
that did not occur or went undetected in previous clinical trials, will be reported by patients. Gene therapies are also subject 
to the potential risk that occurrence of adverse events will be delayed following administration of the gene therapy due to 
persistent biological activity of the genetic material or other components of the vectors used to carry the genetic material. 
Many times, additional safety risks, contraindications, drug interactions, adverse events and side effects are only detectable 
after investigational products are tested in larger scale registrational trials or, in some cases, after they are made available to 
patients on a commercial scale after approval. The FDA generally requires long-term follow-up of study subjects. Although 
the risk profile of a gene therapy candidate is a factor in determining the adequacy of such long-term follow-up, the FDA 
currently recommends that sponsors observe study subjects for potential gene therapy-related adverse events for a 15-year 
period, including a minimum of five years of annual examinations followed by ten years of annual queries, either in person or 
by questionnaire, of study subjects. If additional experience indicates that any of our product candidates -- or similar products 
developed by other companies -- have side effects or causes serious or life-threatening side effects, the development of such 
product candidate may fail or be delayed, or, if the product has received regulatory approval, such approval may be revoked 
or limited.
Gene therapy is still a relatively new approach to disease treatment and additional adverse side effects could develop. 
Possible adverse side effects and adverse events that may occur with treatment with gene therapy products include an 
immunologic reaction early after administration that could substantially limit the effectiveness of the treatment or represent 
safety risks for patients. Another traditional safety concern for gene therapies using viral vectors has been the possibility of 
insertional mutagenesis (or oncogenesis) by the vectors, leading to malignant transformation of transduced cells. There have 
been several adverse events and SAEs attributed to gene therapy treatments in the past, including reported cases of leukemia 
with the use of gammaretrovirus vector and death seen in other clinical trials. In October 2020, we were notified that a patient 
treated with Strimvelis under a compassionate use program in 2016 had been diagnosed with lymphoid T cell leukemia. 
Subsequent findings confirmed that the patient’s leukemia was due to insertional oncogenesis attributable to treatment with 
Strimvelis. The EMA’s Committee for Medicinal Products for Human Use, or CHMP, concluded that the risk-benefit balance 
remains favorable and requested that the Strimvelis product information identify insertional mutagenesis (or oncogenesis) as 
an “important identified risk” instead of an “important potential risk” in light of this event. 
Strimvelis is the only gammaretroviral vector-based gene therapy in our portfolio. Libmeldy and all of our pipeline therapies 
employ the self-inactivating (SIN) lentiviral vector-based approach, which has been specifically designed to avoid insertional 
oncogenesis after administration. Although to our knowledge and as of the date of this report no evidence of insertional 
oncogenesis has been observed with lentiviral vector-based HSC gene therapy in any of our programs, there can be no 
assurance that this will continue to be the case. Moreover, while our gene therapy approach is designed to avoid 
immunogenicity after administration, there can be no assurance that patients would not develop antibodies that may impair 
treatment. Our approach involves the use of integrating vectors, which have the potential for genomic disruption and 
therefore could interfere with other genes with adverse clinical effects. If any of our gene therapy product candidates 
demonstrates adverse side effects or adverse events at unacceptable rates or degrees of severity, we may decide or be required 
to halt or delay clinical development of such product candidates.
In addition to side effects and adverse events caused by our product candidates, the conditioning, administration process or 
related procedures also can cause adverse side effects and adverse events. A gene therapy patient is generally administered 
cytotoxic drugs to remove stem cells from the bone marrow to create sufficient space in the bone marrow for the modified 
stem cells to engraft and produce new cells. This procedure compromises the patient’s immune system. While certain of our 
product candidates are designed to utilize milder conditioning regimens that are intended to require only limited removal of a 
patient’s bone marrow cells, the conditioning regimens may not be successful or may nevertheless result in adverse side 
effects and adverse events. If in the future we are unable to demonstrate that such adverse events were caused by the 
conditioning regimens used, or administration process or related procedure, the FDA, the European Commission, EMA or 
other regulatory authorities could order us to cease further development of, or deny approval of, our product candidates for 
any or all target indications. Even if we are able to demonstrate that adverse events are not related to the drug product or the 
administration of such drug product, such occurrences could affect patient recruitment, the ability of enrolled patients to 
complete the clinical trial, or the commercial viability of any product candidates that obtain regulatory approval.
Additionally, the FDA could require us to adopt a Risk Evaluation and Mitigation Strategy, or REMS, as a condition of 
approval to ensure that the benefits of our product candidates outweigh their risks, which may include, among other things, a 
medication guide outlining the risks of the product for distribution to patients, a communication plan to health care 
practitioners, and restrictions on how or where the product can be distributed, dispensed or used. Other non-U.S. regulatory 

45
authorities could impose other specific obligations, such as through a risk management plan, or RMP, submitted to the EMA. 
Furthermore, if we or others later identify undesirable side effects caused by Strimvelis, Libmeldy or our product candidates, 
several potentially significant negative consequences could result, including:
•
regulatory authorities may suspend or withdraw approvals of such product or product candidate;
•
regulatory authorities may require additional warnings or limitations of use in product labeling;
•
we may be required to change the way a product candidate is distributed, dispensed, or administered or conduct 
additional clinical trials;
•
we could be sued and held liable for harm caused to patients; and
•
our reputation may suffer.
Any of these events could prevent us from achieving or maintaining market acceptance of Libmeldy and any other products 
for which we obtain marketing approval and could significantly harm our business, prospects, financial condition and results 
of operations.
To date, most of the clinical trials for our product candidates were conducted as investigator-sponsored clinical trials 
using drug product manufactured at academic sites. Regulatory authorities may closely scrutinize the data collected from 
these trials and may require that we conduct additional clinical trials prior to any marketing approval.
We have limited experience conducting company-sponsored clinical trials and to date most of our product candidates have 
been evaluated under investigator-sponsored clinical trials using drug product manufactured at the applicable or relevant 
academic site. We did not control the design or administration of these investigator-sponsored trials, nor the submission or 
approval of any IND or foreign equivalent required to conduct these clinical trials. Investigator-sponsored clinical trials are 
often conducted under less rigorous clinical and manufacturing standards than those used in company-sponsored clinical 
trials. For example, the drug product used in our company-sponsored clinical trials is manufactured by third party CDMOs 
using current good manufacturing practices, or cGMP, standards. Accordingly, regulatory authorities may closely scrutinize 
the data collected from these investigator-sponsored clinical trials and may require us to obtain and submit additional clinical 
data prior to granting any marketing approval, which could delay clinical development or marketing approval of our product 
candidates. We will be required to demonstrate comparability between the manufacturing process used at academic centers 
with the manufacturing process used at CDMOs, and we cannot provide assurances that we will satisfy such comparability 
requirements. We may also be required to demonstrate improved quality and drug product manufacturing state of control in 
accordance with cGMP standards. 
For example, in the compassionate use program conducted by Great Osmond Street Hospital, or GOSH, one patient 
experienced an SAE, staphylococcal infection, possibly resulting from a bacterial growth noted in samples of the fresh drug 
product during the transduction procedure at this academic facility. A similar SAE, bacteremia, was observed in the clinical 
trial conducted at University of California Los Angeles, or UCLA, for our since-returned program OTL-101 for ADA-SCID 
with the fresh drug product manufactured at the academic facility, also possibly due to contamination of the drug product. 
The bacteremia resolved on day three without sequelae. We believe that our commercial manufacturing processes for our 
product candidates, together with cryopreserved formulation, which allows for safety/microbiological testing to be completed 
prior to drug infusion to the patient, could mitigate the risk of contamination of products that might have resulted in such 
infections, but there can be no assurance that this will be the case. To the extent that the results of our current company-
sponsored trials are inconsistent with, or different from, the results of any investigator-sponsored trials or raise concerns 
regarding our product candidates, the regulatory authorities may question the results from some or all of these trials, and may 
require us to obtain and submit additional clinical data from drug product manufactured by CDMOs prior to granting any 
marketing approval, which could delay clinical development or marketing approval of our product candidates.
We may be unable to demonstrate comparability between (i) drug product manufactured using HSCs derived from a 
patient’s mobilized peripheral blood and drug product manufactured using HSCs derived from a patient’s bone marrow, 
(ii) drug product that has been cryopreserved and fresh drug product, and (iii) the manufacturing process used at 
academic centers with the manufacturing process used at CDMOs. Failure to demonstrate such comparability could affect 
our ability to secure regulatory approval for our product candidates or could affect the commercial viability of our product 
candidates if approved for use using only HSCs derived from bone marrow or using only fresh drug product.
To date, most of the patients who have been treated in clinical trials involving our product candidates received fresh drug 
product manufactured using HSCs derived from the patient’s bone marrow at academic centers. We are currently evaluating 
our product candidates and plan to seek marketing approval using drug product that is manufactured at CDMOs using HSCs 
derived from either the patient’s bone marrow or mobilized peripheral blood and using a procedure by which the gene-

46
modified HSCs are cryopreserved in order to maintain the cellular material in suitable condition until it is thawed prior to 
being infused into the patient.
In those cases where clinical trials were conducted using vector or drug product manufactured at academic research centers, 
we will need to demonstrate comparability between vector and drug product manufactured by our CDMOs with vector or 
drug product manufactured at such academic centers. Similarly, in those cases where clinical trials were conducted using 
fresh drug product, we will need to demonstrate comparability between drug product that has been cryopreserved and fresh 
drug product. In some cases, clinical trials were conducted using drug product using bone marrow or mobilized peripheral 
blood, or both, as the cellular source. In some cases, we may seek to demonstrate comparability between drug product 
manufactured using one cellular source and another. In other cases, we may elect to initially seek approval of our product 
candidate using one cellular source only and subsequently seek approval for the use of the other cellular source. We cannot 
be assured that the FDA, EMA or other regulatory authority will not require us to conduct additional analytical studies 
(including comparability analyses), pre-clinical studies or clinical trials before approving our product candidates using these 
intended commercial production methods and processes. Moreover, we cannot be assured that our analytical comparability 
analyses or clinical trials will be sufficiently robust to support approval of our product candidates using these production 
methods and processes. 
If any of the FDA, EMA or other regulatory authority does not accept our comparability data or if an adequate potency assay 
for a product candidate is not available or supported by such regulatory authority, our regulatory approval for such product 
candidate, if any, will be limited or delayed. For example, if one or more of these regulatory authorities does not accept that 
our cryopreservation process produces a product candidate that is comparable to our fresh drug product, our regulatory 
approval, if any, would be limited to our fresh product candidate until we are able to provide the regulators with satisfactory 
comparability data, which may include data from additional clinical trials or require additional test method development. 
Potency assays that measure strength (e.g., enzymatic activity, or other relevant function) of each active ingredient are 
required for release testing of licensed biological drug products, comparability and stability analysis. 
If an adequate potency assay for a product candidate is not available, if we face delays, or if the FDA or EMA require 
additional tests or recommend a different approach to support the potency of any of our product candidates, regulatory 
approval for any such product candidates will be delayed and such regulators might request additional clinical data to support 
comparability analysis. Similarly, if one or more of these regulatory authorities does not accept that our drug product 
manufactured with HSCs derived from the patient’s mobilized peripheral blood is comparable to drug product manufactured 
with HSCs derived from the patient’s bone marrow, any regulatory approval would be limited to drug product manufactured 
with HSCs derived from the patient’s bone marrow until we are able to provide the regulators with satisfactory comparability 
data, which may include data from additional clinical trials. 
Our development and commercialization efforts, respectively, may be unsuccessful.
We may spend several years and devote substantial resources to any particular current or future product candidate, and failure 
may occur at any stage. Further, even if we receive approval of a product candidate, we may not achieve commercial success 
for a variety of facts. For example, we may not achieve market acceptance in the medical community, our pricing 
assumptions might be wrong, and our assumptions about the size of the anticipated patient populations may prove inaccurate.
Because we have limited resources, we may forego or delay pursuit of opportunities with certain programs or product 
candidates or for indications that later prove to have greater commercial potential. For example, in May 2020, we announced 
our decision to reduce investment in the development of OTL-101 for treatment of adenosine deaminase severe combined 
immunodeficiency, or ADA-SCID, and OTL-300 for treatment of Beta-thalassemia, or TDT. We have since returned licenses 
to the original licensors relating to both programs. Additionally, in March 2022, we announced that we would discontinue our 
investment in and seek strategic alternatives for our programs in rare primary immune deficiencies, including OTL-103 for 
treatment of Wiskott Aldrich Syndrome, or WAS, OTL-102 for treatment of X-linked chronic granulomatous disease, or X-
CGD, and Strimvelis.
Our focus on the advancement of our other product candidates may ultimately prove to be unsuccessful or less successful 
than if we had continued to prioritize such de-prioritized product candidates, and if we choose to re-prioritize such de-
prioritized product candidates in the future, we may experience delays that would not have otherwise occurred, due to 
inefficiencies from loss of organizational knowledge and ramp up costs. Moreover, we may be unable to realize the savings 
we expect to achieve by de-prioritizing certain programs, which could result from, among other things, higher than expected 
transition or termination costs.
If we do not accurately evaluate the commercial potential for a particular product candidate, we may relinquish valuable 
rights to that product candidate through strategic collaborations, licensing or other arrangements in cases in which it would 
have been more advantageous for us to retain sole development and commercialization rights to such product candidate. 

47
In addition, certain of our current or future product candidates may not demonstrate in patients any or all of the 
pharmacological benefits we believe they may possess or compare favorably to existing, approved therapies, such as bone 
marrow transplantation or enzyme replacement therapy. We may never succeed in demonstrating efficacy and safety of our 
product candidates or any future product candidates in clinical trials or in obtaining marketing approval thereafter. 
If we are unsuccessful in our development efforts, we may not be able to advance the development of our product candidates, 
commercialize products other than Libmeldy, raise capital, expand our business or continue our operations.
Interim data and ad hoc analyses are preliminary in nature. Success in pre-clinical studies or early clinical trials may not 
be indicative of results obtained in later trials. 
From time to time, we may publish interim data or ad hoc analyses from investigator-sponsored or company-sponsored 
clinical trials of our product candidates. Preliminary data and ad hoc analyses from these clinical trials may change as longer-
term patient data become available. In general, we seek to conduct interim analyses at times we pre-specify with the 
applicable regulators prior to commencement of the trial, at which time we lock and reconcile the database. We may 
occasionally elect not to conduct subsequent interim analyses so as not to compromise the statistical analysis plan for the 
trial. Accordingly, our interim analyses do not include data subsequent to the cut-off date and may not be available until the 
next planned interim analysis. From time to time, preliminary data and ad hoc analyses might be presented, typically by 
academic investigators at scientific conferences or in scientific publications.
With respect to clinical trials conducted by our academic or other collaborators, such as University College London, UCLA, 
Telethon-OSR and GSK, we may not have access to the most recent clinical data or the clinical data available to us may 
otherwise be limited or incomplete. Interim data or ad hoc analyses from these clinical trials are not necessarily predictive of 
final results. Interim data or ad hoc analyses are subject to the risk that one or more of the clinical outcomes may materially 
change as patient enrollment continues or more patient data become available to us. Interim, topline and preliminary data and 
ad hoc analyses also remain subject to audit and verification procedures that may result in the final data being materially 
different from the preliminary data available to us or that we previously published. As a result, preliminary and interim data 
and ad hoc analyses should be viewed with caution until the final data are available. Material adverse changes in the final 
data compared to the preliminary or interim data or ad hoc analyses could significantly harm our business prospects.
Similarly, the results of pre-clinical studies and previous clinical trials should not be relied upon as evidence that our ongoing 
or future clinical trials will succeed. Trial designs and results from pre-clinical studies or previous clinical trials are not 
necessarily predictive of future clinical trial results or the ability to obtain marketing approval for our product candidates. Our 
product candidates may fail to show the desired safety and efficacy in clinical development despite demonstrating positive 
results in pre-clinical studies or having successfully advanced through initial clinical trials or preliminary stages of 
registrational clinical trials.
For example, although sustained clinical activity has been observed in clinical trials to date for Libmeldy (OTL-200), follow-
up in these clinical trials is ongoing and there can be no assurance that the results, in each case as of the applicable primary 
endpoint measurement date, seen in clinical trials of any of our product candidates ultimately will result in success in clinical 
trials or provide adequate support for marketing approvals by the FDA, in the case of Libmeldy, without conducting further 
clinical trials. These data, or other positive data, may not continue or occur for these patients or for any future patients in our 
ongoing or future clinical trials, and may not be repeated or observed in ongoing or future trials involving our product 
candidates. There are limited data concerning long-term safety and efficacy following treatment with our product candidates. 
Our product candidates may fail to adequately demonstrate safety and efficacy in clinical development despite positive 
results in pre-clinical studies. Our product candidates may fail to show the desired safety and efficacy in later stages of 
clinical development despite having successfully advanced through initial clinical trials. There can be no assurance that any 
of these trials will ultimately be successful or support further clinical advancement or regulatory approval of our product 
candidates. In addition, there can be no assurance that we will be able to achieve the same or similar success in our pre-
clinical studies and clinical trials of our other product candidates. 
Favorable results from compassionate use programs may not establish proof of concept, and the FDA or other regulatory 
authorities may not accept compassionate use data as sufficient clinical validation in support of our regulatory approval 
efforts.
A number of patients have been administered our autologous ex vivo gene therapies through compassionate use programs. 
Compassionate use is a term that is used to refer to the use of an investigational drug outside of a clinical trial to treat a 
patient with a serious or immediately life-threatening disease or condition who has no comparable or satisfactory alternative 
treatment options. Regulators often allow compassionate use on a case-by-case basis for an individual patient or for defined 
groups of patients with similar treatment needs. Caution should be given when reviewing and interpreting compassionate use 
data. While results from treating patients through compassionate use have in certain cases been encouraging, we cannot be 

48
assured that the results observed in these cases will be observed in our ongoing or future clinical trials or that our ongoing 
and future clinical trials will ultimately be successful.
We plan to submit any data available to us from compassionate use cases as part of any regulatory submission for the 
applicable product candidate. However, because these patients were not treated as part of a clinical trial regulatory framework 
and related requirements, regulatory authorities may not accept compassionate use data as sufficiently robust clinical 
evidence in support of our regulatory approval efforts, or they may find that the data submitted from our clinical trials are 
insufficient to support approval. Such decisions could materially and adversely affect our business, financial condition, 
results of operations and prospects.
We may find it difficult to enroll patients in our clinical trials, which could delay or prevent us from proceeding with 
clinical trials of our product candidates.
Identifying and qualifying patients to participate in clinical trials of our product candidates is critical to our success. The 
timing of our clinical trials depends on our ability to recruit patients to participate as well as the completion of required 
follow-up periods. Patients may be unwilling to participate in our gene therapy clinical trials because of negative publicity 
from adverse events related to the biotechnology or gene therapy fields generally, competitive clinical trials for similar 
patient populations, clinical trials in product candidates employing our vectors, the existence of current treatments or for 
other reasons. Additionally, the COVID-19 global pandemic has had and may continue to have a sustained impact on our 
ability to recruit and follow-up with patients either due to continued or renewed restrictions on travel or shelter-in-place 
orders or policies or due to changes in patient willingness to participate in trials or travel to study sites in the wake of the 
pandemic. Additionally, COVID-19 related study site policies may create delays or setbacks in our ability to continue to 
enroll or to dose patients. In addition, the indications that we are currently targeting and may in the future target are rare 
diseases, which may limit the pool of patients that may be enrolled in our ongoing or planned clinical trials. The timeline for 
recruiting patients, conducting trials and obtaining regulatory approval of our product candidates may be delayed, which 
could result in increased costs, delays in advancing our product candidates, delays in testing the effectiveness of our product 
candidates or termination of the clinical trials altogether.
We may not be able to identify, recruit and enroll a sufficient number of patients, or those with the required or desired 
characteristics, to complete our clinical trials in a timely manner. For example, due to the nature of the indications that we are 
initially targeting, patients with advanced disease progression may not be suitable candidates for treatment with our product 
candidates and may be ineligible for enrollment in our clinical trials. Therefore, early diagnosis in patients with our target 
diseases is critical to our success. Patient enrollment and trial completion is affected by factors including the:
•
size of the patient population and process for identifying subjects;
•
design of the trial protocol;
•
eligibility and exclusion criteria;
•
safety profile, to date, of the product candidate under study;
•
perceived risks and benefits of the product candidate under study;
•
perceived risks and benefits of gene therapy-based approaches to treatment of diseases, including any required 
pre-treatment conditioning regimens;
•
availability of competing therapies and clinical trials;
•
severity of the disease under investigation;
•
degree of progression of the subject’s disease at the time of enrollment;
•
availability of genetic testing for potential patients;
•
proximity and availability of clinical trial sites for prospective subjects;
•
the impact of the COVID-19 global pandemic or future pandemics or similar events on patients’ willingness and 
ability to participate in clinical trials or on study site policies;
•
ability to obtain and maintain subject consent;
•
risk that enrolled subjects will drop out before completion of the trial;
•
patient referral practices of physicians; and
•
ability to monitor subjects adequately during and after treatment.

49
Our current product candidates are being developed to treat rare conditions. We plan to seek initial marketing approvals in 
the United States and the European Union. We may not be able to initiate or continue clinical trials if we cannot enroll a 
sufficient number of eligible patients to participate in the clinical trials required by the FDA or EMA. Our ability to 
successfully initiate, enroll and complete a clinical trial in any foreign country is subject to numerous risks unique to 
conducting business in foreign countries, including:
•
difficulty in establishing or managing relationships with academic partners or contract research organizations, or 
CROs, and physicians;
•
different standards for the conduct of clinical trials;
•
the absence in some countries of established groups with sufficient regulatory expertise for review of gene 
therapy protocols;
•
our inability to locate qualified local consultants, physicians and partners; and
•
the potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, 
including the regulation of pharmaceutical and biotechnology products and treatment.
If we have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned, we may need to delay, 
limit or terminate ongoing or planned clinical trials, any of which would have an adverse effect on our business, financial 
condition, results of operations and prospects.
We may encounter substantial delays in our clinical trials, or we may fail to demonstrate safety and efficacy to the 
satisfaction of applicable regulatory authorities.
Before obtaining marketing approval from regulatory authorities for the sale of our product candidates, we must conduct 
extensive clinical trials to demonstrate the safety and efficacy of the product candidates in humans. Clinical testing is 
expensive, time-consuming and the outcome is uncertain. We cannot guarantee that any clinical trials will be conducted as 
planned or completed on schedule, if at all. A failure of one or more clinical trials can occur at any stage of testing. Events 
that may prevent successful or timely completion of clinical development include:
•
delays in reaching a consensus with regulatory agencies on study design;
•
delays in reaching agreement on acceptable terms with prospective CROs and clinical trial sites;
•
delays in obtaining required Institutional Review Board, or IRB, approval at each clinical trial site;
•
delays in recruiting suitable patients and in sufficient volume to participate in our clinical trials;
•
imposition of a clinical hold by regulatory agencies;
•
failure by our academic partners, CROs, other third parties or us to adhere to clinical trial protocol and record 
keeping requirements;
•
failure to perform in accordance with the FDA’s good clinical practices, or GCP, or applicable regulatory 
guidelines in other countries;
•
delays in the testing, validation, manufacturing and delivery of our product candidates to the clinical sites;
•
delays in having patients complete participation in a study or return for post-treatment follow-up;
•
clinical trial sites or patients dropping out of a study;
•
delays in patient enrollment, missed assessments resulting from remote follow-up visits, or delays in completion 
of participation as a result of the impact of the COVID-19 global pandemic or future pandemics or similar 
events;
•
the occurrence of SAEs associated with the product candidate that are viewed to outweigh its potential benefits; 
or
•
changes in regulatory requirements and guidance that require amending or submitting new clinical protocols.
Any inability to successfully complete pre-clinical and clinical development could result in additional costs to us or impair 
our ability to generate revenue. In addition, if we make changes to our product candidates, we may need to conduct additional 
studies to bridge our modified product candidates to earlier versions, which could delay our clinical development plan or 
marketing approval for our product candidates. Clinical trial delays could also shorten any periods during which we may 

50
have the exclusive right to commercialize our product candidates or allow our competitors to bring products to market before 
we do, which could impair our ability to successfully commercialize our product candidates and may harm our business and 
results of operations.
If the results of our clinical trials are inconclusive or if there are safety concerns or adverse events associated with our 
product candidates, we may:
•
be delayed in obtaining marketing approval for our product candidates, if at all;
•
obtain approval for indications or patient populations that are not as broad as intended or desired;
•
obtain approval with, or later become subject to, labeling or a REMS (or equivalent requirement from a non-U.S. 
regulatory authority) that includes significant use or distribution restrictions or safety warnings, precautions, 
contraindications, drug interactions, or adverse events;
•
be subject to changes with the way the product is administered;
•
be required to perform additional clinical trials to support comparability or approval or be subject to additional 
post-marketing testing requirements;
•
have regulatory authorities withdraw their approval of the product or impose restrictions on its distribution in the 
form of a REMS (or equivalent requirement from a non-U.S. regulatory authority);
•
be sued by competitors, patent holders, patients, or third parties; or
•
experience damage to our reputation.
Any of these events could prevent us from achieving or maintaining market acceptance of our product candidates and impair 
our ability to commercialize our products.
We may elect to initiate a rolling BLA for our product candidates, in which case the FDA will not complete, and may 
delay initiating, its review of the BLA until we submit all of the required information.
A rolling BLA is an application process that allows us to submit the information required by the BLA in sections. The FDA 
will not complete, and may delay initiating, its review of our BLA until we submit all of the required information for a full 
BLA. If we are delayed or unable to provide this required information it could delay or prevent our ability to obtain 
regulatory approvals, as a result of which our business, prospects, financial condition and results of operations may suffer.
Even if we complete the necessary pre-clinical studies and clinical trials, we cannot predict when or if we will obtain 
regulatory approval to commercialize a product candidate, and the approval may be for a narrower indication than we 
seek. 
We cannot commercialize a product until the appropriate regulatory authorities have reviewed and approved such product 
candidate. Even if a product candidate demonstrates safety and efficacy in clinical trials, the regulatory agencies may not 
complete their review processes in a timely manner, or we may not be able to obtain regulatory approval. Many companies in 
the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials even after 
achieving promising results in pre-clinical testing and earlier-stage clinical trials. Additional delays may result if an FDA 
Advisory Committee or other regulatory authority recommends non-approval or restrictions on approval. In addition, we may 
experience delays or rejections based upon additional government regulation from future legislation or administrative action 
or changes in regulatory agency policy during the period of product development, clinical trials and the review process. We 
could also face delays if regulatory authorities are unable to complete required inspections, which could occur for reasons 
outside of our control, such as travel restrictions.
In addition, regulatory agencies may not approve the labeling claims that are necessary or desirable for the successful 
commercialization of our product candidates. For example, regulatory agencies may approve a product candidate for fewer or 
more limited indications than requested or may grant approval subject to the performance of post-marketing studies. 
Regulators may approve a product candidate for a smaller patient population, drug formulation (such as drug product using 
HSCs derived from bone marrow as opposed to mobilized peripheral blood or vice versa) or manufacturing processes (such 
as fresh drug product as opposed to cryopreserved or use of different manufacturing facilities) than we are seeking. If we are 
delayed in obtaining or unable to obtain necessary regulatory approvals, or if we obtain more limited regulatory approvals 
than we expect, our business, prospects, financial condition and results of operations may suffer. 
Even if we complete the necessary pre-clinical studies and clinical trials, the marketing approval process is expensive, 
time-consuming and uncertain and may prevent us from obtaining approvals for the commercialization of some or all of 
our product candidates. If we or any future collaborators are not able to obtain, or if there are delays in obtaining, 

51
required regulatory approvals, we or they will not be able to commercialize our product candidates, and our ability to 
generate revenue will be materially impaired.
Our product candidates and the activities associated with their development and commercialization, including their design, 
testing, manufacture, safety, efficacy, record keeping, labeling, storage, approval, advertising, promotion, sale and 
distribution, export and import, are subject to comprehensive regulation by the FDA, other regulatory agencies in the United 
States, the EMA, and comparable regulatory authorities in other countries. Failure to obtain marketing approval for a product 
candidate will prevent us from commercializing such product candidate. We have only limited experience in submitting and 
supporting the applications necessary to gain marketing approvals, and we expect to rely on third-party CROs to assist us in 
this process.
Securing marketing approval requires the submission of extensive pre-clinical and clinical data and supporting information to 
the various regulatory authorities for each therapeutic indication to establish the product candidate’s safety and efficacy. 
Securing regulatory approval also requires the submission of extensive information about the product manufacturing process 
and controls up to and including inspection of manufacturing facilities by, the relevant regulatory authority. Our product 
candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side 
effects, toxicities or other characteristics that may preclude our obtaining marketing approval or prevent or limit commercial 
use.
The process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years if 
additional clinical trials are required, if approval is obtained at all, and can vary substantially based upon a variety of factors, 
including the type, complexity and novelty of the product candidates involved. Changes in marketing approval policies 
during the development period, changes in or the enactment of additional statutes or regulations, or changes in regulatory 
review for each submitted product application, may cause delays in the approval or rejection of an application. The FDA and 
comparable authorities in other countries have substantial discretion in the approval process and may refuse to accept any 
application or may decide that our data are insufficient for approval and require additional pre-clinical, clinical or other 
studies. In addition, varying interpretations of the data obtained from pre-clinical and clinical testing could delay, limit or 
prevent marketing approval of a drug candidate. Any marketing approval of our product candidates that we, or any future 
collaborators, ultimately obtain may be limited or subject to restrictions or post-approval commitments that render the 
approved product not commercially viable.
Accordingly, if we or any future collaborators experience delays in obtaining approval or if we or they fail to obtain approval 
of our product candidates, the commercial prospects for our product candidates may be harmed and our ability to generate 
revenue will be materially impaired.
Even if we obtain and maintain approval for our product candidates in one jurisdiction, we may never obtain approval for 
our product candidates in other jurisdictions, which would limit our market opportunities and adversely affect our 
business. 
Approval of a product candidate in the United States by the FDA does not ensure approval of such product candidate by the 
EMA or other regulatory authorities in other countries or jurisdictions, and approval by the EMA or another regulatory 
authority does not ensure approval by regulatory authorities in other foreign countries or by the FDA. For example, though 
we received standard marketing authorization of Libmeldy (OTL-200) from the European Commission in December 2020, 
there is no guarantee that we will receive approval from the FDA. 
Sales of our product candidates outside of the United States will be subject to foreign regulatory requirements governing 
clinical trials and marketing approval. Even if the FDA grants marketing approval for a product candidate, comparable 
regulatory authorities of foreign countries also must approve the manufacturing and marketing of the product candidates in 
those countries. Approval procedures vary among jurisdictions and can involve requirements and administrative review 
periods different from, and more onerous than, those in the United States, including additional pre-clinical studies or clinical 
trials. In many countries outside the United States, a product candidate must be approved for reimbursement before it can be 
approved for sale in that country. In some cases, the price that we intend to charge for our products, if approved, is also 
subject to approval. We intend to submit an MAA to the EMA for approval of our product candidates in the European Union, 
but obtaining such approval from the European Commission following the opinion of EMA is a lengthy and expensive 
process. 
Even if a product candidate is approved, the FDA or the European Commission may limit the indications for which the 
product may be marketed, require extensive warnings on the product labeling or require expensive and time-consuming 
additional clinical trials or reporting as conditions of approval. Regulatory authorities in countries outside of the United 
States and the European Union also have requirements for approval of product candidates with which we must comply prior 
to marketing in those countries. Obtaining foreign regulatory approvals and compliance with foreign regulatory requirements 

52
could result in significant delays, difficulties and costs for us and could delay or prevent the introduction of our product 
candidates in certain countries.
Further, clinical trials conducted in one country may not be accepted by regulatory authorities in other countries. Also, 
regulatory approval for any of our product candidates may be withdrawn. If we fail to comply with the regulatory 
requirements, our target market will be reduced and our ability to realize the full market potential of our product candidates 
will be harmed and our business, financial condition, results of operations and prospects may be harmed.
Additionally, the UK formally left the EU in January 2020. The EU and the UK have concluded a Trade and Cooperation 
Agreement, or TCA, which has been formally applicable since May 2021. The TCA includes specific provisions concerning 
pharmaceuticals, which include the mutual recognition of GMP, inspections of manufacturing facilities for medicinal 
products and GMP documents issued, but does not foresee wholesale mutual recognition of UK and EU pharmaceutical 
regulations. At present, Great Britain has implemented EU legislation on the marketing, promotion and sale of medicinal 
products through the Human Medicines Regulations 2012 (as amended) (under the Northern Ireland Protocol, the EU 
regulatory framework will continue to apply in Northern Ireland). The regulatory regime in Great Britain therefore currently 
aligns in the most part with EU regulations, however it is possible that these regimes will diverge in the future now that Great 
Britain’s regulatory system is independent from the EU and the TCA does not provide for mutual recognition of UK and EU 
pharmaceutical legislation. For example, the new Clinical Trials Regulation, which became effective in the EU on January 
31, 2022, and provides for a streamlined clinical trial application and assessment procedure covering multiple EU Member 
States, has not been implemented into UK law, and a separate application will need to be submitted for clinical trial 
authorization in the UK. The separate, and potentially diverging, regulatory regimes between Great Britain and the EU may 
increase our regulatory burden of applying for and obtaining authorization in Great Britain and the EU. 
Most of the clinical trials for our product candidates conducted to date were conducted at sites outside the United States, 
and the FDA may not accept data from trials conducted in such locations.
To date, most of the clinical trials conducted on our product candidates have been conducted outside the United States. 
Although the FDA may accept data from clinical trials conducted outside the U.S., acceptance of these data is subject to 
conditions imposed by the FDA. For example, the clinical trial must be well designed and conducted and performed by 
qualified investigators in accordance with ethical principles. The trial population must also adequately represent the U.S. 
population, and the data must be applicable to the U.S. population and U.S. medical practice in ways that the FDA deems 
clinically meaningful. In addition, while these clinical trials are subject to the applicable local laws, FDA acceptance of the 
data will depend on its determination that the trials also complied with all applicable U.S. laws and regulations. If the FDA 
does not accept data from any trial that we conduct outside the U.S., due to study design or otherwise, it would likely result in 
the need for additional trials, which would be costly and time-consuming and would delay or permanently halt our 
development of the applicable product candidates. Further, if we do not have an IND open for a product candidate, we forego 
more frequent interactions and dialogue with the FDA regarding the design and conduct of our trials as well as product 
comparability, which may delay or halt the development of such product candidates later in development should the FDA 
later disagree with the design or conduct of our trials or product comparability approach.
In addition, in order to commence a clinical trial in the U.S., we are required to seek FDA acceptance of an IND for each of 
our product candidates. We cannot be sure any IND we submit to the FDA, or any similar CTA we submit in other countries, 
will be accepted. We may be required to conduct additional pre-clinical testing prior to submitting an IND for any of our 
product candidates, and the results of any such testing may not be positive. Consequently, we may be unable to successfully 
and efficiently execute and complete necessary clinical trials in a way that leads to a BLA submission and approval of our 
product candidates. We may require more time and incur greater costs than our competitors and may not succeed in obtaining 
regulatory approvals of product candidates that we develop. Failure to commence or complete, or delays in, our planned 
clinical trials, could prevent us from or delay us in commercializing our product candidates.
While we intend to seek designations for our product candidates with the FDA and other comparable regulatory 
authorities that are intended to confer benefits such as a faster development process or an accelerated regulatory pathway, 
there can be no assurance that we will successfully obtain such designations. In addition, even if one or more of our 
product candidates are granted such designations, we may not be able to realize the intended benefits of such 
designations.
The FDA and comparable other regulatory authorities offer certain designations for product candidates that are designed to 
encourage the research and development of product candidates that are intended to address conditions with significant unmet 
medical need. These designations may confer benefits such as additional interaction with regulatory authorities, a potentially 
accelerated regulatory pathway and priority review. OTL-200 for MLD received RMAT designation from the FDA, and 
OTL-203 for MPS-IH received a Priority Medicines, or PRIME, designation from EMA. Despite these designations, there 
can be no assurance that we will successfully obtain these or other designations for any of our other product candidates. In 
addition, while such designations could expedite the development or review process, they generally do not change the 

53
standards for approval. Even if we obtain such designations for one or more of our product candidates, there can be no 
assurance that we will realize their intended benefits. 
For example, we may seek a Breakthrough Therapy designation for some of our other product candidates. A breakthrough 
therapy is defined as a therapy that is intended, alone or in combination with one or more other therapies, to treat a serious or 
life-threatening disease or condition, and preliminary clinical evidence indicates that the therapy may demonstrate substantial 
improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects 
observed early in clinical development. For therapies that have been designated as breakthrough therapies, interaction and 
communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical 
development while minimizing the number of patients placed in ineffective control regimens. Therapies designated as 
breakthrough therapies by the FDA are also eligible for accelerated approval. Designation as a breakthrough therapy is within 
the discretion of the FDA. Accordingly, even if we believe one of our product candidates meets the criteria for designation as 
a breakthrough therapy, the FDA may disagree and instead determine not to make such designation. In any event, the receipt 
of a Breakthrough Therapy designation for a product candidate may not result in a faster development process, review or 
approval compared to therapies considered for approval under conventional FDA procedures and does not assure ultimate 
approval by the FDA. In addition, even if one or more of our product candidates qualify as breakthrough therapies, the FDA 
may later decide that such product candidates no longer meet the conditions for qualification.
In addition, we may seek RMAT designation for some of our other product candidates. An RMAT is defined as cell 
therapies, therapeutic tissue engineering products, human cell and tissue products, and combination products using any such 
therapies or products. Gene therapies, including genetically modified cells that lead to a durable modification of cells or 
tissues may meet the definition of a regenerative medicine therapy. The RMAT program is intended to facilitate efficient 
development and expedite review of RMATs, which are intended to treat, modify, reverse, or cure a serious or life-
threatening disease or condition and for which preliminary clinical evidence indicates that the drug has the potential to 
address unmet medical needs for such disease or condition. A BLA for an RMAT may be eligible for priority review or 
accelerated approval. An RMAT may be eligible for priority review if it treats a serious condition, and, if approved, would 
provide a significant improvement in the safety or effectiveness of the treatment of the condition. An RMAT may be eligible 
for accelerated approval through (1) surrogate or intermediate endpoints reasonably likely to predict long-term clinical 
benefit or (2) reliance upon data obtained from a meaningful number of sites. Benefits of such designation also include early 
interactions with FDA to discuss any potential surrogate or intermediate endpoint to be used to support accelerated approval. 
A regenerative medicine therapy that is granted accelerated approval and is subject to post-approval requirements may fulfill 
such requirements through the submission of clinical evidence, clinical trials, patient registries, or other sources of real-world 
evidence, such as electronic health records, the collection of larger confirmatory data sets, or post-approval monitoring of all 
patients treated with such therapy prior to its approval. RMAT designation is within the discretion of the FDA. Accordingly, 
even if we believe one of our product candidates meets the criteria for designation as a RMAT, the FDA may disagree and 
instead determine not to make such designation. In any event, the receipt of RMAT designation for a product candidate may 
not result in a faster development process, review or approval compared to drugs considered for approval under conventional 
FDA procedures and does not assure ultimate approval by the FDA. In addition, even if one or more of our product 
candidates qualify as for RMAT designation, the FDA may later decide that the biological products no longer meet the 
conditions for qualification.
In addition, the FDA has granted Rare Pediatric Disease designation to OTL-200 for MLD, OTL-201 for MPS-IIIA and 
OTL-203 for MPS-IH, and we may seek Rare Pediatric Disease designation for some of our other product candidates. The 
FDA defines a “rare pediatric disease” as a serious or life-threatening disease in which the serious of life-threatening 
manifestations primarily affect individuals aged from birth to 18 years and the disease affects fewer than 200,000 individuals 
in the U.S. or affects more than 200,000 in the U.S. and for which there is no reasonable expectation that the cost of 
developing and making in the U.S. a drug for such disease or condition will be received from sales in the U.S. of such drug. 
Under the FDA’s Rare Pediatric Disease Priority Review Voucher, or PRV, program, upon the approval of a BLA for the 
treatment of a rare pediatric disease, the sponsor of such application would be eligible for a Rare Pediatric Disease PRV that 
can be used to obtain priority review for a subsequent new drug application or BLA. The PRV may be sold or transferred an 
unlimited number of times. Congress has extended the PRV program through September 30, 2024, with potential for PRVs to 
be granted through September 30, 2026. This program has been subject to criticism, including by the FDA, and it is possible 
that even if we obtain approval for Libmeldy (OTL-200), OTL-201 for MPS-IIIA and OTL-203 for MPS-IH and qualify for 
such a PRV, the program may no longer be in effect at the time or the value of any such PRV may decrease such that we are 
may not be able to realize the benefits of such PRV. 
In addition, we may seek Fast Track Designation for some of our product candidates. If a therapy is intended for the 
treatment of a serious or life-threatening condition and the therapy demonstrates the potential to address unmet medical needs 
for this condition, the therapy sponsor may apply for Fast Track Designation. The FDA has broad discretion whether or not to 
grant this designation, so even if we believe a particular product candidate is eligible for this designation, there can be no 

54
assurance that the FDA would decide to grant it. Even if we do receive Fast Track Designation, we may not experience a 
faster development process, review or approval compared to conventional FDA procedures, and receiving a Fast Track 
Designation does not provide assurance of ultimate FDA approval. In addition, the FDA may withdraw Fast Track 
Designation if it believes that the designation is no longer supported by data from our clinical development program.
We may seek priority review designation for one or more of our product candidates, but we might not receive such 
designation, and even if we do, such designation may not lead to a faster regulatory review or approval process. 
If the FDA determines that a product candidate offers a treatment for a serious condition and, if approved, the product would 
provide a significant improvement in safety or effectiveness, the FDA may designate the product candidate for priority 
review. A priority review designation means that the goal for the FDA to review an application is six months, rather than the 
standard review period of ten months. We may request priority review for our product candidates. The FDA has broad 
discretion with respect to whether or not to grant priority review status to a product candidate, so even if we believe a 
particular product candidate is eligible for such designation or status, in particular if such product candidate has received a 
Breakthrough Therapy designation or RMAT designation, the FDA may decide not to grant it. Moreover, a priority review 
designation does not result in expedited development and does not necessarily result in expedited regulatory review or 
approval process or necessarily confer any advantage with respect to approval compared to conventional FDA procedures. 
Receiving priority review from the FDA does not guarantee approval within the six-month review cycle or at all.
Under the terms of the GSK Agreement, we are required to use commercially reasonable efforts to obtain a PRV from the 
FDA for certain product candidates, including Libmeldy, and to transfer the first such PRV to GSK. GSK also has an option 
to acquire at a defined price any PRV granted to us thereafter for certain product candidates. In the event that GSK does not 
exercise this option with respect to any PRV, we may sell the PRV to a third party and must share any proceeds in excess of a 
specified sale price equally with GSK.
We have sought and received orphan drug designation for Libmeldy (OTL-200) and OTL-201 for MPS-IIIA from the 
FDA and EMA and for OTL-203 for MPS-IH from the FDA, but we may be unable to obtain orphan drug designation for 
our other product candidates. Even if we obtain such designation, we may not be able to realize the benefits of such 
designation, including potential marketing exclusivity of our product candidates, if approved.
Regulatory authorities in some jurisdictions, including the United States and other major markets, may designate drugs 
intended to treat conditions or diseases affecting relatively small patient populations as orphan drugs. Under the Orphan Drug 
Act of 1983, the FDA may designate a product candidate as an orphan drug if it is intended to treat a rare disease or 
condition, which is generally defined as having a patient population of fewer than 200,000 individuals in the United States, or 
a patient population greater than 200,000 in the United States where there is no reasonable expectation that the cost of 
developing the drug will be recovered from sales in the United States. In the EU, the EMA’s Committee for Orphan 
Medicinal Products grants orphan designation in respect of a medicinal product if the sponsor can establish that such product 
is intended for the diagnosis, prevention or treatment of a life-threatening or chronically debilitating condition affecting not 
more than five in 10,000 persons in the EU. Additionally, orphan designation may be granted for products intended for the 
diagnosis, prevention or treatment of a life-threatening, seriously debilitating or serious and chronic condition and when, 
without incentives, it is unlikely such products would generate sufficient return in the EU to justify the necessary investment 
their development. In either case, the applicant for orphan designation must also demonstrate that no satisfactory method of 
diagnosis, prevention, or treatment for the condition has been authorized for marketing in the EU (or, if a method exists, the 
new product would be a significant benefit to those affected by the condition).
We have sought and received orphan drug designation for Libmeldy and OTL-201 for MPS-IIIA from the FDA and EMA 
and for OTL-203 for MPS-IH from the FDA. If we request orphan drug designation for any of our other product candidates, 
there can be no assurances that the FDA or EMA will grant any of our other product candidates such designation. 
Additionally, the designation of any of our product candidates as an orphan product does not mean that any regulatory agency 
will accelerate regulatory review of, or ultimately approve, that product candidate, nor does it limit the ability of any 
regulatory agency to grant orphan drug designation to product candidates of other companies that treat the same indications 
as our product candidates prior to our product candidates receiving exclusive marketing approval.
Generally, if a product candidate with an orphan drug designation receives the first marketing approval for the indication for 
which it has such designation, the product is entitled to a period of marketing exclusivity, which precludes the FDA or EMA 
from approving another marketing application for a product that constitutes the same drug treating the same indication for 
that marketing exclusivity period, except in limited circumstances. If another sponsor receives such approval before we do 
(regardless of our orphan drug designation), we will be precluded from receiving marketing approval for our product for the 
applicable exclusivity period. The applicable period is seven years in the United States and 10 years in the EU. The 
exclusivity period in the EU can be reduced to six years if a product no longer meets the criteria for orphan designation, 
including if the product is sufficiently profitable so that market exclusivity is no longer justified. Orphan drug exclusivity 

55
may be revoked if any regulatory agency determines that the request for designation was materially defective or if the 
manufacturer is unable to assure sufficient quantity of the product to meet the needs of patients with the rare disease or 
condition.
Even if we obtain orphan drug exclusivity for a product candidate, that exclusivity may not effectively protect the product 
candidate from competition because different drugs can be approved for the same condition. In the United States, even after 
an orphan drug is approved, the FDA may subsequently approve another drug for the same condition if the FDA concludes 
that the latter drug is not the same drug or is clinically superior in that it is shown to be safer, more effective or makes a 
major contribution to patient care. In the EU, a marketing authorization may be granted to a similar medicinal product for the 
same orphan indication if:
•
the second applicant can establish in its application that its medicinal product, although similar to the orphan 
medicinal product already authorized, is safer, more effective or otherwise clinically superior;
•
the holder of the marketing authorization for the original orphan medicinal product consents to a second orphan 
medicinal product application; or
•
the holder of the marketing authorization for the original orphan medicinal product cannot supply sufficient 
quantities of orphan medicinal product.
We may seek a conditional marketing authorization in Europe for some or all of our current product candidates, but we 
may not be able to obtain or maintain such designation.
As part of its marketing authorization process, the EMA may grant marketing authorizations for certain categories of 
medicinal products on the basis of less complete data than is normally required, where the benefit of immediate availability 
of the medicine outweighs the risk inherent in the fact that additional data are still required or in the interests of public health. 
In such cases, it is possible for the CHMP to recommend the granting of a marketing authorization, subject to certain specific 
obligations to be reviewed annually, which is referred to as a conditional marketing authorization. This may apply to 
medicinal products for human use that fall under the jurisdiction of the EMA, including those that aim at the treatment, the 
prevention, or the medical diagnosis of seriously debilitating or life-threatening diseases and those designated as orphan 
medicinal products.
A conditional marketing authorization may be granted when the CHMP finds that, although comprehensive clinical data 
referring to the safety and efficacy of the medicinal product have not been supplied, all the following requirements are met:
•
the risk-benefit balance of the medicinal product is positive;
•
it is likely that the applicant will be in a position to provide the comprehensive clinical data post-authorization;
•
unmet medical needs will be fulfilled; and
•
the benefit to public health of the immediate availability on the market of the medicinal product concerned 
outweighs the risk inherent in the fact that additional data is still required.
The granting of a conditional marketing authorization is restricted to situations in which only the clinical part of the 
application is not yet fully complete. Incomplete pre-clinical or quality data may only be accepted if duly justified and only in 
the case of a product intended to be used in emergency situations in response to public health threats. Conditional marketing 
authorizations are valid for one year, on a renewable basis. The holder will be required to complete ongoing trials or to 
conduct new trials with a view to confirming that the benefit-risk balance is positive. In addition, specific obligations may be 
imposed in relation to the collection of pharmacovigilance data.
Granting a conditional marketing authorization allows medicines to reach patients with unmet medical needs earlier than 
might otherwise be the case and will ensure that additional data on a product is generated, submitted, assessed and acted 
upon. Although we may seek a conditional marketing authorization for one or more of our product candidates by the EMA, 
the CHMP may ultimately not agree that the requirements for such conditional marketing authorization have been satisfied 
and hence delay the commercialization of our product candidates.
Even if we obtain regulatory approval for a product candidate, our products will remain subject to regulatory oversight. 
Libmeldy and any of our product candidates for which we obtain regulatory approval will be subject to ongoing regulatory 
requirements for manufacturing, labeling, packaging, storage, advertising, promotion, sampling, record-keeping and 
submission of safety and other post-market information. For example, as a post-marketing commitment, we are continuing to 
follow patients in the OTL-200 clinical development program for up to 15 years, and data will be presented to regulators at 
agreed points in order to further characterize the long-term efficacy and safety of Libmeldy. 

56
Any regulatory approvals that we receive for our product candidates also may be subject to a REMS or equivalent 
requirement from a non-U.S. regulatory authority, limitations on the approved indicated uses for which the product may be 
marketed or to the conditions of approval, or contain requirements for potentially costly post-marketing testing, including 
Phase 4 clinical trials, and surveillance to monitor the quality, safety and efficacy of the product. For example, in the United 
States, the holder of an approved BLA is obligated to monitor and report adverse events and any failure of a product to meet 
the specifications in the BLA. FDA guidance advises that patients treated with some types of gene therapy undergo long-term 
safety and efficacy follow-up for as long as 15 years post therapy. The holder of an approved BLA must also submit new or 
supplemental applications and obtain FDA approval for certain changes to the approved product, product labeling or 
manufacturing process. Advertising and promotional materials must comply with FDA rules and are subject to FDA review, 
in addition to other potentially applicable federal and state laws.
In the EU, the advertising and promotion of our products are subject to EU laws governing promotion of medicinal products, 
interactions with physicians, misleading and comparative advertising and unfair commercial practices. In addition, other 
legislation adopted by individual EU Member States may apply to the advertising and promotion of medicinal products. 
These laws require that promotional materials and advertising for medicinal products are consistent with the product’s 
Summary of Product Characteristics, or SmPC, as approved by the competent authorities. The SmPC is the document that 
provides information to physicians concerning the safe and effective use of the medicinal product. It forms an intrinsic and 
integral part of the marketing authorization granted for the medicinal product. Promotion of a medicinal product that does not 
comply with the SmPC is considered to constitute off-label promotion. The off-label promotion of medicinal products is 
prohibited in the EU. The applicable laws at EU level and in the individual EU Member States also prohibit the direct-to-
consumer advertising of prescription-only medicinal products. Violations of the rules governing the promotion of medicinal 
products in the EU could be penalized by administrative measures, fines and imprisonment. These laws may further limit or 
restrict the advertising and promotion of our products to the general public and may also impose limitations on our 
promotional activities with health care professionals.
In addition, product manufacturers and their facilities are subject to payment of user fees and continual review and periodic 
inspections by the FDA and other regulatory authorities for compliance cGMP requirements and adherence to commitments 
made in the BLA or foreign marketing application. If we, or a regulatory authority, discover previously unknown problems 
with a product, such as adverse events of unanticipated severity or frequency, or problems with the facility where the product 
is manufactured or disagrees with the promotion, marketing or labeling of that product, a regulatory authority may impose 
restrictions relative to that product, the manufacturing facility or us, including requiring recall or withdrawal of the product 
from the market or suspension of manufacturing.
If we fail to comply with applicable regulatory requirements following approval of any of our product candidates, a 
regulatory authority may:
•
issue a warning letter asserting that we are in violation of the law;
•
seek an injunction or impose administrative, civil or criminal penalties or monetary fines;
•
suspend or withdraw regulatory approval;
•
suspend any ongoing clinical trials;
•
refuse to approve a pending BLA or comparable foreign marketing application (or any supplements thereto) 
submitted by us or our strategic partners;
•
restrict the marketing or manufacturing of the product;
•
seize or detain the product or otherwise require the withdrawal of the product from the market;
•
refuse to permit the import or export of products; or
•
refuse to allow us to enter into supply contracts, including government contracts.
Any government investigation of alleged violations of law could require us to expend significant time and resources in 
response and could generate negative publicity. The occurrence of any event or penalty described above may inhibit our 
ability to commercialize our product candidates and adversely affect our business, financial condition, results of operations 
and prospects.
In addition, the FDA’s policies, and those of the EMA and other regulatory authorities, may change and additional 
government regulations may be enacted that could prevent, limit or delay regulatory approval of our product candidates. We 
cannot predict the likelihood, nature or extent of government regulation that may arise from future legislation or 
administrative action, either in the United States or abroad. If we are slow or unable to adapt to changes in existing 
requirements or the adoption of new requirements or policies, or if we are not able to maintain regulatory compliance, we 

57
may lose any marketing approval that we may have obtained and we may not achieve or sustain profitability, which would 
materially and adversely affect our business, financial condition, results of operations and prospects.
Both marketing authorization holders and manufacturers of medicinal products are subject to comprehensive regulatory 
oversight by the EMA and the competent authorities of the individual EU Member States both before and after grant of the 
manufacturing and marketing authorizations. This includes compliance with cGMP rules, which govern quality control of the 
manufacturing process and require documentation policies and procedures. We and our third-party manufacturers would be 
required to ensure that all of our processes, quality systems, methods, and equipment are compliant with cGMP. Failure by us 
or by any of our third-party partners, including suppliers, manufacturers, and distributors to comply with EU laws and the 
related national laws of individual EU Member States governing the conduct of clinical trials, manufacturing approval, 
marketing authorization of medicinal products, both before and after the grant of a marketing authorization, and marketing of 
such products following the grant of an authorization may result in administrative, civil, or criminal penalties. These penalties 
could include delays in or refusal to authorize the conduct of clinical trials or to grant marketing authorization, product 
withdrawals and recalls, product seizures, suspension, or variation of the marketing authorization, total or partial suspension 
of production, distribution, manufacturing, or clinical trials, operating restrictions, injunctions, suspension of licenses, fines, 
and criminal penalties.
In addition, EU legislation related to pharmacovigilance, or the assessment and monitoring of the safety of medicinal 
products, provides that the EMA and the competent authorities of the EU Member States have the authority to require 
companies to conduct additional post-approval clinical efficacy and safety studies. The legislation also governs the 
obligations of marketing authorization holders with respect to additional monitoring, adverse event management and 
reporting. Under the pharmacovigilance legislation and its related regulations and guidelines, we may be required to conduct 
a burdensome collection of data regarding the risks and benefits of marketed products and may be required to engage in 
ongoing assessments of those risks and benefits, including the possible requirement to conduct additional clinical trials, 
which may be time-consuming and expensive and could impact our profitability. Non-compliance with such obligations can 
lead to the variation, suspension or withdrawal of a marketing authorization or imposition of financial penalties or other 
enforcement measures.
 
Risks related to manufacturing and supply
 
Gene therapies are novel, complex and difficult to manufacture. We have limited manufacturing experience, and we rely 
on third party manufacturers that are often our single source of supply. We could experience manufacturing problems 
that result in delays in the development or commercialization of our commercial products or our product candidates or 
otherwise harm our business. 
Biological products are inherently difficult to manufacture, and gene therapy products are complex biological products, the 
development and manufacture of which necessitates substantial expertise and capital investment. Libmeldy, Strimvelis and 
our product candidates are individually manufactured for each patient using complex processes in specialized facilities. Our 
production process requires a variety of raw materials, some of which are highly specialized, including the viral vector that 
encodes for the functional copy of the missing or faulty gene to treat a specific disease. Some of these raw materials have 
limited and, in some cases, sole suppliers. Even though we plan to have back-up supplies of raw materials whenever possible, 
we cannot be certain such supplies will be sufficient if our primary sources are unavailable. A shortage of a critical raw 
material or a technical issue during manufacturing may lead to delays in clinical development or commercialization of our 
product candidates. Additionally, each manufacturing batch must meet certain analytical specifications to be released and 
production difficulties caused by unforeseen events may delay the availability of one or more of the necessary raw materials 
or delay the manufacture of our product candidates for use in clinical trials or for commercial supply. 
We have contracted with third party CDMOs for the manufacture of our viral vectors and drug product. We expect these 
CDMOs will be capable of providing sufficient quantities of our viral vectors and gene therapy products to meet the 
anticipated scale of our clinical trials and current and initial commercial demands, if any additional products are approved. 
However, to meet our projected needs for further commercial manufacturing and clinical trials of new product candidates, 
third parties with whom we currently work might need to increase their scale and frequency of production or we will need to 
secure alternate suppliers or develop in-house capabilities. We believe that there are alternate sources of supply that can 
satisfy our clinical and commercial requirements; however, identifying and establishing relationships with such sources, if 
necessary, could result in significant delays or material additional costs, which could delay or prevent the development of our 
product candidates and would have a negative impact on our business, financial condition and results of operations.
Additionally, the manufacturers of pharmaceutical products must comply with strictly enforced cGMP requirements, state 
and federal regulations, as well as foreign requirements when applicable. Any failure of our CDMOs to adhere to or 
document compliance to such regulatory requirements could lead to a delay or interruption in the availability of our program 
materials for clinical trials. If our manufacturers were to fail to comply with the FDA, EMA, or other regulatory authority, it 
could result in sanctions being imposed on us, including clinical holds, fines, injunctions, civil penalties, delays, suspension 

58
or withdrawal of approvals, license revocation, seizures or recalls of raw materials, product candidates or products, operating 
restrictions and criminal prosecutions, any of which could significantly and adversely affect supplies of our product 
candidates. Our dependence upon others for the manufacture of our gene therapies may also adversely affect our future profit 
margins and our ability to commercialize any product candidates that receive regulatory approval on a timely and competitive 
basis.
 
Delays in obtaining regulatory approval of our or our CDMOs’ manufacturing process and facility or disruptions in our 
manufacturing process may delay or disrupt our commercialization efforts. Until recently, no cGMP gene therapy 
manufacturing facility in the United States had received approval from the FDA for the manufacture of an approved gene 
therapy product.
Before we can begin to commercially manufacture our viral vector or product candidates in a CDMO facility, we must obtain 
regulatory approval from the FDA for our manufacturing processes and for the facility in which manufacturing is performed. 
A manufacturing authorization must also be obtained from the appropriate European Union regulatory authorities. Until 
recently, no cGMP gene therapy manufacturing facility in the United States had received approval from the FDA for the 
manufacture of an approved gene therapy product; therefore, the time frame required for us to obtain such approval is 
uncertain. In addition, we must pass a pre-approval inspection of our CDMOs manufacturing facility by the FDA and other 
relevant regulatory authorities before any of our gene therapy product candidates can obtain marketing approval. 
In order to obtain approval, we will need to ensure that all of our processes, quality systems, methods, equipment, policies 
and procedures are compliant with cGMP, and perform extensive audits of vendors, contract laboratories, CDMOs and 
suppliers. If any of our vendors, contract laboratories, CDMOs or suppliers is found to be out of compliance with cGMP, we 
may experience delays or disruptions in manufacturing while we work with these third parties to remedy the violation or 
while we work to identify suitable replacement vendors. The cGMP requirements govern quality control of the 
manufacturing process and documentation policies and procedures. In complying with cGMP, we will be obligated to spend 
time, money and effort in production, record keeping and quality control to assure that the product meets applicable 
specifications and other requirements. If we fail to comply with these requirements, we would be subject to possible 
regulatory action and may not be permitted to sell any products that we may develop. 
Any problems in our manufacturing process or facilities could make us a less attractive collaborator for potential partners, 
including larger pharmaceutical companies and academic research institutions, which could limit our access to additional 
attractive development programs.
We do not have experience as a company managing a complex supply chain or satisfying manufacturing-related 
regulatory requirements. 
The FDA, EMA and other foreign regulatory authorities may require us to submit samples of any lot of any approved product 
together with the protocols showing the results of applicable tests at any time. Under some circumstances, the FDA, EMA or 
other foreign regulatory authorities may require that we not distribute a product lot until the relevant agency authorizes its 
release. Slight deviations in the manufacturing process, including those affecting quality attributes and stability, may result in 
unacceptable changes in a viral vector or a gene therapy product that could result in lot failures or product recalls. Lot failures 
or product recalls could cause us to delay product launches or clinical trials, which could be costly to us and otherwise harm 
our business, financial condition, results of operations and prospects. Problems in our manufacturing processes could restrict 
our ability to meet market demand for our products. 
Managing an autologous ex vivo gene therapy supply chain is highly complex. We must identify, engage and coordinate 
with treatment centers where a patient’s cellular source material must be collected, prepared, stored and transported to the 
manufacturing facility and the cryopreserved drug product must be returned to the treatment center for administration 
into the patient using controlled temperature shipping containers. 
Once collected from the patient, the cellular source material must be prepared and stored according to specified procedures. 
While we intend to standardize the processes at treatment centers, if there is a deviation of the processes, the cellular source 
material from a patient could be adversely impacted and potentially result in manufacturing failures. The patient’s cellular 
materials must be transported to the manufacturing facility using a shipping container that maintains the material at a cool 
temperature and must typically be delivered and processed within three days of collection. While we intend to use reputable 
couriers and agents for the transport of such materials, if the shipping container is opened or damaged such that the cool 
temperature is not maintained, the cellular source material may be adversely impacted and it may not be feasible to 
manufacture a drug product for the patient. Similarly, if a shipment is delayed due to adverse weather, misrouting, being held 
up at a customs point, COVID-19 impacts or other events, the cellular source material may not be delivered within a time 
window that will allow for its use for the successful manufacture of a drug product. 

59
Similarly, the patient’s autologous drug product must be returned to the clinical site for administration into the patient using a 
specialized shipping container that maintains the material at a very low temperature for a period of typically up to ten days. 
While we intend to use reputable couriers and agents for the transport of our drug products, if the shipping container is 
opened or damaged such that the very low temperature is not maintained, the drug product may be adversely impacted and it 
may not be feasible to administer it to the patient or, if administered, it could cause harm to the patient. Similarly, if a 
shipment is delayed due to adverse weather, misrouting, being held up at a customs point, COVID-19 impacts or other 
events, and is not delivered to the clinical site within the time period that the very low temperature is maintained, the drug 
product may be adversely affected and be unable to be administered or, if administered, could cause harm to the patient.
We may be delayed or unable to identify, engage, successfully coordinate or qualify with treatment centers in the regions we 
are targeting as part of our commercial strategy, which could delay or prevent patients from receiving gene therapy 
treatments, if approved. If our treatment centers fail to perform satisfactorily, we may suffer reputational, operational, and 
business harm. 
Any of the above events, should they happen, could adversely affect our development timelines and our business, financial 
condition, results of operations and prospects.
Our gene therapies are for autologous use only. Therefore, if a drug product is administered to the wrong patient, the 
patient could suffer harm.
Our gene therapies are autologous, so they must be administered back only to the patient from which the cellular source 
material was collected. While we implement specific identifiers, lot numbers and labels with cross checks for our products 
and operations from collection of cellular source material, through manufacture of drug product, transport of product to the 
clinical site up to thawing and administration of the product, it is possible that a product may be administered into the wrong 
patient. If an autologous gene therapies were to be administered into the wrong patient, the patient could suffer harm, 
including experiencing a severe adverse immune reaction.
Any microbial contamination in the manufacturing process for our viral vectors or drug product, shortages of raw 
materials or failure of any of our key suppliers to deliver necessary components could result in delays in our clinical 
development or marketing schedules.
Given the nature of biologics manufacturing, there is a risk of microbial contamination. Any microbial contamination could 
adversely affect our ability to produce, release or administer our gene therapies on schedule and could, therefore, harm our 
results of operations and cause reputational damage. Additionally, although our gene therapies are tested for microbial 
contamination prior to release, if a contaminated product was administered to a patient, it could result in harm to the patient.
Some of the raw materials required in our manufacturing processes are derived from biologic sources. Such raw materials are 
difficult to procure and may be subject to contamination or recall. A material shortage, contamination, recall or restriction on 
the use of biologically derived substances in the manufacture of our vectors or drug product could adversely impact or disrupt 
the commercial manufacturing or the production of clinical material, which could adversely affect our development timelines 
and our business.
Interruptions in the supply of viral vectors or drug products or inventory loss may harm our operating results and 
financial condition. 
Our viral vectors and drug products are manufactured using technically complex processes in specialized facilities, 
sometimes using specialized equipment with highly specific raw materials and other production constraints. The complexity 
of these processes, as well as strict government standards for the manufacture and storage of our gene therapies, subjects us 
to manufacturing risks. While viral vectors and drug product released for use in clinical trials or for commercialization 
undergo sample testing, some defects may only be identified following their release. In addition, process deviations or 
unanticipated effects of approved process changes may result in viral vector or drug product not complying with stability 
requirements or specifications. Our viral vectors and drug product must be stored and transported at temperatures within a 
certain range. If these environmental conditions deviate, our viral vectors and drug products’ remaining shelf-lives could be 
impaired or their efficacy and safety could be negatively impacted, making them no longer suitable for use. For example, 
patients’ cellular material must be received by the manufacturing facility typically within three days after collection, and our 
gene therapy must be received by the clinical site typically within ten days after shipping from the manufacturing facility. 
The occurrence, or suspected occurrence, of manufacturing and distribution difficulties can lead to lost inventories and, in 
some cases, product recalls, with consequential reputational damage and the risk of product liability. The investigation and 
remediation of any identified problems can cause production delays, substantial expense, lost sales and delays of new product 
launches. Any interruption in the supply of finished products, due to transportation or other delays, including delays or 
disruptions resulting from the impact of the COVID-19 pandemic, or the loss thereof could hinder our ability to timely 
distribute our products and satisfy customer demand. Any unforeseen failure in the storage of the viral vectors or drug 

60
products or loss in supply could delay our clinical trials and result in a loss of our market share for our commercial products 
or our product candidates, if approved, and negatively affect our business, financial condition, results of operations and 
prospects.
Our cryopreserved product candidates require specific storage, handling and administration at the clinical sites. 
Our cryopreserved product candidates must be stored at very low temperatures in specialized freezers or specialized shipping 
containers until immediately prior to use. For administration, the cryopreserved drug product container must be carefully 
removed from storage, and rapidly thawed under controlled temperature conditions in an area proximal to the patient’s 
bedside and administered into the patient. The handling, thawing and administration of the cryopreserved gene therapy 
product must be performed according to specific instructions, typically using specific disposables and in some steps within 
specific time periods. Failure to correctly handle the product, follow the instructions for thawing and administration and or 
failure to administer the product within the specified period post-thaw could negatively impact the efficacy and or safety of 
the product. 
Risks related to our reliance on third parties
We have in the past, and in the future we may, enter into collaborations with third parties to develop or commercialize 
product candidates. These collaborations may not be successful.
We have entered into licensing and collaboration agreements with third parties, including the GSK Agreement, pursuant to 
which GSK transferred several programs to us, including Strimvelis and Libmeldy (OTL-200). In addition, GSK novated to 
us its research and collaboration agreement, or the R&D Agreement, with Telethon-OSR. These agreements impose, and we 
expect that future license agreements will impose, various due diligence, milestone payment, royalty, insurance and other 
obligations on us. The termination of these agreements could result in our loss of rights to practice the intellectual property 
licensed to us under these agreements and could compromise our development and commercialization efforts for our current 
or any future product candidates. 
There could also be disagreements as to whether certain amounts are payable under our licensing and collaboration 
agreements. For example, there could be disputes as to whether certain milestone payments have been triggered. Such 
disputes would divert management attention, could harm our relationship with our collaborators or licensors, and could lead 
to payments that we do not currently anticipate.
We also entered into a collaboration with Pharming Group N.V., or Pharming, pursuant to which Pharming was granted 
worldwide rights to OTL-105, an investigational ex vivo autologous hematopoietic stem cell gene therapy for the treatment 
of hereditary angioedema. The Company will lead the completion of IND-enabling activities and oversee manufacturing of 
OTL-105 during pre-clinical and clinical development, which will be funded by Pharming.
We may enter into additional collaborations in the future. We have limited control over the amount and timing of resources 
that our current and future collaborators dedicate to the development or commercialization of our product candidates. Our 
ability to generate revenue from these arrangements will depend on our and our collaborators’ abilities to successfully 
perform the functions assigned to each of us in these arrangements. Moreover, an unsuccessful outcome in any clinical trial 
for which our collaborator is responsible could be harmful to the public perception and prospects of our gene therapy 
platform.
Any collaborations we enter into in the future may pose several risks, including the following:
•
collaborators have significant discretion in determining the efforts and resources that they will apply to these 
collaborations;
•
collaborators may not perform their obligations as expected;
•
we may not achieve any milestones, or receive any payments, under our collaborations, including milestones or 
payments that we expect to achieve or receive;
•
the clinical trials conducted as part of these collaborations may not be successful;
•
collaborators may not pursue development and commercialization of any product candidates that achieve 
regulatory approval or may elect not to continue or renew development or commercialization programs based on 
clinical trial results, changes in the collaborators’ strategic focus or available funding or external factors, such as 
an acquisition, that divert resources or create competing priorities;

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•
collaborators may delay clinical trials, provide insufficient funding for clinical trials, stop a clinical trial or 
abandon a product candidate, repeat or conduct new clinical trials or require a new formulation of a product 
candidate for clinical testing;
•
we may not have access to, or may be restricted from disclosing, certain information regarding product 
candidates being developed or commercialized under a collaboration and, consequently, may have limited ability 
to inform our shareholders about the status of such product candidates;
•
collaborators could independently develop, or develop with third parties, products that compete directly or 
indirectly with our product candidates if the collaborators believe that competitive products are more likely to be 
successfully developed or can be commercialized under terms that are more economically attractive than ours;
•
product candidates developed in collaboration with us may be viewed by our collaborators as competitive with 
their own product candidates or products, which may cause collaborators to cease to devote resources to the 
commercialization of our product candidates;
•
a collaborator with marketing and distribution rights to one or more of our product candidates that achieve 
regulatory approval may not commit sufficient resources to the marketing and distribution of any such product 
candidate;
•
disagreements with collaborators, including disagreements over proprietary rights, contract interpretation or the 
preferred course of development of any product candidates, may cause delays or termination of the research, 
development or commercialization of such product candidates, may lead to additional responsibilities for us with 
respect to such product candidates or may result in litigation or arbitration, any of which would be time-
consuming and expensive;
•
collaborators may not properly maintain or defend our intellectual property rights or may use our proprietary 
information in such a way as to invite litigation that could jeopardize or invalidate our intellectual property or 
proprietary information or expose us to potential litigation;
•
disputes may arise with respect to the ownership of intellectual property developed pursuant to our 
collaborations;
•
collaborators may infringe the intellectual property rights of third parties, which may expose us to litigation and 
potential liability; and
•
collaborations may be terminated for the convenience of the collaborator and, if terminated, we could be required 
to raise additional capital to pursue further development or commercialization of the applicable product 
candidates.
If our collaborations do not result in the successful development and commercialization of products or if one of our 
collaborators terminates its agreement with us, we may not receive any future research funding or milestone or royalty 
payments under such collaborations. If we do not receive the funding we expect under these agreements, our development of 
product candidates could be delayed, and we may need additional resources to develop our product candidates. In addition, if 
one of our collaborators terminates its agreement with us, we may find it more difficult to attract new collaborators and the 
perception of us in the business and financial communities could be adversely affected. 
We may in the future decide to collaborate with other pharmaceutical and biotechnology companies for the development and 
potential commercialization of product candidates. These relationships, or those like them, may require us to incur non-
recurring and other charges, increase our near- and long-term expenditures, issue securities that dilute our existing 
shareholders or disrupt our management and business. In addition, we could face significant competition in seeking 
appropriate collaborators and the negotiation process will likely be time-consuming and complex. Our ability to reach a 
definitive collaboration agreement in such instances will depend, among other things, upon our assessment of the 
collaborator’s resources and expertise, the terms and conditions of the proposed collaboration and the proposed collaborator’s 
evaluation of several factors. If we license rights to additional product candidates, we may not be able to realize the benefit of 
such transactions if we are unable to successfully integrate them with our existing operations and company culture.
We utilize, and expect to continue to utilize, third parties to conduct some or all aspects of our vector production and 
product manufacturing for the foreseeable future, and these third parties may not perform satisfactorily. 
We are not able to independently manufacture material for our planned clinical programs or our commercial supply of 
Libmeldy or any other product for which we obtain marketing approval, if any, and we do not expect to be able to in the 
foreseeable future. We currently rely on our CDMOs and in some cases academic partners for the production of our viral 
vectors and product candidates for our ongoing registrational and clinical trials and pre-clinical studies. For future clinical 

62
trials and for Libmeldy and other products for which we obtain marketing approval, if any, we intend to utilize materials 
manufactured by CDMOs. If our academic partners or these CDMOs do not successfully carry out their contractual duties, 
meet expected deadlines or manufacture our viral vector and product candidates in accordance with regulatory requirements 
or if there are disagreements between us and our academic partners or these CDMOs, we will not be able to complete, or may 
be delayed in completing, the pre-clinical studies and clinical trials required to support approval of our product candidates or 
the FDA, EMA or other regulatory agencies may refuse to accept our clinical or pre-clinical data. In such instances, we may 
need to enter into an appropriate third-party relationship, which may not be readily available or available on acceptable terms. 
This could cause additional delay or increased expense prior to the approval of our product candidates and could have a 
negative impact on our business, financial condition, results of operations and prospects.
We partner with CDMOs and intend to utilize viral vectors and gene therapy products manufactured by CDMOs for our 
future clinical trials and products for which we obtain marketing approval. In some cases, we may need to perform clinical or 
analytical or other animal or cell-based testing to demonstrate that materials produced by these CDMOs, or any other third-
party manufacturer that we engage, is comparable to the material produced by our academic partners and utilized in our 
registrational and clinical trials of our product candidates. There is no assurance that these CDMOs, or any other future third-
party manufacturer that we engage, will be successful in producing any or all of our viral vector or product candidates, that 
any such product will, if required, pass the required comparability testing, or that any materials produced by these CDMOs or 
any other third-party manufacturer that we engage will have the same effect in patients that we have observed to date with 
respect to materials produced by our academic partners. We believe that our manufacturing network will have sufficient 
capacity to meet demand for our clinical and existing and expected initial commercial needs, but there is a risk that if supplies 
are interrupted or result in poor yield or quality, it would materially harm our business. Additionally, if the gene therapy 
industry were to grow, we may encounter increasing competition for the raw materials and consumables necessary to produce 
our product candidates. Furthermore, demand for CDMO cGMP manufacturing capabilities may grow at a faster rate than 
existing manufacturing capacity, which could disrupt our ability to find and retain third-party manufacturers capable of 
producing sufficient quantities of our viral vectors or product candidates for future clinical trials or to meet expected initial 
commercial demand.
Under certain circumstances, our current CDMOs may terminate their engagements with us. If we need to enter into 
alternative arrangements, it could delay our development activities. Our reliance on our CDMOs for certain manufacturing 
activities will reduce our control over these activities but will not relieve us of our responsibility to ensure compliance with 
all required regulations.
In addition to our current CDMOs, we may rely on additional third parties to manufacture our viral vectors or drug products 
in the future and to perform quality testing. Reliance on these third parties entails risks that we would not be subject to if we 
manufactured the product candidates ourselves, including:
•
reduced control for certain aspects of manufacturing activities;
•
termination or non-renewal of manufacturing and service agreements with third parties in a manner or at a time 
that is costly or damaging to us; and
•
disruptions to the operations of our third-party manufacturers and service providers caused by conditions 
unrelated to our business or operations, including the bankruptcy of the manufacturer or service provider or 
future pandemics or disruptions.
Any of these events could lead to clinical trial delays, failure to obtain regulatory approval or impact our ability to 
successfully commercialize any of our product candidates. Some of these events could be the basis for FDA, EMA or other 
regulatory authority action, including injunction, recall, seizure or total or partial suspension of product manufacture.
We rely on third parties, including independent clinical investigators and CROs, to conduct and sponsor some of the 
clinical trials of our product candidates. Any failure by a third party to meet its obligations with respect to the clinical 
development of our product candidates may delay or impair our ability to obtain regulatory approval for our product 
candidates.
We have relied upon and plan to continue to rely upon third parties, including independent clinical investigators and third-
party CROs, to conduct our pre-clinical studies and clinical trials, including in some instances sponsoring such clinical trials, 
and to monitor and manage data for our ongoing pre-clinical and clinical programs. While we will have agreements 
governing the activities of our academic partners and CROs, we will control only certain aspects of their activities and have 
limited influence over their actual performance.
Nevertheless, we are responsible for ensuring that each of our pre-clinical studies and clinical trials is conducted in 
accordance with the applicable protocol and legal, regulatory and scientific standards, and our reliance on these third parties 
does not relieve us of our regulatory responsibilities. We and our third-party contractors and CROs are required to comply 

63
with GLP and GCP requirements, which are regulations and guidelines enforced by the FDA, the Competent Authorities of 
the Member States of the EEA, and comparable foreign regulatory authorities for all of our products in clinical development. 
Regulatory authorities enforce these GCP requirements through periodic inspections of trial sponsors, principal investigators 
and trial sites. The FDA, EMA or comparable foreign regulatory authorities may deem the clinical data generated in our 
clinical trials unreliable and may require us to perform additional clinical trials before approving our marketing applications 
if, among other things, we fail to exercise adequate oversight over any of our academic partners or CROs or if our academic 
partners or CROs do not successfully carry out their respective contractual duties or obligations, fail to meet expected 
deadlines or if the quality or accuracy of the clinical data they obtain is compromised due to the failure to adhere to our 
clinical protocols or regulatory requirements. We cannot assure that upon a regulatory inspection of us, our academic partners 
or our CROs or other third parties performing services in connection with our clinical trials, such regulatory authority will 
determine that any of our clinical trials complies with GCP regulations. In addition, our clinical trials must be conducted with 
product produced under applicable cGMP regulations. Our failure to comply with these regulations may require us to repeat 
clinical trials, which would delay the regulatory approval process. As a result, our financial results and the commercial 
prospects for our product candidates would be harmed, our costs could increase, and our ability to generate revenue could be 
delayed.
We do not control the design or conduct of the academic-sponsored trials, and it is possible that the FDA or EMA will not 
view these academic-sponsored trials as providing adequate support for future clinical trials or market approval, whether 
controlled by us or third parties, for any one or more reasons, including elements of the design or execution of the trials or 
safety concerns or other trial results. Such arrangements provide us certain information rights with respect to the academic-
sponsored trials, including access to and the ability to use and reference the data, including for our own regulatory 
submissions, resulting from the academic-sponsored trials. However, we do not have control over the timing and reporting of 
the data from academic-sponsored trials, nor do we own the data from the academic-sponsored trials. If we are unable to 
confirm or replicate the results from the academic-sponsored trials or if negative results are obtained, we would likely be 
further delayed or prevented from advancing further clinical development of OTL-201 for MPS-IIIA, OTL-203 for MPS-IH 
or any other product candidate investigated in an academic-sponsored clinical trial. Further, if investigators or institutions 
breach their obligations with respect to the clinical development of our product candidates or if the data proves to be 
inadequate compared to the first-hand knowledge we might have gained had the academic-sponsored trials been sponsored 
and conducted by us, then our ability to design and conduct any future clinical trials ourselves may be adversely affected.
Additionally, the FDA or EMA may disagree with the sufficiency of our right of reference to the pre-clinical, manufacturing 
or clinical data generated by these academic-sponsored trials or our interpretation of pre-clinical, manufacturing or clinical 
data from these academic-sponsored trials. If so, the FDA or EMA may require us to obtain and submit additional pre-
clinical, manufacturing or clinical data.
We and our contract manufacturers are subject to significant regulation with respect to manufacturing our viral vectors 
and drug products. The manufacturing facilities on which we rely may not continue to meet regulatory requirements and 
have limited capacity.
We currently have relationships with a limited number of suppliers for the manufacturing of our viral vectors and drug 
products. Each supplier may require licenses to manufacture such components if such processes are not owned by the 
supplier or in the public domain, and we may be unable to transfer or sublicense the intellectual property rights we may have 
with respect to such activities.
All entities involved in the preparation of therapeutics for clinical trials or commercial sale, including our existing CDMOs 
for our viral vectors and drug product, are subject to extensive regulation. Components of a finished therapeutic product 
approved for commercial sale or used in clinical trials, including in some cases critical raw materials used in the manufacture 
thereof, must be manufactured in accordance with cGMP. Poor control of production processes can lead to the introduction of 
adventitious agents or other contaminants, or to inadvertent changes in the properties or stability of our viral vectors or 
product candidates that may not be detectable in final product testing. We or our CDMOs must supply all necessary 
documentation in support of a BLA or MAA on a timely basis and must adhere to the FDA’s and EMA’s cGMP and other 
applicable regulations that are enforced through facilities inspection programs. Some of our CDMOs have not produced a 
commercially-approved product and have never been inspected by the FDA or other regulatory body. Our quality systems 
and the facilities and quality systems of some or all of our CDMOs must pass a pre-approval inspection for compliance with 
the applicable regulations as a condition of regulatory approval of our product candidates or any of our other potential 
products. In addition, the regulatory authorities may, at any time, audit or inspect a manufacturing facility involved with the 
preparation of our viral vector or drug product or our other potential products or the associated quality systems for 
compliance with the regulations applicable to the activities being conducted.
If any such inspection or audit identifies a failure to comply with applicable regulations or if a violation of our product 
specifications or applicable regulations occurs independent of such an inspection or audit, we or the relevant regulatory 

64
authority may require remedial measures that may be costly or time-consuming for us or a third party to implement and that 
may include the temporary or permanent suspension of a clinical trial or commercial sales or the temporary or permanent 
closure of a facility. Any such remedial measures imposed upon us or third parties with whom we contract could materially 
harm our business.
If we or any of our CDMOs fail to maintain regulatory compliance, the FDA can impose regulatory sanctions including, 
among other things, refusal to approve a pending application for a new product or biologic product, or revocation of a pre-
existing approval. As a result, our business, financial condition and results of operations may be materially harmed.
These factors could cause the delay of clinical trials, regulatory submissions, required approvals of our product candidates or 
commercialization of our commercial products or product candidates, if approved, and cause us to incur higher costs and 
prevent us from commercializing our products successfully. Furthermore, if our suppliers fail to meet contractual 
requirements, and we are unable to secure one or more replacement suppliers capable of production at a substantially 
equivalent cost, our pre-clinical studies and clinical trials may be delayed.
We are dependent on a limited number of suppliers and, in some instances, a sole supplier, for some of our components 
and materials used in our product candidates. 
We currently depend on a limited number of suppliers and, in some instances, a sole supplier, for some of the components 
and equipment necessary for the production of our viral vectors and drug product. We cannot be sure that these suppliers will 
remain in business, or that they will not be purchased by one of our competitors or another company that is not interested in 
continuing to produce these materials for our intended purpose. Our use of a sole or a limited number of suppliers of raw 
materials, components and finished goods exposes us to several risks, including disruptions in supply, price increases, late 
deliveries and an inability to meet customer demand. There are, in general, relatively few alternative sources of supply for 
these components, and, in some cases, no alternatives. These vendors may be unable or unwilling to meet our future demands 
for our clinical trials or commercial sale. Establishing additional or replacement suppliers for these components could take a 
substantial amount of time and it may be difficult to establish replacement suppliers who meet regulatory requirements. Any 
disruption in supply from any supplier or manufacturing location could lead to supply delays or interruptions which would 
damage our business, financial condition, results of operations and prospects.
If we are required to switch to a replacement supplier, the manufacture and delivery of our viral vectors and product 
candidates could be interrupted for an extended period, adversely affecting our business. Establishing additional or 
replacement suppliers may not be accomplished quickly. If we are able to find a replacement supplier, the replacement 
supplier would need to be qualified and may require additional regulatory authority approval, which could result in further 
delay. For example, the FDA or EMA could require additional supplemental data, manufacturing data and comparability data 
up to and including clinical trial data if we rely upon a new supplier. While we seek to maintain adequate inventory of the 
components and materials used in our product candidates, any interruption or delay in the supply of components or materials, 
or our inability to obtain components or materials from alternate sources at acceptable prices in a timely manner, could 
impair our ability to conduct our clinical trials and, if our product candidates are approved, to meet the demand of our 
customers and cause them to cancel orders.
In addition, as part of the FDA’s approval of our product candidates, the FDA must review and approve the individual 
components of our production process, which includes raw materials, the manufacturing processes and facilities of our 
suppliers. Some of our current suppliers have not undergone this process nor have they had any components included in any 
product approved by the FDA.
Our reliance on these suppliers subjects us to a number of risks that could harm our reputation, business, and financial 
condition, including, among other things:
•
the interruption of supply resulting from modifications to or discontinuation of a supplier’s operations;
•
delays in product shipments resulting from uncorrected defects, reliability issues, or a supplier’s variation in a 
component;
•
a lack of long-term supply arrangements for key components with our suppliers;
•
the inability to obtain adequate supply in a timely manner, or to obtain adequate supply on commercially 
reasonable terms;
•
difficulty and cost associated with locating and qualifying alternative suppliers for our components in a timely 
manner;
•
production delays related to the evaluation and testing of products from alternative suppliers, and corresponding 
regulatory qualifications;

65
•
a delay in delivery due to our suppliers prioritizing other customer orders over ours;
•
damage to our reputation caused by defective components produced by our suppliers;
•
increased cost of our warranty program due to product repair or replacement based upon defects in components 
produced by our suppliers; 
•
interruptions, shortages, delivery delays and potential discontinuation of supply as a result of the ongoing 
COVID-19 global pandemic, or any recurrence of the pandemic or future pandemics; and
•
fluctuation in delivery by our suppliers due to changes in demand from us or their other customers.
If any of these risks materialize, costs could significantly increase and our ability to conduct our clinical trials and, if our 
product candidates are approved, to meet demand for our products could be impacted.
Our reliance on third parties requires us to share our trade secrets, which increases the possibility that a competitor will 
discover them or that our trade secrets will be misappropriated or disclosed.
Because we currently rely on third parties to manufacture our vectors and our commercial products and product candidates, 
and because we collaborate with various organizations and academic institutions on the advancement of our gene therapy 
approach, we must, at times, share trade secrets with such third parties. We seek to protect our proprietary technology in part 
by entering into confidentiality agreements and, if applicable, material transfer agreements, collaborative research 
agreements, consulting agreements or other similar agreements with our collaborators, advisors, employees and consultants 
prior to beginning research or disclosing proprietary information. These agreements typically limit the rights of the third 
parties to use or disclose our confidential information, such as trade secrets.
Despite the contractual provisions employed when working with third parties, the need to share trade secrets and other 
confidential information increases the risk that such trade secrets become known by our competitors, are inadvertently 
incorporated into the technology of others, or are disclosed or used in violation of these agreements. Given that our 
proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade secrets or 
other unauthorized use or disclosure would impair our competitive position and may have a material adverse effect on our 
business.
In addition, these agreements typically restrict the ability of our collaborators, advisors, employees and consultants to publish 
data potentially relating to our trade secrets. Our academic collaborators typically have rights to publish data, provided that 
we are notified in advance and may delay publication for a specified time in order to secure our intellectual property rights 
arising from the collaboration. In other cases, publication rights are controlled exclusively by us, although in some cases we 
may share these rights with other parties. Despite our efforts to protect our trade secrets, our competitors may discover our 
trade secrets, either through breach of these agreements, independent development or publication of information including 
our trade secrets in cases where we do not have proprietary or otherwise protected rights at the time of publication. A 
competitor’s discovery of our trade secrets would impair our competitive position and have an adverse impact on our 
business.
Risks related to commercialization of our product candidates 
 
 
If we are unable to either establish effective sales and marketing capabilities or enter into agreements with third parties 
for such services, we may be unable to generate product revenue. 
We are working to successfully commercialize Libmeldy in Europe, and we intend to commercialize our product candidates, 
if approved, in the United States, Europe and other markets. Given the relative rarity of the indications that we are targeting, 
we are commercializing Libmeldy, and we currently intend to commercialize any product candidates that are approved, 
directly with specialized teams. We currently have a limited marketing and sales team, and we must build and expand our 
commercial infrastructure and capabilities or make arrangements with third parties to perform those services. If we are unable 
to do so, we may be unable to generate sufficient revenue to sustain our business. 
Regardless of whether we establish our own sales and marketing capabilities or enter into third-party arrangements, there are 
risks involved. On the one hand, recruiting and training a commercial organization is both expensive and time consuming, 
and we could face delays in any product launch. If a product launch is delayed or does not occur, we may be unable to recoup 
our investment if we cannot retain or reposition our sales and marketing personnel. There are several factors that could inhibit 
our efforts to commercialize Libmeldy and our product candidates, if approved, on our own. These include, but are not 
limited to:
•
we may be unable to recruit, train and retain adequate numbers of effective sales and marketing personnel;

66
•
our sales personnel may be unable to obtain access to physicians or may be unable to persuade adequate numbers 
of physicians to prescribe Libmeldy and any future products that we may develop;
•
we may face changes or setbacks at treatment centers contracted for the administration of any approved 
treatments;
•
adverse events could occur; 
•
we are unable to offer complementary treatments, which may put us at a competitive disadvantage relative to 
companies with more extensive product lines; and
•
we may experience unforeseen costs and expenses associated with creating an independent sales and marketing 
organization.
 In addition, we will need to commit significant additional management and other resources to maintain and grow our sales 
organization. We may not be able to achieve the necessary development and growth in a cost-effective manner or realize a 
positive return on our investment. 
On the other hand, there are risks with entering into third party arrangements for the performance of sales, marketing and 
distribution services. These include, but are not limited to:
•
our product revenue or the profitability to us from these revenue streams may be lower than if we were to 
perform these services ourselves;
•
we may be unable to enter into suitable third-party arrangements or we may only be able to do so on unfavorable 
terms, particularly given that we face competition in any search for third-party assistance; and
•
we will likely have limited control over third parties, and they may fail to devote the necessary resources and 
attention to market and sell our products or product candidates, if approved, effectively. 
If we do not establish sales and marketing capabilities successfully, either on our own or in collaboration with third parties, 
we may be unable to generate product revenue.
We face significant competition in our industry and there can be no assurance that our commercial products or our 
product candidates, if approved, will achieve acceptance in the market over existing established therapies. In addition, our 
competitors may develop therapies that are more advanced or effective than ours, which may adversely affect our ability to 
successfully market or commercialize any of our product candidates.
We operate in a highly competitive segment of the biopharmaceutical market. We face competition from many different 
sources, including larger pharmaceutical, specialty pharmaceutical and biotechnology companies, as well as from academic 
institutions, government agencies and private and public research institutions. Our product candidates, if successfully 
developed and approved, will compete with established therapies, some of which are being marketed by large and 
international companies. In addition, we expect to compete with new treatments that are under development or may be 
advanced into the clinic by our competitors. There are a variety of product candidates, including gene therapies, in 
development for the indications that we are targeting, including new areas that we may target as part of our strategic 
initiatives.
We rely primarily on know-how and trade secret protection for aspects of our proprietary technologies, Libmeldy and our 
product candidates. This means that barriers to entry that typically apply in the case of pharmaceutical and biopharmaceutical 
companies with issued patents covering aspects of their proprietary technologies, products and product candidates, such as 
composition of matter claims, will generally not apply to our commercial products or our product candidates, and this may 
expose us to competition from other biopharmaceutical companies, particularly those companies that possess greater 
financial resources and more mature product candidate development, manufacturing, marketing and distribution resources 
than we do. Although our product candidates, if approved, may be eligible for marketing and data exclusivities in, for 
example, the United States and Europe, these exclusivities would not prevent another biopharmaceutical company from 
conducting its own clinical trials to develop and seek regulatory approval of a competitive product. We are not the only 
company that is developing and commercializing products using a lentiviral-based autologous ex vivo gene therapy approach, 
and these competitive approaches may be comparable or superior to our approach. One or more of these companies may seek 
to develop products that compete directly with our commercial products or one or more of our product candidates, the result 
of which could have a material adverse effect on our business. In addition, many universities and private and public research 
institutes are active in our target disease areas.
Many of our competitors have significantly greater financial, product candidate development, manufacturing and marketing 
resources than we do. Large pharmaceutical and biotechnology companies have extensive experience in clinical testing and 
obtaining regulatory approval for their products, and mergers and acquisitions within these industries may result in even more 

67
resources being concentrated among a smaller number of larger competitors. Established pharmaceutical companies may also 
invest heavily to accelerate discovery and development of novel therapeutics or to in-license novel therapeutics that could 
make the product candidates that we develop obsolete. Competition may increase further as a result of advances in the 
commercial applicability of technologies and greater availability of capital for investment in these industries. Our business 
would be materially and adversely affected if competitors develop and commercialize products that are safer, more effective, 
have fewer or less severe side effects, have broader market acceptance, are more convenient or are less expensive than any 
product candidate that we may develop.
Even if we obtain regulatory approval of our product candidates, the availability and price of our competitors’ products could 
limit the demand and the price we are able to charge for our product candidates. We may not be able to implement our 
business plan if the acceptance of our product candidates is inhibited by price competition or the reluctance of physicians to 
switch from existing methods of treatment to our product candidates, or if physicians switch to other new drug or biologic 
products or choose to reserve our product candidates for use in limited circumstances.
If the size and value of the market opportunities for our commercial products or product candidates are smaller than our 
estimates, or if we have difficulty in finding patients that meet eligibility requirements for Libmeldy or any of our product 
candidates, if approved, our product revenue may be adversely affected and our business may suffer. 
We focus our research and product development on treatments for immunological disorders and inherited neurometabolic and 
neurodegenerative genetic disorders. We base our market opportunity estimates on a variety of factors, including our 
estimates of the number of people who have these diseases, the potential scope of our approved product labels, the subset of 
people with these diseases who have the potential to benefit from treatment with our product candidates, various pricing 
scenarios, and our understanding of reimbursement policies for rare diseases in particular countries. These estimates are 
based on many assumptions and may prove to be incorrect, and new studies may reduce the estimated incidence or 
prevalence of these diseases. Estimating market opportunities can be particularly challenging for ultra-rare indications, such 
as the ones we currently address, as epidemiological data is often more limited than for more prevalent indications and can 
require additional assumptions to assess potential patient populations. For example, as we advance our product candidates 
towards commercialization, learn more about market dynamics and engage with regulators on potential marketing approvals, 
our view of the initial potential market opportunity for our products will become more refined. In some cases, the approved 
label may initially be directed to a narrower patient population with the opportunity to expand the label upon submission of 
additional clinical data. For example, in the case of Libmeldy, we are initially focused primarily on annual incidence of the 
disease. This means the initial market opportunity for Libmeldy may be smaller than the total addressable market opportunity 
that could be achieved over time. If we are unable to advance product candidates with attractive market opportunities, our 
future product revenue may be smaller than anticipated and our business may suffer. Patient identification efforts also 
influence the ability to address a patient population. If efforts in patient identification are unsuccessful or less impactful than 
anticipated, for instance, because of a lack of newborn screening or diagnostic initiatives, inadequate disease awareness 
among healthcare providers, or otherwise, we may not address the entirety of the opportunity we are seeking. As a result, 
patients may be difficult to identify and access, the addressable patient population in the United States, Europe and elsewhere 
may turn out to be lower than expected, or patients may not be otherwise amenable to treatment with our products, all of 
which would adversely affect our business, financial condition, results of operations and prospects. 
The commercial success of any current or future product candidate will depend upon the degree of market acceptance by 
physicians, patients, payors and others in the medical community.
Even if we obtain regulatory approval for our product candidates, the commercial success of our product candidates will 
depend in part on the medical community, patients, and payors accepting gene therapy products in general, and our product 
candidates in particular, as effective, safe and cost-effective. Any product that we bring to the market may not gain market 
acceptance by physicians, patients, payors and others in the medical community. The degree of market acceptance of these 
product candidates, if approved for commercial sale, will depend on a number of factors, including:
•
the potential efficacy and potential advantages over alternative treatments;
•
the frequency and severity of any side effects, including any limitations or warnings contained in a product’s 
approved labeling;
•
the frequency and severity of any side effects resulting from the conditioning regimen or follow-up requirements 
for the administration of our product candidates;
•
the relative convenience and ease of administration;
•
the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies;

68
•
the strength of marketing and distribution support and timing of market introduction of competitive products;
•
publicity concerning our products or competing products and treatments; and
•
sufficient third-party insurance coverage or reimbursement.
Even if a product candidate displays a favorable efficacy and safety profile in pre-clinical studies and clinical trials, market 
acceptance of the product, if approved for commercial sale, will not be known until after it is launched. Our efforts to educate 
the medical community and payors on the benefits of our product candidates may require significant resources and may never 
be successful. Such efforts to educate the marketplace may require more resources than are required by the conventional 
technologies marketed by our competitors. If these products do not achieve an adequate level of acceptance, we may not 
generate significant product revenue and may not become profitable.
The insurance coverage and reimbursement status of newly-approved products is uncertain. Failure to obtain or maintain 
adequate coverage and reimbursement for any of our product candidates, if approved, could limit our ability to market 
those products and decrease our ability to generate revenue.
We expect the cost of a single administration of gene therapy products, such as those we are developing, to be substantial, 
when and if they achieve market approval. In the United States and markets in other countries, patients generally rely on 
third-party payors to reimburse all or part of the costs associated with their treatment. The availability and extent of 
reimbursement by governmental and private payors is essential for most patients to be able to afford expensive treatments, 
such as stem cell transplants. Sales of our product candidates will depend substantially, both domestically and abroad, on the 
extent to which the costs of our product candidates will be covered and paid by health maintenance, managed care, pharmacy 
benefit and similar healthcare management organizations, or reimbursed by government health administration authorities, 
private health coverage insurers and other payors. If coverage and adequate reimbursement are not available, or are available 
only to limited levels, we may not be able to successfully commercialize our product candidates. Even if coverage is 
provided, the approved reimbursement amount may not be high enough to allow us to establish or maintain pricing sufficient 
to realize a sufficient return on our investment. 
We may not be able to provide data sufficient to gain acceptance with respect to coverage and reimbursement. If 
reimbursement is not available, or is available only at limited levels, we may not be able to successfully commercialize our 
product candidates, if approved. The process for determining whether a payor will provide coverage for a product may be 
separate from the process for setting the reimbursement rate that the payor will pay for the product. Payors may limit 
coverage to specific products on an approved list, or formulary, which might not include all of the FDA-approved products 
for a particular indication. A decision by a payor not to cover our gene therapies could reduce physician utilization of our 
products once approved and have a material adverse effect on our sales, results of operations and financial condition. 
There is significant uncertainty related to the insurance coverage and reimbursement of newly approved products. In the 
United States, the principal decisions about coverage and reimbursement for new medicines are typically made by the 
Centers for Medicare & Medicaid Services, or CMS, an agency within the U.S. Department of Health and Human Services, 
or HHS. CMS decides whether and to what extent a new medicine will be covered and reimbursed under Medicare. Private 
payors tend to follow the CMS to a substantial degree. It is difficult to predict what the CMS will decide with respect to 
reimbursement for fundamentally novel products such as ours, as there is no body of established practices and precedents for 
these new products. Factors payors consider in determining reimbursement are based on whether the product is:
•
a covered benefit under its health plan; 
•
safe, effective and medically necessary; 
•
appropriate for the specific patient; 
•
cost-effective; and 
•
neither experimental nor investigational.
Outside the United States, certain countries, including a number of member states of the European Union, set prices and 
reimbursement for pharmaceutical products, or medicinal products, as they are commonly referred to in the European Union, 
with limited participation from the marketing authorization holders. We cannot be sure that such prices and reimbursement 
will be acceptable to us or our collaborators. If the regulatory authorities in these jurisdictions set prices or reimbursement 
levels that are not commercially attractive for us or our collaborators, our revenue from sales by us or our collaborators, and 
the potential profitability of our drug products, in those countries would be negatively affected. Some countries may also 
require the completion of clinical trials that compare the cost effectiveness of a particular product candidate to currently 
available therapies. An increasing number of countries are taking initiatives to attempt to reduce large budget deficits by 
focusing cost-cutting efforts on pharmaceuticals for their state-run health care systems. These international price control 

69
efforts have impacted all regions of the world, but have been most drastic in the European Union. Additionally, some 
countries require approval of the sale price of a product before it can be marketed. In many countries, the pricing review 
period begins after marketing or product licensing approval is granted. As a result, we might obtain marketing approval for a 
product in a particular country, but then may experience delays in the reimbursement approval of our product or be subject to 
price regulations that would delay our commercial launch of the product, possibly for lengthy time periods, which could 
negatively impact the revenue we are able to generate from the sale of the product in that particular country. There can be no 
assurance that any country that has price controls or reimbursement limitations for pharmaceutical products will allow 
favorable reimbursement and pricing arrangements for any of our product candidates. Historically, products launched in the 
European Union do not follow price structures of the U.S. and generally prices tend to be significantly lower.
Moreover, efforts by governmental and payors, in the United States and abroad, to cap or reduce healthcare costs may cause 
such organizations to limit both coverage and level of reimbursement for new products approved, and, as a result, they may 
not cover or provide adequate payment for our product candidates. We expect to experience pricing pressures in connection 
with the sale of any of our product candidates, due to the trend toward managed healthcare, the increasing influence of health 
maintenance organizations and additional legislative changes. The downward pressure on healthcare costs in general, 
particularly prescription drugs and surgical procedures and other treatments, has become very intense. As a result, 
increasingly high barriers are being erected to the entry of new products.
Due to the novel nature of our technology and the potential for our product candidates to offer therapeutic benefit in a 
single administration, we face uncertainty related to pricing and reimbursement for these product candidates.
We are targeting rare diseases for which the patient populations are relatively small. In addition, treatment with any of our 
product candidates involves only a single administration. As a result, the pricing and reimbursement of our product 
candidates, if approved, must be adequate to support commercial infrastructure. It is possible that commercially available 
products may serve as a reference price that, for various reasons, may be lower than the price we need to obtain for our 
product candidates. If we are unable to obtain adequate levels of reimbursement, our ability to successfully market and sell 
our products, if approved, will be adversely affected. The manner and level at which reimbursement is provided for services 
related to our product candidates (e.g., for administration of our product to patients) is also important. Inadequate 
reimbursement for such services may lead to physician resistance and adversely affect our ability to market or sell our 
product candidates, if approved. 
Risks related to our business operations
Our gene therapy approach utilizes vectors derived from viruses, which may be perceived as unsafe or may result in 
unforeseen adverse events. Negative public opinion and increased regulatory scrutiny of gene therapy and genetic 
research may damage public perception of our product candidates or adversely affect our ability to conduct our business 
or obtain regulatory approvals for our product candidates.
Gene therapy remains a novel technology with only a limited number of gene therapy products approved to date. Public 
perception may be influenced by claims that gene therapy is unsafe, and gene therapy may not gain the acceptance of the 
public or the medical community. Adverse events in other lentiviral gene therapy trials unrelated to our product candidates 
could negatively impact our business. Our success will depend upon physicians specializing in the treatment of those diseases 
that our product candidates target prescribing treatments that involve the use of our product candidates in lieu of, or in 
addition to, existing treatments they are already familiar with and for which greater clinical data may be available. More 
restrictive government regulations or negative public opinion would have a negative effect on our business or financial 
condition and may delay or impair the development and commercialization of our product candidates or demand for any 
products we may develop. Adverse events in our clinical trials, even if not ultimately attributable to our product candidates 
(such as the many adverse events that typically arise from the conditioning process), or adverse events in other lentiviral gene 
therapy trials, and the resulting publicity could result in increased governmental regulation, unfavorable public perception, 
potential regulatory delays in the testing or approval of our potential product candidates, stricter labeling requirements for 
those product candidates that are approved and a decrease in demand for any such product candidates.
Increasing demand for compassionate use of our unapproved therapies could result in losses.
We are developing our autologous ex vivo gene therapies to address rare diseases for which there are currently limited or no 
available therapeutic options. Media attention to individual patients’ expanded access requests has resulted in the introduction 
and passage of legislation at the local and national level referred to as “Right to Try” laws, which are intended to help enable 
patient access to unapproved therapies. Such legislation includes the Trickett Wendler, Frank Mongiello, Jordan McLinn, and 
Matthew Bellina Right to Try Act of 2017, which was signed into law in May 2018. New and emerging legislation regarding 
expanded access to unapproved drugs for life-threatening illnesses could negatively impact our business in the future.

70
A possible consequence of both activism and legislation in this area is the need for us to initiate an unanticipated expanded 
access program or to make our product candidates more widely available sooner than anticipated. We have limited resources 
and unanticipated trials or access programs could result in diversion of resources from our primary goals.
In addition, patients who receive access to unapproved drugs through compassionate use or expanded access programs have 
life-threatening illnesses and have exhausted all other available therapies. The risk for SAEs in this patient population is high, 
which could have a negative impact on the safety profile of our product candidates. This could cause significant delays or an 
inability to successfully commercialize our product candidates, which could materially harm our business.
We may be unable to effectively manage our programs.
In some instances we may decide to discontinue our investment in programs after we’ve invested time and capital into such 
programs. For example, in May 2020, we announced a reduction of the investment in and scope of OTL-101 for ADA-SCID 
and OTL-300 for TDT, and we have since returned licenses for both programs to the licensor. Additionally, in March 2022, 
we announced that we would discontinue our investment in and seek alternatives for Strimvelis, OTL-103 for treatment of 
WAS and OTL-102 for treatment of X-CGD. We may in the future decide to discontinue additional programs, and we may 
incur transition and termination costs. In addition, we may in the future decide to expand our operations to different 
territories and indications, including through in-licenses. Managing these expanded operations will pose challenges for us, 
and we cannot assure that we will be successful. 
We face potential product liability.
The use of our product candidates in clinical trials and the sale of Strimvelis and Libmeldy or any products for which we 
obtain marketing approval exposes us to the risk of product liability claims. Product liability claims might be brought against 
us by consumers, healthcare providers, pharmaceutical companies or others selling or otherwise coming into contact with our 
products. If we cannot successfully defend against product liability claims, we could incur substantial liability and costs. In 
addition, regardless of merit or eventual outcome, product liability claims may result in:
•
the impairment of our business reputation;
•
the withdrawal of clinical trial participants;
•
costs due to related litigation;
•
the distraction of management’s attention from our primary business;
•
substantial monetary awards to patients or other claimants;
•
the inability to commercialize our product candidates; and
•
decreased demand for our product candidates, if approved for commercial sale.
We believe our product liability insurance coverage is sufficient in light of our current commercial and clinical programs; 
however, we may not be able to maintain insurance coverage at a reasonable cost or in sufficient amounts to protect us 
against losses due to liability. We intend to expand our insurance coverage as appropriate if and as we commercialize 
additional products, but we may be unable to obtain product liability insurance on commercially reasonable terms or in 
adequate amounts. On occasion, large judgments have been awarded in class action lawsuits based on drugs or medical 
treatments that had unanticipated adverse effects. A successful product liability claim or series of claims brought against us 
could adversely affect our results of operations and business.
Patients with the diseases targeted by certain of our product candidates are often already in severe and advanced stages of 
disease and have both known and unknown significant pre-existing and potentially life- threatening health risks. During the 
course of treatment, patients may suffer adverse events, including death, for reasons that may be related to our product 
candidates. Such events could subject us to costly litigation, require us to pay substantial amounts of money to injured 
patients, delay, negatively impact or end our opportunity to receive or maintain regulatory approval to market our products, 
or require us to suspend or abandon our commercialization efforts. Even in a circumstance in which we do not believe that an 
adverse event is related to our products, the investigation into the circumstance may be time-consuming or inconclusive. 
These investigations may interrupt our sales efforts, delay our regulatory approval process in other countries, or impact and 
limit the type of regulatory approvals our product candidates receive or maintain. As a result of these factors, a product 
liability claim, even if successfully defended, could have a material adverse effect on our business, financial condition or 
results of operations.

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An information security incident, including a cybersecurity breach, could have a negative impact to the Company’s 
business or reputation.
Security incidents have become more prevalent across industries and may occur on our systems or on the systems of our 
third-party service providers. These security incidents may be caused by, or result in, security breaches, computer malware or 
malicious software, ransomware, computer hacking, denial of service attacks, security system control failures in our own 
systems or from service providers we use, email phishing, software vulnerabilities, social engineering, sabotage, drive-by 
downloads and the malfeasance of our or our service providers’ employees, among other things. We have taken measures to 
detect, remediate and prevent future attacks and security threats. However, we may be affected, particularly given that such 
attacks are increasing in volume and sophistication and attack techniques frequently change.
Despite our security measures, our internal computer systems and those of our current and any future collaborators and other 
contractors or consultants are vulnerable to, among other things, damage from computer viruses, unauthorized access, 
ransomware, natural disasters, terrorism, war and telecommunication and electrical failures. Furthermore, the ongoing 
COVID-19 pandemic and the related disruptions to our business and our collaborators’, contractors’ and consultants’ 
businesses may increase the risk of security incidents. If any cyberattack or data breach were to occur in the future and cause 
interruptions in our or our collaborators’, contractors’ or consultants’ operations, it could result in a material disruption of our 
development programs and our business operations, whether due to a loss of our trade secrets or other proprietary 
information or other similar disruptions. For example, the loss of clinical trial data from completed or future clinical trials 
could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. 
To the extent that any disruption or security breach were to result in a loss of, or damage to, our data or applications, or the 
inappropriate disclosure of confidential or proprietary information, we could incur liability, our competitive position could be 
harmed and the further development and commercialization of our product candidates could be delayed.
Our future success depends on our ability to retain key employees, consultants and advisors and to attract, retain and 
motivate qualified personnel.
We are highly dependent on principal members of our executive team and key employees, including our Chief Executive 
Officer and our President & Chief Operating Officer, the loss of whose services may adversely impact the achievement of our 
objectives. While we have entered into employment agreements with each of our executive officers, any of them could leave 
our employment at any time. We do not maintain “key person” insurance policies on the lives of these individuals or the lives 
of any of our other employees. The loss of the services of one or more of our current employees might impede the 
achievement of our research, development and commercialization objectives. 
Recruiting and retaining qualified employees, consultants and advisors for our business, including scientific and technical 
personnel, will also be critical to our success. Competition for skilled personnel, including in gene therapy research and 
vector manufacturing, is intense and the turnover rate can be high. We may not be able to attract and retain personnel on 
acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for individuals with 
similar skill sets. In addition, failure to succeed in pre-clinical or clinical trials may make it more challenging to recruit and 
retain qualified personnel. The inability to recruit or the loss of the services of any key employee or advisor could harm our 
business.
Our employees, principal investigators, consultants and commercial partners may engage in misconduct or other 
improper activities, including non-compliance with regulatory standards and requirements and insider trading.
We are exposed to the risk of fraud or other misconduct by our employees, principal investigators, consultants and 
commercial partners, CROs and CDMOs. It is not always possible to identify and deter misconduct by employees and other 
third parties, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or 
unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a 
failure to comply with these laws or regulations. Misconduct by these parties could include intentional failures to (i) comply 
with the regulations of the FDA, EMA or of other foreign regulatory authorities, (ii) provide accurate information to the 
FDA, EMA and other foreign regulatory authorities, (iii) comply with healthcare fraud and abuse laws and regulations in the 
United States and abroad, (iv) report financial information or data accurately or (v) disclose unauthorized activities to us. In 
particular, sales, marketing and business arrangements in the healthcare industry are subject to extensive laws and regulations 
intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and regulations may 
restrict or prohibit a wide range of pricing, discounting, marketing and promotion, sales commission, customer incentive 
programs and other business arrangements. Such misconduct could also involve the improper use of information obtained in 
the course of clinical trials, which could result in regulatory sanctions and cause serious harm to our reputation. We have 
adopted a code of conduct applicable to all of our employees, but it is not always possible to identify and deter employee 
misconduct, and the precautions we take to detect and prevent this activity may not be effective in controlling unknown or 
unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a 

72
failure to comply with these laws or regulations. If any such actions are instituted against us, and we are not successful in 
defending ourselves or asserting our rights, those actions could have a significant impact on our business, including the 
imposition of significant fines or other sanctions such as criminal and administrative penalties, damages, imprisonment, 
possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, additional reporting 
requirements and oversight if we become subject to a corporate integrity agreement or similar agreement to resolve 
allegations of noncompliance with these laws, contractual damages, reputational harm, diminished profits and future 
earnings, and curtailment of our operations.
Healthcare legislative reform measures and constraints on national budget social security systems may have a material 
adverse effect on our business and results of operations.
Successful commercialization of our products depends, in part, on the availability of reimbursement for such products in the 
markets where we sell our products. Governmental health authorities, private health insurers and other organizations are 
focused on controlling healthcare costs, and these methods are not always specifically adapted for new technologies, such as 
gene therapy and therapies addressing rare diseases. Legislative and regulatory action affecting reimbursement could impact 
our ability to sell our products profitably. 
There have been, and likely will continue to be, legislative and regulatory proposals at the foreign, federal and state levels 
directed at broadening the availability of healthcare and containing or lowering the cost of healthcare. We cannot predict the 
initiatives that may be adopted in the future. The continuing efforts of the government, insurance companies, managed care 
organizations and other payors of healthcare services to contain or reduce costs of healthcare or impose price controls may 
adversely affect:
•
the demand for our products, if approved;
•
our ability to set a sufficient price;
•
our ability to generate revenue and achieve or maintain profitability; and
•
the level of taxes that we are required to pay.
Any denial in coverage or reduction in reimbursement from Medicare or other government programs may result in a similar 
denial or reduction in payments from private payors, which may adversely affect our future profitability.
We are subject to the UK Bribery Act 2010, or the Bribery Act, the U.S. Foreign Corrupt Practices Act of 1977, as 
amended, or the FCPA, and other anti-corruption laws, as well as export control laws, import and customs laws, trade and 
economic sanctions laws and other laws governing our operations.
Our operations are subject to anti-corruption laws, including the Bribery Act, the FCPA, the U.S. domestic bribery statute 
contained in 18 U.S.C. §201, the U.S. Travel Act, and other anti-corruption laws that apply in countries where we do 
business. The Bribery Act, the FCPA and these other laws generally prohibit us and our employees and intermediaries from 
authorizing, promising, offering, or providing, directly or indirectly, improper or prohibited payments, or anything else of 
value, to government officials or other persons to obtain or retain business or gain some other business advantage. Under the 
Bribery Act, we may also be liable for failing to prevent a person associated with us from committing a bribery offense. We 
and our commercial partners operate in a number of jurisdictions that pose a high risk of potential Bribery Act or FCPA 
violations, and we participate in collaborations and relationships with third parties whose corrupt or illegal activities could 
potentially subject us to liability under the Bribery Act, FCPA or local anti-corruption laws, even if we do not explicitly 
authorize or have actual knowledge of such activities. In addition, we cannot predict the nature, scope or effect of future 
regulatory requirements to which our international operations might be subject or the manner in which existing laws might be 
administered or interpreted.
We are also subject to other laws and regulations governing our international operations, including regulations administered 
by the governments of the United Kingdom and the United States, and authorities in the European Union, including 
applicable export control regulations, economic sanctions and embargoes on certain countries and persons, anti-money 
laundering laws, import and customs requirements and currency exchange regulations, collectively referred to as the Trade 
Control laws.
There is no assurance that we will be completely effective in ensuring our compliance with all applicable anti-corruption 
laws, including the Bribery Act, the FCPA or other legal requirements, including Trade Control laws. If we are not in 
compliance with the Bribery Act, the FCPA and other anti-corruption laws or Trade Control laws, we may be subject to 
criminal and civil penalties, disgorgement and other sanctions and remedial measures, and legal expenses, which could have 
an adverse impact on our business, financial condition, results of operations and liquidity. Likewise, any investigation of any 
potential violations of the Bribery Act, the FCPA, other anti-corruption laws or Trade Control laws by United Kingdom, 

73
United States or other authorities could also have an adverse impact on our reputation, our business, results of operations and 
financial condition.
We may be subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws health 
information privacy and security laws, and other health care laws and regulations. If we are unable to comply, or have not 
fully complied, with such laws, we could face substantial penalties.
If we obtain FDA approval for any of our product candidates and begin commercializing those products in the United States, 
our operations will be directly, or indirectly through our prescribers, customers and purchasers, subject to various federal and 
state fraud and abuse laws and regulations, including, without limitation, the federal Health Care Program Anti-Kickback 
Statute, the federal civil and criminal False Claims Act and Physician Payments Sunshine Act and regulations. These laws 
will impact, among other things, our proposed sales, marketing and educational programs. In addition, we may be subject to 
patient privacy laws by both the federal government and the states in which we conduct our business. The laws that will 
affect our operations include, but are not limited to, the below:
•
The federal Anti-Kickback Statute, which prohibits, among other things, persons or entities from knowingly and 
willfully soliciting, receiving, offering or paying any remuneration (including any kickback, bribe or rebate), 
directly or indirectly, overtly or covertly, in cash or in kind, to induce, or in return for, the purchase, lease, order, 
arrangement, or recommendation of any good, facility, item or service for which payment may be made, in whole 
or in part, under a federal healthcare program, such as the Medicare and Medicaid programs. A person or entity 
does not need to have actual knowledge of the federal Anti-Kickback Statute or specific intent to violate it to 
have committed a violation. Violations are subject to civil and criminal fines and penalties for each violation, 
plus up to three times the remuneration involved, imprisonment, and exclusion from government healthcare 
programs. In addition, the government may assert that a claim including items or services resulting from a 
violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the federal 
False Claims Act or federal civil money penalties.
•
The federal civil and criminal false claims laws and civil monetary penalty laws, such as the federal False Claims 
Act, which impose criminal and civil penalties and authorize civil whistle blower or qui tam actions, against 
individuals or entities for, among other things: knowingly presenting, or causing to be presented, to the federal 
government, claims for payment that are false or fraudulent; knowingly making, using or causing to be made or 
used, a false statement of record material to a false or fraudulent claim or obligation to pay or transmit money or 
property to the federal government or knowingly concealing or knowingly and improperly avoiding or decreasing 
an obligation to pay money to the federal government. Manufacturers can be held liable under the federal False 
Claims Act even when they do not submit claims directly to government payors if they are deemed to “cause” the 
submission of false or fraudulent claims. The federal False Claims Act also permits a private individual acting as 
a “whistle blower” to bring actions on behalf of the federal government alleging violations of the federal False 
Claims Act and to share in any monetary recovery.
•
The anti-inducement law, which prohibits, among other things, the offering or giving of remuneration, which 
includes, without limitation, any transfer of items or services for free or for less than fair market value (with 
limited exceptions), to a Medicare or Medicaid beneficiary that the person knows or should know is likely to 
influence the beneficiary’s selection of a particular supplier of items or services reimbursable by a federal or state 
governmental program.
•
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created new federal 
criminal statutes that prohibit a person from knowingly and willfully executing, or attempting to execute, a 
scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, 
representations or promises, any of the money or property owned by, or under the custody or control of, any 
healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully 
falsifying, concealing or covering up by any trick or device a material fact or making any materially false, 
fictitious, or fraudulent statements or representations in connection with the delivery of, or payment for, 
healthcare benefits, items or services relating to healthcare matters; similar to the federal Anti-Kickback Statute, 
a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to 
have committed a violation.
•
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or 
HITECH and their respective implementing regulations, including the Final Omnibus Rule published in January 
2013, which impose requirements on certain covered healthcare providers, health plans, and healthcare 
clearinghouses as well as their respective business associates, independent contractors or agents of covered 
entities, that perform services for them that involve the creation, maintenance, receipt, use, or disclosure of, 

74
individually identifiable health information relating to the privacy, security and transmission of individually 
identifiable health information. HITECH also created new tiers of civil monetary penalties, amended HIPAA to 
make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new 
authority to file civil actions for damages or injunctions in federal courts to enforce the federal HIPAA laws and 
seek attorneys’ fees and costs associated with pursuing federal civil actions. In addition, there may be additional 
federal, state and non-U.S. laws which govern the privacy and security of health and other personal information 
in certain circumstances, many of which differ from each other in significant ways and may not have the same 
effect, thus complicating compliance efforts.
•
The U.S. federal transparency requirements under the ACA, including the provision commonly referred to as the 
Physician Payments Sunshine Act, and its implementing regulations, which requires applicable manufacturers of 
drugs, devices, biologics and medical supplies for which payment is available under Medicare, Medicaid or the 
Children’s Health Insurance Program to report annually to CMS, information related to payments or other 
transfers of value made to physicians (defined to include doctors, dentists, optometrists, podiatrists and 
chiropractors) and teaching hospitals, as well as ownership and investment interests held by the physicians 
described above and their immediate family members. Effective January 1, 2022, these reporting obligations 
extend to include transfers of value made to certain non-physician providers such as physician assistants and 
nurse practitioners.
•
The federal government price reporting laws, which require us to calculate and report complex pricing metrics in 
an accurate and timely manner to government programs.
•
The federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and 
activities that potentially harm consumers. 
•
Many states in the United States have enacted laws that regulate the privacy and security of certain types of 
personal information. For example, in California, the California Consumer Protection Act (CCPA), which went 
into effect on January 1, 2020, establishes a new privacy framework for covered businesses by creating an 
expanded definition of personal information, establishing new data privacy rights for consumers in the State of 
California, imposing special rules on the collection of consumer data from minors, and creating a new and 
potentially severe statutory damages framework for violations of the CCPA and for businesses that fail to 
implement reasonable security procedures and practices to prevent data breaches. The CCPA provides for civil 
penalties for violations, as well as a private right of action for data breaches that is expected to increase data 
breach litigation. The CCPA may increase our compliance costs and potential liability. Some observers have 
noted that the CCPA could mark the beginning of a trend toward more stringent privacy legislation in the U.S., 
which could increase our potential liability and adversely affect our business.
•
Additionally, a new California ballot initiative, the California Privacy Rights Act, or “CPRA,” was passed in 
November 2020. The CPRA imposes additional obligations on companies covered by the legislation and will 
significantly modify the CCPA, including by expanding consumers’ rights with respect to certain sensitive 
personal information. The CPRA also creates a new state agency that will be vested with authority to implement 
and enforce the CCPA and the CPRA. The effects of the CCPA and the CPRA are potentially significant and 
may require us to modify our data collection or processing practices and policies and to incur substantial costs 
and expenses in an effort to comply and increase our potential exposure to regulatory enforcement or litigation. 
•
Certain other state laws impose similar privacy obligations, and we also expect anticipate that more states to may 
enact legislation similar to the CCPA, which provides consumers with new privacy rights and increases the 
privacy and security obligations of entities handling certain personal information of such consumers. The CCPA 
has prompted a number of proposals for new federal and state-level privacy legislation. Such proposed 
legislation, if enacted, may add additional complexity, variation in requirements, restrictions and potential legal 
risk, require additional investment of resources in compliance programs, impact strategies and the availability of 
previously useful data and could result in increased compliance costs or changes in business practices and 
policies.
•
Following the UK’s withdrawal from the EU, the EU GDPR was incorporated into UK domestic law. UK-based 
organizations doing business in the EU will need to continue to comply with the EU GDPR and now also the UK 
GDPR. The UK is now regarded as a third country under the EU GDPR, but the European Commission has 
issued a decision recognizing the UK as providing adequate protection under the EU GDPR (“Adequacy 
Decision”). Therefore, transfers of personal data originating in the EU to the UK remain unrestricted. The UK 
Government has also confirmed that transfers of personal data originating in the UK to the EU may continue to 
flow freely. The UK Government has also now introduced a Data Protection and Digital Information Bill (“UK 

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Bill”) into the UK legislative process. The aim of the UK Bill is to reform the UK’s data protection regime 
following Brexit. If passed, the final version of the UK Bill may have the effect of further altering the similarities 
between the UK and EEA data protection regime and threaten the UK Adequacy Decision from the EU 
Commission. This may lead to additional compliance costs and could increase our overall risk. The respective 
provisions and enforcement of the EU GDPR and UK GDPR may further diverge in the future and create 
additional regulatory challenges and uncertainties.
Additionally, we are subject to state and foreign equivalents of each of the healthcare laws and regulations described above, 
among others, some of which may be broader in scope and may apply regardless of the payor. Many U.S. states have adopted 
laws similar to the federal Anti-Kickback Statute and False Claims Act and may apply to our business practices, including, 
but not limited to, research, distribution, sales or marketing arrangements and claims involving healthcare items or services 
reimbursed by non-governmental payors, including private insurers. In addition, some states have passed laws that require 
pharmaceutical companies to comply with the April 2003 Office of Inspector General Compliance Program Guidance for 
Pharmaceutical Manufacturers or the Pharmaceutical Research and Manufacturers of America’s Code on Interactions with 
Healthcare Professionals. Several states also impose other marketing restrictions or require pharmaceutical companies to 
make marketing or price disclosures to the state and require the registration of pharmaceutical sales representatives. State and 
foreign laws, including for example the GDPR also govern the privacy and security of health information in some 
circumstances, many of which differ from each other in significant ways and often are not preempted by HIPAA, thus 
complicating compliance efforts. There are ambiguities as to what is required to comply with these state requirements, and if 
we fail to comply with an applicable state law requirement we could be subject to penalties. Finally, there are state and 
foreign laws governing the privacy and security of health information, many of which differ from each other in significant 
ways and often are not preempted by HIPAA, thus complicating compliance efforts.
In the event we decide to conduct additional clinical trials or continue to enroll subjects in our ongoing or future clinical 
trials, we may be subject to additional privacy restrictions. The collection, use, storage, disclosure, transfer or other 
processing of personal data regarding individuals in the EEA or the UK, including personal health data, is subject to the 
GDPR. The GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data, 
including requirements relating to processing health and other sensitive data, where required obtaining consent of the 
individuals to whom the personal data relates, providing information to individuals regarding data processing activities, 
implementing safeguards to protect the security and confidentiality of personal data, where required providing notification of 
data breaches, and taking certain measures when engaging third-party processors, including concluding data processing 
agreements, where required appointing data protection officers, where required conducting data protection impact 
assessments, and record-keeping. The GDPR also imposes strict rules and restrictions on the transfer of personal data to 
countries outside the EEA or the UK, including the United States (see below), and permits data protection authorities to 
impose large penalties for violations of the GDPR, including potential fines of up to €20.0 million (£17.5 million) or 4% of 
annual global revenue, whichever is greater. The GDPR also confers a private right of action on data subjects and consumer 
associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages 
resulting from violations of the GDPR. The GDPR may increase our responsibility and liability in relation to personal data 
that we process where such processing is subject to the GDPR, and we may be required to put in place additional mechanisms 
to ensure compliance with the GDPR, including as implemented by individual countries. Compliance with the GDPR will be 
a rigorous and time-intensive process that may increase our cost of doing business or require us to change our business 
practices, and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational 
harm in connection with our European activities. 
Significantly, adequate safeguards must be implemented to enable the transfer of personal data outside of the EEA or the UK, 
in particular to the United States, in compliance with the GDPR (for example, the European Commission approved Standard 
Contractual Clauses, or SCCs, and the UK International Data Transfer Agreement/Addendum (“UK IDTA”). Where relying 
on the SCCs /UK IDTA for data transfers, we may also be required to carry out transfer impact assessments to assess whether 
the recipient is subject to local laws which allow public authority access to personal data. The international transfer 
obligations under the EEA and UK data protection regimes will require significant effort and cost, and may result in us 
needing to make strategic considerations around where EEA and UK personal data is transferred and which service providers 
we can utilize for the processing of EEA and UK personal data.  
Because of the breadth of these laws and the narrowness of the statutory exceptions and safe harbors available, it is possible 
that some of our business activities could be subject to challenge and may not comply under one or more of such laws, 
regulations or guidance. Law enforcement authorities are increasingly focused on enforcing fraud and abuse laws, and it is 
possible that some of our practices may be challenged under these laws. Efforts to ensure that our current and future business 
arrangements with third parties, and our business generally, will comply with applicable healthcare laws and regulations will 
involve substantial costs. If our operations, including our arrangements with physicians and other healthcare providers, some 
of whom receive share options as compensation for services provided, are found to be in violation of any of such laws or any 

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other governmental regulations that apply to us, we may be subject to penalties, including, without limitation, administrative, 
civil and criminal penalties, damages, fines, disgorgement, contractual damages, reputational harm, diminished profits and 
future earnings, the curtailment or restructuring of our operations, exclusion from participation in federal and state healthcare 
programs (such as Medicare and Medicaid), and imprisonment, as well as additional reporting obligations and oversight if we 
become subject to a corporate integrity agreement or other agreement to resolve allegations of non-compliance with these 
laws, any of which could adversely affect our ability to operate our business and our financial results.
If we or our CDMOs and CROs fail to comply with environmental, health and safety laws and regulations, we could 
become subject to fines or penalties or incur costs that could have a material adverse effect on the success of our business.
We and third parties such as our CDMOs and CROs are subject to numerous environmental, health and safety laws and 
regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of 
hazardous materials and wastes. Our operations involve the use of hazardous and flammable materials, including chemicals 
and biological materials. Our operations also produce hazardous waste products. We generally contract with third parties for 
the disposal of these materials and wastes. We cannot eliminate the risk of contamination or injury from these materials. In 
the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting 
damages, and any liability could exceed our resources. We also could incur significant costs associated with civil or criminal 
fines and penalties. Furthermore, environmental laws and regulations are complex, change frequently and have tended to 
become more stringent. We cannot predict the impact of such changes and cannot be certain of our future compliance. In 
addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and 
regulations. These current or future laws and regulations may impair our research, development or production efforts. Failure 
to comply with these laws and regulations also may result in substantial fines, penalties or other sanctions.
Although we maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to 
our employees resulting from the use of hazardous materials or other work-related injuries, this insurance may not provide 
adequate coverage against potential liabilities. In addition, we may incur substantial costs in order to comply with current or 
future environmental, health and safety laws and regulations. These current or future laws and regulations may impair our 
research, development or production efforts. Failure to comply with these laws and regulations also may result in substantial 
fines, penalties or other sanctions or liabilities, which could materially adversely affect our business, financial condition, 
results of operations and prospects.
As a company based outside of the United States, our business is subject to economic, political, regulatory and other risks 
associated with international operations.
As a company based partly in the United Kingdom and EU countries, our business is subject to risks associated with 
conducting business outside of the United States. Many of our suppliers and clinical trial relationships are located outside the 
United States. Accordingly, our future results could be harmed by a variety of factors, including:
•
economic weakness, including inflation, or political instability in the United Kingdom and other non-U.S. 
economies and markets;
•
differing and changing regulatory requirements for product approvals;
•
differing jurisdictions could present different issues for securing, maintaining or obtaining freedom to operate in 
such jurisdictions;
•
potentially reduced protection for intellectual property rights;
•
difficulties in compliance with different, complex and changing laws, regulations and court systems of multiple 
jurisdictions and compliance with a wide variety of foreign laws, treaties and regulations;
•
changes in non-U.S. regulations and customs, tariffs and trade barriers;
•
changes in non-U.S. currency exchange rates of the pound sterling, U.S. dollar, euro and currency controls;
•
changes in a specific country’s or region’s political or economic environment, including the implications of the 
recent decision of the eligible members of the UK electorate for the United Kingdom to withdraw from the 
European Union;
•
trade protection measures, import or export licensing requirements or other restrictive actions by governments;
•
differing reimbursement regimes and price controls in certain non-U.S. markets;
•
negative consequences from changes in tax laws or practice;

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•
compliance with tax, employment, immigration and labor laws for employees living or traveling abroad, 
including, for example, the variable tax treatment in different jurisdictions of options granted under our share 
option schemes or equity incentive plans;
•
workforce uncertainty in countries where labor unrest is more common than in the United States;
•
litigation or administrative actions resulting from claims against us by current or former employees or 
consultants individually or as part of class actions, including claims of wrongful terminations, discrimination, 
mis-classification or other violations of labor law or other alleged conduct;
•
difficulties associated with staffing and managing international operations, including differing labor relations;
•
production shortages resulting from any events affecting raw material supply or manufacturing capabilities 
abroad; and
•
business interruptions resulting from geo-political actions, including war and terrorism, or natural disasters 
including earthquakes, typhoons, floods, fires and public health epidemics and pandemics, including the current 
COVID-19 global pandemic.
Risks related to our intellectual property
We may become subject to claims that we are infringing certain third-party patents, for example, patents relating to 
lentiviral vectors, or other third-party intellectual property rights, any of which may prevent or delay our development and 
commercialization efforts and have a material adverse effect on our business.
Our commercial success depends in part on avoiding infringing, misappropriating and otherwise violating the patents and 
other intellectual property and proprietary rights of third parties. There is a substantial amount of litigation, both within and 
outside the United States, involving patent and other intellectual property rights in the biotechnology and pharmaceutical 
industries, including patent infringement lawsuits, and administrative proceedings such as interferences, inter partes review 
and post grant review proceedings before the U.S. Patent and Trademark Office, or USPTO, and opposition proceedings 
before foreign patent offices. Numerous U.S. and foreign issued patents and pending patent applications, which are owned or 
controlled by third parties, including our competitors, exist in the fields in which we are pursuing products and product 
candidates. As the biotechnology and pharmaceutical industries expand and more patents are issued, the risk increases that 
our products and product candidates may be subject to claims of infringement of the patent rights of third parties.
Third parties may assert that we or our licensors are employing their proprietary technology without authorization. There may 
be third party patents or patent applications with claims to materials, formulations, methods of manufacture or methods for 
treatment relating to our products and product candidates and, because patent applications can take many years to issue, there 
may be currently pending third party patent applications which may later result in issued patents, in each case that our 
products and product candidates, their manufacture or use may infringe or be alleged to infringe.
Parties making patent infringement claims against us may obtain injunctive or other equitable relief, which could effectively 
block our ability to further develop and commercialize one or more of our products or product candidates. Defense of these 
claims, including demonstrating non-infringement, invalidity or unenforceability of the respective patent rights in question, 
regardless of their merit, is time-consuming, would involve substantial litigation expense and would be a substantial 
diversion of employee resources from our business. For example, in order to successfully challenge the validity of any U.S. 
patent in federal court, we would need to overcome a presumption of validity. This is a high burden requiring us to present 
clear and convincing evidence as to the invalidity of any such U.S. patent claim, and we can provide no assurance that a court 
of competent jurisdiction would invalidate the claims of any such U.S. patent. We may not have sufficient resources to bring 
these actions to a successful conclusion. There could also be public announcements of the results of hearings, motions or 
other interim proceedings or developments.
In the event that a holder of any such patents seeks to enforce its patent rights against us with respect to one or more of our 
products or product candidates, and our defenses against the infringement of such patent rights are unsuccessful, we may be 
precluded from commercializing such products and product candidates, even if approved, without first obtaining a license to 
some or all of these patents, which may not be available on commercially reasonable terms or at all. Moreover, we may be 
required to pay significant fees and royalties to secure a license to the applicable patents. Such a license may only be non-
exclusive, in which case our ability to stop others from using or commercializing technology and products similar or identical 
to ours may be limited. Furthermore, we could be liable for damages to the holders of these patents, which may be significant 
and could include treble damages if we are found to have willfully infringed such patents. In the event that a challenge to 
these patents were to be unsuccessful or we were to become subject to litigation or unable to obtain a license on 

78
commercially reasonable terms with respect to these patents, it could harm our business, financial condition, results of 
operations and prospects.
We are aware of third-party issued patents and patent applications relating to the lentiviral vectors used in the manufacture or 
use of one or more our product candidates or relating to one or more of our product candidates. If these patent rights were 
enforced against us, we believe that we have defenses against any such action, including that these patents would not be 
infringed by our product candidates or that these patents are not valid. However, if these patents were enforced against us and 
defenses to such enforcement were unsuccessful, unless we obtain a license to these patents, which may not be available on 
commercially reasonable terms, or at all, we could be liable for damages and precluded from commercializing any products 
and product candidates that were ultimately held to infringe these patents, which could have a material adverse effect on our 
business, financial condition, results of operations and prospects.
Even in the absence of a finding of infringement, we may need to obtain licenses from third parties to advance our research or 
allow commercialization of our products and product candidates. We may fail to obtain any of these licenses at a reasonable 
cost or on reasonable terms, or at all. In that event, we would be unable to further develop and commercialize our products 
and product candidates. Claims that we have misappropriated the confidential information or trade secrets of third parties 
could have a similar negative impact on our business. Any of the foregoing could materially adversely affect our business, 
results of operations and financial condition.
In addition, our trade secrets may otherwise become known or be independently discovered by competitors. Competitors and 
other third parties could purchase our products and product candidates and attempt to replicate some or all of the competitive 
advantages we derive from our development efforts, willfully infringe, misappropriate or otherwise violate our intellectual 
property rights, design around our protected technology or develop their own competitive technologies that fall outside of our 
intellectual property rights. If any of our trade secrets were to be lawfully obtained or independently developed by a 
competitor or other third party, we would have no right to prevent them, or those to whom they communicate it, from using 
that technology or information to compete with us. If our trade secrets are not adequately protected or sufficient to provide an 
advantage over our competitors, our competitive position could be adversely affected, as could our business. Additionally, if 
the steps taken to maintain our trade secrets are deemed inadequate, we may have insufficient recourse against third parties 
for misappropriating our trade secrets.
We are highly dependent on intellectual property and data licensed from third parties to develop and commercialize our 
products and product candidates, and our development and commercialization abilities are subject, in part, to the terms 
and conditions of licenses granted to us by such third parties.
We are highly dependent on the intellectual property and data licensed to us by third parties, including technology related to 
the manufacture and use of our products and product candidates. We have in-licensed certain know-how and data from GSK 
and Telethon-OSR relating to Libmeldy, certain know-how and data from Telethon-OSR relating to OTL-203 for MPS-IH, 
and certain other intellectual property for our clinical and pre-clinical programs. Any termination of these license rights could 
result in the loss of significant rights and could harm or prevent our ability to commercialize our products and product 
candidates.
Our in-licensed intellectual property is often limited to particular fields and is often subject to certain retained rights. We may 
not have rights to use in-licensed intellectual property, data or know-how from one program in another program. As a result, 
we may not be free to commercialize certain of our products or product candidates in fields or territories of interest to us. 
Furthermore, if the licenses are not exclusive in territories of interest to us, we may be unable to prevent competitors from 
developing and commercializing competitive products in territories included in our licenses. Licenses (including sublicenses) 
to additional third-party technology that may be required for our development programs may not be available in the future or 
may not be available on commercially reasonable terms, or at all, which could have a material adverse effect on our business.
In some circumstances, we may not have the right to control the preparation, filing and prosecution of patent applications, or 
to maintain the patents, covering technology that we license from third parties. Therefore, we cannot be certain that these 
patents and applications will be prosecuted, maintained and enforced in a manner consistent with the best interests of our 
business. If our licensors fail to maintain such patents, or lose rights to those patents or patent applications, the rights we have 
licensed may be reduced or eliminated and our right to develop and commercialize any of our products and product 
candidates that are the subject of such licensed rights could be adversely affected.
Our current license agreements impose, and we expect that future license agreements that we may enter into will impose, 
various obligations, including diligence and certain payment obligations. If we fail to satisfy our obligations, the particular 
licensor may have the right to terminate such agreements. Disputes may arise between us and any of our licensors regarding 
intellectual property subject to such agreements and other issues. Such disputes over intellectual property that we have 
licensed or the terms of our license agreements may prevent or impair our ability to maintain our current arrangements on 
acceptable terms, or at all, or may impair the value of the arrangement to us. Any such dispute could have a material adverse 

79
effect on our business. If we cannot maintain a necessary license agreement or if the agreement is terminated, we may be 
unable to successfully develop and commercialize the affected products and product candidates. Termination of our license 
agreements or reduction or elimination of our rights under them may result in our having to negotiate a new or reinstated 
agreement, which may not be available to us on equally favorable terms, or at all, which may mean we are unable to develop 
or commercialize the affected product or product candidate or cause us to lose our rights under the agreement. Any of the 
foregoing could have a material adverse effect on our business.
If we are unable to obtain and maintain patent and other intellectual property protection for our products and product 
candidates, or if the scope of the patent and other intellectual property protection obtained is not sufficiently broad, our 
competitors could develop and commercialize products similar or identical to ours, and our ability to successfully 
commercialize our products and product candidates may be adversely affected.
Our ability to compete effectively will depend, in part, on our ability to maintain the proprietary nature of our technology and 
manufacturing processes. We rely on manufacturing and other know-how, patents, trade secrets, license agreements and 
contractual provisions to establish our intellectual property rights and protect our products and product candidates. These 
legal means, however, afford only limited protection and may not adequately protect our rights. We currently do not own any 
patents or patent applications and have not in-licensed any issued patents related to Libmeldy. Many of our products and 
product candidates are in-licensed from third parties. Accordingly, in some cases, the availability and scope of potential 
patent protection is limited based on prior decisions by our licensors or the inventors, such as decisions on when to file patent 
applications or whether to file patent applications at all. Our or our licensors’ failure to obtain, maintain, enforce or defend 
such intellectual property rights, for any reason, could allow third parties, in particular, other established and better-financed 
gene therapy companies having established development, manufacturing and distribution capabilities, to make competing 
products or impact our ability to develop, manufacture and market our products and product candidates, even if approved, on 
a commercially viable basis, if at all, which could have a material adverse effect on our business.
In particular, we rely primarily on trade secrets, know-how and other unpatented technology, which are difficult to protect. 
Although we seek such protection in part by entering into confidentiality agreements with our vendors, employees, 
consultants and others who may have access to proprietary information, we cannot be certain that these agreements will not 
be breached, adequate remedies for any breach would be available, or our trade secrets, know-how and other unpatented 
proprietary technology will not otherwise become known to or be independently developed by our competitors. If we are 
unsuccessful in protecting our intellectual property rights, sales of our products may suffer and our ability to generate 
revenue could be severely impacted.
In certain situations, and as considered appropriate, we and our licensors have sought, and we intend to continue to seek to 
protect our proprietary position by filing patent applications in the United States and, in at least some cases, one or more 
countries outside the United States relating to current and future products and product candidates that are important to our 
business. However, we cannot predict whether the patent applications currently being pursued will issue as patents, whether 
the claims of any resulting patents will provide us with a competitive advantage or prevent competitors from designing 
around our claims to develop competing technologies in a non-infringing manner, or whether we will be able to successfully 
pursue patent applications in the future relating to our current or future products and product candidates. Moreover, the patent 
application and approval process is expensive and time-consuming. We may not be able to file and prosecute all necessary or 
desirable patent applications at a reasonable cost or in a timely manner. Furthermore, we, or any future partners, 
collaborators, or licensees, may fail to identify patentable aspects of inventions made in the course of development and 
commercialization activities before it is too late to obtain patent protection on them. Therefore, we may miss potential 
opportunities to seek additional patent protection.
It is possible that defects of form in the preparation or filing of patent applications may exist, or may arise in the future, for 
example with respect to proper priority claims, inventorship, claim scope, or requests for patent term adjustments. If we fail 
to establish, maintain or protect such patents and other intellectual property rights, such rights may be reduced or eliminated. 
If there are material defects in the form, preparation, prosecution or enforcement of our patents or patent applications, such 
patents may be invalid or unenforceable, and such applications may never result in valid, enforceable patents. Any of these 
outcomes could impair our ability to prevent competition from third parties, which may have an adverse impact on our 
business.
Other parties, many of whom have substantially greater resources and have made significant investments in competing 
technologies, have developed or may develop technologies that may be related or competitive with our approach, and may 
have filed or may file patent applications and may have been issued or may be issued patents with claims that overlap or 
conflict with our patent applications, either by claiming the same compositions, formulations or methods or by claiming 
subject matter that could dominate our patent position. In addition, the laws of foreign countries may not protect our rights to 
the same extent as the laws of the United States. As a result, any patents we may obtain in the future may not provide us with 
adequate and continuing patent protection sufficient to exclude others from commercializing products similar to our products 
and product candidates.

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We may not be able to protect our intellectual property rights throughout the world.
Filing, prosecuting, maintaining, defending and enforcing patents on products and product candidates in all countries 
throughout the world would be prohibitively expensive, and our intellectual property rights in some countries outside the 
United States could be less extensive than those in the United States. There can be no assurance that we will obtain or 
maintain patent rights in or outside the United States under any future license agreements. In addition, the laws of some 
foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the United States 
even in jurisdictions where we and our licensors may pursue patent protection. Consequently, we and our licensors may not 
be able to prevent third parties from practicing our inventions in all countries outside the United States (even in jurisdictions 
where we and our licensors pursue patent protection) or from selling or importing products made using our inventions in and 
into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions where we and our 
licensors have not pursued and obtained patent protection to develop their own products, and they may export otherwise 
infringing products to territories where we have patent protection but enforcement is not as strong as that in the United States. 
These products may compete with our products and product candidates and our patents or other intellectual property rights 
may not be effective or sufficient to prevent them from competing. 
Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign 
jurisdictions. The legal systems of certain countries, particularly certain developing countries, do not favor the enforcement 
of patents, trade secrets and other intellectual property protection, particularly those relating to biotechnology products, 
which could make it difficult for us to stop the infringement of our patents or marketing of competing products in violation of 
our proprietary rights generally. Proceedings to enforce our patent rights, even if obtained, in foreign jurisdictions could 
result in substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk 
of being invalidated or interpreted narrowly and our patent applications at risk of not issuing and could provoke third parties 
to assert claims against us. We may not prevail in any lawsuits that we initiate, and the damages or other remedies awarded, 
if any, may not be commercially meaningful. Accordingly, our efforts to enforce our intellectual property rights around the 
world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or 
license.
Issued patents covering our products and product candidates could be found invalid or unenforceable if challenged in 
court or in administrative proceedings. We may not be able to protect our trade secrets in court.
If we or one of our licensing partners initiate legal proceedings against a third party to enforce a patent covering one of our 
products or product candidates, should such a patent issue, the defendant could counterclaim that the patent covering our 
product or product candidate is invalid or unenforceable. In patent litigation in the United States, defendant counterclaims 
alleging invalidity or unenforceability are commonplace. Grounds for a validity challenge could be an alleged failure to meet 
any of several statutory requirements, including lack of novelty, obviousness, written description or non-enablement. 
Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent 
withheld information material to patentability from the USPTO, or made a misleading statement, during prosecution. Third 
parties also may raise similar claims before administrative bodies in the United States or abroad, even outside the context of 
litigation. Such mechanisms include re-examination, post grant review, inter partes review and equivalent proceedings in 
foreign jurisdictions. An adverse determination in any of the foregoing proceedings could result in the revocation or 
cancellation of, or amendment to, our patents in such a way that they no longer cover our products or product candidates. The 
outcome following legal assertions of invalidity and unenforceability is unpredictable. With respect to the validity question, 
for example, we cannot be certain that there is no invalidating prior art, of which the patent examiner and we or our licensing 
partners were unaware during prosecution. If a defendant or third party were to prevail on a legal assertion of invalidity or 
unenforceability, we could lose at least part, and perhaps all, of the patent protection on one or more of our products and 
product candidates. Such a loss of patent protection could have a material adverse impact on our business.
In addition to the protection afforded by patents, we rely on trade secret protection and confidentiality agreements to protect 
proprietary know-how that is not patentable or that we elect not to patent, processes for which patents are difficult to enforce 
and any other elements of our product candidate discovery and development processes that involve proprietary know-how, 
information or technology that is not covered by patents. However, trade secrets can be difficult to protect and some courts 
inside and outside the United States are less willing or unwilling to protect trade secrets. We seek to protect our proprietary 
technology and processes, in part, by entering into confidentiality agreements with our employees, consultants, scientific 
advisors, and contractors. We cannot guarantee that we have entered into such agreements with each party that may have or 
have had access to our trade secrets or proprietary technology and processes. We also seek to preserve the integrity and 
confidentiality of our data and trade secrets by maintaining physical security of our premises and physical and electronic 
security of our information technology systems. While we have confidence in these individuals, organizations and systems, 
agreements or security measures may be breached, and we may not have adequate remedies for any breach.

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If we do not obtain patent term extension and data exclusivity for our products and product candidates, our business may 
be materially harmed.
Patents have a limited lifespan. In the United States, if all maintenance fees are timely paid, the natural expiration of a patent 
is generally 20 years from its earliest U.S. non-provisional filing date. Various extensions may be available, but the life of a 
patent, and the protection it affords, is limited. Even if patents covering our products and product candidates are obtained, 
once the patent life has expired for a product or product candidate, we may be open to competition from competitive 
products. Given the amount of time required for the development, testing and regulatory review of new product candidates, 
patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our 
owned and licensed patent portfolio may not provide us with sufficient rights to exclude others from commercializing 
products and product candidates similar or identical to ours.
In the future, if we obtain an issued patent covering one of our present or future product candidates, depending upon the 
timing, duration and specifics of any FDA marketing approval of such product candidates, such patent may be eligible for 
limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984, or Hatch-Waxman 
Amendments. The Hatch-Waxman Amendments permit a patent extension term of up to five years as compensation for 
patent term lost during the FDA regulatory review process. A patent term extension cannot extend the remaining term of a 
patent beyond a total of 14 years from the date of product approval, only one patent may be extended and only those claims 
covering the approved drug, a method for using it or a method for manufacturing it may be extended. A patent may only be 
extended once and only based on a single approved product. However, we may not be granted an extension because of, for 
example, failure to obtain a granted patent before approval of a product candidate, failure to exercise due diligence during the 
testing phase or regulatory review process, failure to apply within applicable deadlines, failure to apply prior to expiration of 
relevant patents or otherwise our failure to satisfy applicable requirements. Moreover, the applicable time period or the scope 
of patent protection afforded could be less than we request. If we are unable to obtain patent term extension or the term of 
any such extension is less than we request, our competitors may obtain approval of competing products following our patent 
expiration, and our revenue could be reduced, possibly materially. In addition, we do not control the efforts of our licensors 
to obtain a patent term extension, and there can be no assurance that they will pursue or obtain such extensions to patents that 
we may license from them.
Some intellectual property which we have in-licensed may have been discovered through government funded programs 
and thus may be subject to federal regulations such as “march-in” rights, certain reporting requirements, and a 
preference for U.S. industry. Compliance with such regulations may limit our exclusive rights and limit our ability to 
contract with non-U.S. manufacturers.
Some of the intellectual property rights we have licensed may have been generated through the use of U.S. government and 
state funding and may therefore be subject to certain federal and state laws and regulations. As a result, the U.S. government 
may have certain rights to intellectual property embodied in our current or future products and product candidates pursuant to 
the Bayh-Dole Act of 1980. These U.S. government rights in certain inventions developed under a government-funded 
program include a non-exclusive, non-transferable, irrevocable worldwide license to use inventions for any governmental 
purpose. In addition, the U.S. government has the right to require us to grant exclusive, partially exclusive, or non-exclusive 
licenses to any of these inventions to a third party if it determines that: (i) adequate steps have not been taken to 
commercialize the invention; (ii) government action is necessary to meet public health or safety needs; or (iii) government 
action is necessary to meet requirements for public use under federal regulations (also referred to as “march-in rights”). The 
U.S. government also has the right to take title to these inventions if we, or the applicable licensor, fail to disclose the 
invention to the government and fail to file an application to register the intellectual property within specified time limits. 
Intellectual property generated under a government -funded program is also subject to certain reporting requirements, 
compliance with which may require us or the applicable licensor to expend substantial resources. In addition, the U.S. 
government requires that products embodying the subject invention or produced through the use of the subject invention be 
manufactured substantially in the United States. The manufacturing preference requirement can be waived if the owner of the 
intellectual property can show that reasonable but unsuccessful efforts have been made to grant licenses on similar terms to 
potential licensees that would be likely to manufacture substantially in the United States or that under the circumstances 
domestic manufacture is not commercially feasible. This preference for U.S. manufacturers may limit our ability to contract 
with non-U.S. product manufacturers for products covered by such intellectual property. With respect to state funding, 
specifically funding via the California Institute of Regenerative Medicine, or CIRM, the grantee has certain obligations and 
the state or CIRM has certain rights. For example, the grantee has an obligation to share intellectual property, including 
research results, generated by CIRM-funded research, for research use in California.

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Intellectual property rights and regulatory exclusivity rights do not necessarily address all potential threats.
The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights 
have limitations, and they may not adequately protect our business or permit us to maintain our competitive advantage. For 
example:
•
the patents of others may have an adverse effect on our business;
•
others, including one or more of our competitors, may reverse engineer or independently develop the know-how 
or data, including clinical data, that we rely on for a competitive advantage;
•
others may be able to make gene therapy products that are similar to our products or product candidates but that 
are not covered by the claims of the patents that we license or may own or license in the future or by our other 
intellectual property rights;
•
we, our license partners or current or future collaborators, might not have been the first to make the inventions 
covered by the issued patents or pending patent applications that we license or may own or license in the future;
•
we, our license partners or current or future collaborators, might not have been the first to file patent applications 
covering certain of our or their inventions;
•
others may independently develop similar or alternative technologies or duplicate any of our technologies 
without infringing, misappropriating or otherwise violating our owned or licensed intellectual property rights;
•
it is possible that our pending licensed patent applications or those that we may own or license in the future will 
not lead to issued patents;
•
issued patents that we hold rights to or may hold rights to in the future may be held invalid or unenforceable, 
including as a result of legal challenges by our competitors;
•
one or more of our products or product candidates may never be protected by patents;
•
our competitors might conduct research and development activities in countries where we do not have patent 
rights and then use the information learned from such activities to develop competitive products for sale in our 
major commercial markets;
•
we may not develop additional proprietary technologies that are patentable; and
•
we or our licensors or collaborators may choose not to file a patent application for certain trade secrets or know-
how, and a third party may subsequently file a patent application or obtain a patent covering such intellectual 
property.
Should any of these events occur, they could significantly harm our business, financial condition, results of operations and 
prospects.
We may become involved in lawsuits to protect or enforce our patents and other intellectual property, which could be 
expensive, time consuming and unsuccessful.
Competitors may infringe, misappropriate or otherwise violate patents, trademarks, copyrights or other intellectual property 
that we own or in-license. To counter infringement, misappropriation or other unauthorized use, we may be required to file 
claims, which can be expensive and time consuming and divert the time and attention of our management and scientific 
personnel. Any claims we assert against perceived violators could provoke these parties to assert counterclaims against us 
alleging that we infringe, misappropriate or otherwise violate their intellectual property, in addition to counterclaims 
asserting that our patents are invalid or unenforceable, or both. In any future patent infringement proceeding, there is a risk 
that a court will decide that a patent of ours is invalid or unenforceable, in whole or in part, and that we do not have the right 
to stop the other party from using the invention at issue. There is also a risk that, even if the validity of such patents is upheld, 
the court will construe the patent’s claims narrowly or decide that we do not have the right to stop the other party from using 
the invention at issue on the grounds that our patent claims do not cover the invention. An adverse outcome in a litigation or 
proceeding involving our patents could limit our ability to assert our patents against those parties or other competitors and 
may curtail or preclude our ability to exclude third parties from making and selling similar or competitive products. Any of 
these occurrences could adversely affect our competitive business position, business prospects and financial condition.
Even if we establish infringement, misappropriation or another violation of our intellectual property rights, a court may 
decide not to grant an injunction against the offender and instead award only monetary damages, which may not be an 

83
adequate remedy. Furthermore, because of the substantial amount of discovery required in connection with intellectual 
property litigation, there is a risk that some of our confidential information could be compromised by disclosure during 
litigation. There could also be public announcements of the results of hearings, motions or other interim proceedings or 
developments. If securities analysts or investors perceive these results to be negative, it could have a material adverse effect 
on the price of shares of our ADSs. Moreover, there can be no assurance that we will have sufficient financial or other 
resources to file and pursue such claims, which typically last for years before they are concluded. Even if we ultimately 
prevail in such claims, the monetary cost of such litigation and the diversion of the attention of our management and 
scientific personnel could outweigh any benefit we receive as a result of the proceedings. Any of the foregoing may have a 
material adverse effect on our business, financial condition, results of operations and prospects.
We may be subject to claims asserting that our employees, consultants or advisors have wrongfully used or disclosed 
alleged trade secrets of their current or former employers or claims asserting ownership of what we regard as our own 
intellectual property.
Certain of our employees, consultants or advisors are currently, or were previously, employed at universities or other 
biotechnology or pharmaceutical companies, including our competitors or potential competitors. Although we try to ensure 
that our employees, consultants and advisors do not use the proprietary information or know-how of others in their work for 
us, we may be subject to claims that these individuals or we have used or disclosed intellectual property, including trade 
secrets or other proprietary information, of any such individual’s current or former employer. Litigation may be necessary to 
defend against these claims. If we fail in defending any such claims, in addition to paying monetary damages, we may lose 
valuable intellectual property rights or personnel. Even if we are successful in defending against such claims, litigation could 
result in substantial costs and be a distraction to management. Our licensors may face similar risks, which could have an 
adverse impact on intellectual property that is licensed to us.
We may be subject to claims challenging the inventorship or ownership of the patents and other intellectual property that 
we own or license.
We or our licensors may be subject to claims that former employees, collaborators or other third parties have an ownership 
interest in the patents and intellectual property that we own or license or that we may own or license in the future. While it is 
our policy to require our employees and contractors who may be involved in the development of intellectual property to 
execute agreements assigning such intellectual property to us, we may be unsuccessful in executing such an agreement with 
each party who in fact develops intellectual property that we regard as our own or such assignments may not be self-
executing or may be breached. Our licensors may face similar obstacles. We could be subject to ownership disputes arising, 
for example, from conflicting obligations of employees, consultants or others who are involved in developing our products or 
product candidates. Litigation may be necessary to defend against any claims challenging inventorship or ownership. If we or 
our licensors fail in defending any such claims, we may have to pay monetary damages and may lose valuable intellectual 
property rights, such as exclusive ownership of, or right to use, intellectual property, which could adversely impact our 
business, results of operations and financial condition.
Changes in patent law in the United States and other jurisdictions could diminish the value of patents in general, which 
could impair our ability to protect our products and product candidates.
Changes in either the patent laws or the interpretation of the patent laws in the United States or other jurisdictions could 
increase the uncertainties and costs surrounding the prosecution of patent applications and the enforcement or defense of 
issued patents. 
The patent positions of companies engaged in the development and commercialization of biologics are particularly uncertain. 
Two cases involving diagnostic method claims and “gene patents” have been decided by the Supreme Court. The Supreme 
Court issued a decision in Mayo Collaborative Services v. Prometheus Laboratories, Inc., or Prometheus, a case involving 
patent claims directed to a process of measuring a metabolic product in a patient to optimize a drug dosage for the patient. 
According to the Supreme Court, the addition of well-understood, routine or conventional activity such as “administering” or 
“determining” steps was not enough to transform an otherwise patent-ineligible natural phenomenon into patent-eligible 
subject matter. Thereafter, the USPTO issued a guidance memo to patent examiners indicating that process claims directed to 
a law of nature, a natural phenomenon or a naturally occurring relation or correlation that do not include additional elements 
or steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied and 
the claim amounts to significantly more than the natural principle itself should be rejected as directed to not patent-eligible 
subject matter. Subsequently, the Supreme Court issued its decision in Association for Molecular Pathology v. Myriad 
Genetics, Inc., or Myriad, a case involving patent claims held by Myriad Genetics, Inc. relating to the breast cancer 
susceptibility genes BRCA1 and BRCA2. Myriad held that an isolated segment of naturally occurring DNA, such as the 
DNA constituting the BRCA1 and BRCA2 genes, is not patent-eligible subject matter, but that complementary DNA, which 

84
is an artificial construct that may be created from RNA transcripts of genes, may be patent-eligible. Thereafter, the USPTO 
issued a guidance memorandum instructing USPTO examiners on the ramifications of the Prometheus and Myriad rulings 
and apply the Myriad ruling to natural products and principles including all naturally occurring nucleic acids.
Certain claims of our in-licensed patent applications contain, and any future patents we may obtain may contain, claims that 
relate to specific recombinant DNA sequences that are naturally occurring at least in part and, therefore, could be the subject 
of future challenges made by third parties.
We cannot assure that our efforts to seek patent protection for one or more of our products and product candidates will not be 
negatively impacted by the decisions described above, rulings in other cases, or changes in guidance or procedures issued by 
the USPTO. We cannot fully predict what impact the Supreme Court’s decisions in Prometheus and Myriad may have on the 
ability of life science companies to obtain or enforce patents relating to their products in the future. These decisions, the 
guidance issued by the USPTO and rulings in other cases or changes in USPTO guidance or procedures could have a material 
adverse effect on our existing patent rights and our ability to protect and enforce our intellectual property in the future.
Moreover, although the Supreme Court held in Myriad that isolated segments of naturally occurring DNA are not patent-
eligible subject matter, certain third parties could allege that activities that we may undertake infringe other gene-related 
patent claims, and we may deem it necessary to defend ourselves against these claims by asserting non-infringement or 
invalidity positions, or paying to obtain a license to these claims. In any of the foregoing or in other situations involving 
third-party intellectual property rights, if we are unsuccessful in defending against claims of patent infringement, we could be 
forced to pay damages or be subjected to an injunction that would prevent us from utilizing the patented subject matter, the 
result of which could have a material adverse effect on our business.
Risks related to ownership of our securities
The market price of our ADSs may be highly volatile and may fluctuate due to factors beyond our control. 
The trading price of our ADSs has fluctuated and may continue to fluctuate significantly. The market price of our ADSs 
depends on a number of factors, some of which are beyond our control. For example, the trading price of our ADSs may be 
affected by:
•
adverse results or delays in pre-clinical studies or clinical trials;
•
reports of adverse events in other gene therapy products or clinical trials of such products;
•
an inability to obtain additional funding;
•
failure by us to successfully develop and commercialize our product candidates;
•
failure by our current or future collaborators to successfully develop and commercialize product candidates for 
which we are eligible to receive milestone and royalty payments;
•
failure by us to adequately scale our manufacturing capabilities and commercial and sales organization to 
succeed in our commercialization efforts of Libmeldy;
•
failure by us to succeed in our ongoing commercialization of Strimvelis;
•
failure by us to gain broad insurance coverage and reimbursement for our product candidates, if approved;
•
failure by us to maintain our existing strategic collaborations or enter into new collaborations;
•
failure by us or our licensors and strategic partners to prosecute, maintain or enforce our intellectual property 
rights;
•
changes in laws or regulations applicable to future products;
•
an inability to obtain adequate product supply for our product candidates or the inability to do so at acceptable 
prices;
•
adverse regulatory decisions;
•
the introduction of new products, services or technologies by our competitors;
•
failure by us to meet or exceed financial or other projections we may provide to the public;
•
failure by us to meet or exceed the financial or other projections of the investment community;

85
•
the perception of the pharmaceutical industry by the public, legislatures, regulators and the investment 
community;
•
announcements of significant acquisitions, strategic partnerships, joint ventures or capital commitments by us, 
our strategic partner or our competitors;
•
disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability 
to obtain patent protection for our technologies;
•
additions or departures of key scientific or management personnel;
•
significant lawsuits, including patent or shareholder litigation;
•
changes in the market valuations of similar companies;
•
general economic, geopolitical and market conditions, including the significant disruptions to the U.S. and global 
economies and the related significant volatility and negative pressure in financial markets caused by the COVID-
19 global pandemic, supply chain issues, inflationary pressures and the ongoing conflict in the Ukraine;
•
sales of our ADSs by us or our shareholders in the future; and
•
the trading volume of our ADSs.
In addition, companies trading in the stock market in general, and the Nasdaq Capital Market and in particular, have 
experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating 
performance of these companies. Broad market and industry factors may negatively affect the market price of our ADSs, 
regardless of our actual operating performance.
If securities or industry analysts do not continue to publish research about our business or publish inaccurate or 
unfavorable research, our ADS price and trading volume could decline. 
The trading market for our ADSs depends in part on the research and reports that securities or industry analysts publish about 
us or our business. We do not have any control over these analysts. In the event one or more analysts downgrade our ADSs or 
change their opinion of our ADSs, our ADS price would likely decline. In addition, if one or more analysts cease coverage of 
our company or fail to regularly publish reports on us, we could lose visibility in the financial markets, which could cause our 
ADS price or trading volume to decline.
Concentration of ownership of our ordinary shares (including ordinary shares in the form of ADSs) among our existing 
executive officers, directors and principal shareholders may prevent new investors from influencing significant corporate 
decisions.
Based upon our ordinary shares outstanding as of March 3, 2023, our executive officers, directors, greater than five percent 
shareholders and their affiliates beneficially own approximately 47.6% of our ordinary shares and ADSs. In computing the 
number of ordinary shares beneficially owned by a person, ordinary shares subject to options, or other rights held by such 
person that are currently exercisable or will become exercisable within 60 days of March 3, 2023, are considered outstanding. 
These ordinary shares, however, are not included in the number of shares outstanding as of March 3, 2023. (In other words, 
in calculating the beneficial ownership percentage, there are ordinary shares in the numerator that are not reflected in the 
denominator.) Depending on the level of attendance at our meetings of shareholders, these shareholders either alone or voting 
together as a group may be in a position to determine or significantly influence the outcome of decisions taken at any such 
meeting. Any shareholder or group of shareholders controlling more than 50% of the share capital present and voting at our 
meetings of shareholders may control any shareholder resolution requiring a simple majority, including the appointment of 
board members, certain decisions relating to our capital structure, and the approval of certain significant corporate 
transactions. Among other consequences, this concentration of ownership may prevent or discourage unsolicited acquisition 
proposals that our shareholders may believe are in their best interest as shareholders. Some of these persons or entities may 
have interests that are different than those of our other shareholders. For example, because many of these shareholders 
purchased their ordinary shares at prices substantially below the price at which ADSs were sold in our initial public offering 
and have held their ordinary shares for a longer period, they may be more interested in selling our company to an acquirer 
than other investors or they may want us to pursue strategies that deviate from the interests of other shareholders. 
Future sales, or the possibility of future sales, of a substantial number of our securities could adversely affect the price of 
the shares and dilute shareholders. 
Additional sales of our ADSs, or the perception that these sales could occur, could cause the market price of our ADSs to 
decline. If any of our large shareholders or members of our management team sell substantial amounts of ADSs in the public 

86
market, or the market perceives that such sales may occur, the market price of our ADSs and our ability to raise capital 
through an issue of equity securities in the future could be adversely affected. Additionally, we filed a registration statement 
with the SEC and may issue securities in one or more underwritten transactions, in “at-the-market” offerings or in other 
transactions from time to time. If we were to issue such securities in the public market, the trading price of our ADSs could 
decline.
Holders of ADSs are not treated as holders of our ordinary shares
Holders of our publicly traded securities are holders of ADSs with underlying ordinary shares in a company incorporated 
under English law. Holders of ADSs are not treated as holders of our ordinary shares, unless they withdraw the ordinary 
shares underlying their ADSs in accordance with the deposit agreement and applicable laws and regulations. The depositary 
is the holder of the ordinary shares underlying the ADSs. Holders of ADSs therefore do not have any rights as holders of our 
ordinary shares, other than the rights that they have pursuant to the deposit agreement.
Holders of ADSs may be subject to limitations on the transfer of their ADSs and the withdrawal of the underlying 
ordinary shares. 
ADSs are transferable on the books of the depositary. However, the depositary may close its books at any time or from time 
to time when it deems expedient in connection with the performance of its duties. The depositary may refuse to deliver, 
transfer or register transfers of ADSs generally when our books or the books of the depositary are closed, or at any time if we 
or the depositary think it is advisable to do so because of any requirement of law, government or governmental body, or 
under any provision of the deposit agreement, or for any other reason, subject to the right of ADS holders to cancel their 
ADSs and withdraw the underlying ordinary shares. Temporary delays in the cancellation of the holder’s ADSs and 
withdrawal of the underlying ordinary shares may arise because the depositary has closed its transfer books or we have 
closed our transfer books, the transfer of ordinary shares is blocked to permit voting at a shareholders’ meeting or we are 
paying a dividend on our ordinary shares. In addition, ADS holders may not be able to cancel their ADSs and withdraw the 
underlying ordinary shares when they owe money for fees, taxes and similar charges and when it is necessary to prohibit 
withdrawals in order to comply with any laws or governmental regulations that apply to ADSs or to the withdrawal of 
ordinary shares or other deposited securities.
We are entitled to amend the deposit agreement and to change the rights of ADS holders under the terms of such 
agreement, or to terminate the deposit agreement, without the prior consent of the ADS holders.
We are entitled to amend the deposit agreement and to change the rights of the ADS holders under the terms of such 
agreement without the prior consent of the ADS holders. We and the depositary may agree to amend the deposit agreement in 
any way we decide is necessary or advantageous to us or to the depositary. Amendments may reflect, among other things, 
operational changes in the ADS program, legal developments affecting ADSs or changes in the terms of our business 
relationship with the depositary. If the terms of an amendment are materially disadvantageous to ADS holders, ADS holders 
are only entitled to receive 30 days’ advance notice of the amendment and no prior consent of the ADS holders is required. 
Furthermore, we may decide to direct the depositary to terminate the ADS facility at any time for any reason. For example, 
termination may occur if we decide to list our ordinary shares on a non-U.S. securities exchange and determine not to 
continue to sponsor an ADS facility or if we become the subject of a takeover or a going-private transaction. If the ADS 
facility terminates, ADS holders will receive at least 30 days’ prior notice but no prior consent is required from them. If we 
make an amendment to the deposit agreement that is disadvantageous to ADS holders or terminate the deposit agreement, the 
ADS holders may choose to sell their ADSs or surrender their ADSs and become direct holders of the underlying ordinary 
shares, but they will have no right to any compensation whatsoever.
ADSs holders may not be entitled to a jury trial with respect to claims arising under the deposit agreement, which could 
result in less favorable outcomes to the plaintiff(s) in any such action.
The deposit agreement governing the ADSs representing our ordinary shares provides that, to the fullest extent permitted by 
law, holders and beneficial owners of ADSs irrevocably waive the right to a jury trial of any claim they may have against us 
or the depositary arising out of or relating to the ADSs or the deposit agreement.
If this jury trial waiver provision is not permitted by applicable law, an action could proceed under the terms of the deposit 
agreement with a jury trial. If we or the depositary opposed a jury trial demand based on the waiver, the court would 
determine whether the waiver was enforceable based on the facts and circumstances of that case in accordance with the 
applicable state and federal law. To our knowledge, the enforceability of a contractual pre-dispute jury trial waiver in 
connection with claims arising under the federal securities laws has not been finally adjudicated by the Supreme Court. 
However, we believe that a contractual pre-dispute jury trial waiver provision is generally enforceable, including under the 
laws of the State of New York, which govern the deposit agreement, by a federal or state court in the City of New York, 

87
which has non-exclusive jurisdiction over matters arising under the deposit agreement. In determining whether to enforce a 
contractual pre-dispute jury trial waiver provision, courts will generally consider whether a party knowingly, intelligently and 
voluntarily waived the right to a jury trial. We believe that this is the case with respect to the deposit agreement and the 
ADSs.
If any holders or beneficial owners of ADSs bring a claim against us or the depositary in connection with matters arising 
under the deposit agreement or the ADSs, including claims under federal securities laws, such holder or beneficial owner 
may not be entitled to a jury trial with respect to such claims, which may have the effect of limiting and discouraging 
lawsuits against us or the depositary. If a lawsuit is brought against us or the depositary under the deposit agreement, it may 
be heard only by a judge or justice of the applicable trial court, which would be conducted according to different civil 
procedures and may result in different outcomes than a trial by jury would have had, including results that could be less 
favorable to the plaintiff(s) in any such action, depending on, among other things, the nature of the claims, the judge or 
justice hearing such claims, and the venue of the hearing.
No condition, stipulation or provision of the deposit agreement or ADSs serves as a waiver by any holder or beneficial owner 
of ADSs or by us or the depositary of compliance with any substantive provision of the U.S. federal securities laws and the 
rules and regulations promulgated thereunder.
Holders of our ADSs do not have the same voting rights as the holders of our ordinary shares and may not receive voting 
materials in time to be able to exercise the holder’s right to vote.
Except as described in the deposit agreement, holders of the ADSs will not be able to exercise voting rights attaching to the 
ordinary shares represented by the ADSs. Under the terms of the deposit agreement, holders of the ADSs may instruct the 
depositary to vote the ordinary shares underlying their ADSs. Otherwise, holders of ADSs will not be able to exercise their 
right to vote unless they withdraw the ordinary shares underlying their ADSs to vote them in person or by proxy in 
accordance with applicable laws and regulations and our Articles of Association. Even so, ADS holders may not know about 
a meeting far enough in advance to withdraw those ordinary shares. If we ask for the instructions of holders of the ADSs, the 
depositary, upon timely notice from us, will notify ADS holders of the upcoming vote and arrange to deliver our voting 
materials to them. Upon our request, the depositary will mail to holders a shareholder meeting notice that contains, among 
other things, a statement as to the manner in which voting instructions may be given. We cannot guarantee that ADS holders 
will receive the voting materials in time to ensure that they can instruct the depositary to vote the ordinary shares underlying 
their ADSs. A shareholder is only entitled to participate in, and vote at, the meeting of shareholders, provided that it holds 
our ordinary shares as of the record date set for such meeting and otherwise complies with our Articles of Association. In 
addition, the depositary's liability to ADS holders for failing to execute voting instructions or for the manner of executing 
voting instructions is limited by the deposit agreement. As a result, holders of ADSs may not be able to exercise their right to 
give voting instructions or to vote in person or by proxy and they may not have any recourse against the depositary or us if 
their ordinary shares are not voted as they have requested or if their shares cannot be voted.
Holders of our ADSs may not receive distributions on our ordinary shares represented by the ADSs or any value for them 
if it is illegal or impractical to make them available to holders of ADSs.
The depositary for the ADSs has agreed to pay to the holders of our ADSs the cash dividends or other distributions it or the 
custodian receives on our ordinary shares or other deposited securities after deducting its fees and expenses. Holders of our 
ADSs will receive these distributions in proportion to the number of our ordinary shares such holder’s ADSs represent. 
However, in accordance with the limitations set forth in the deposit agreement, it may be unlawful or impractical to make a 
distribution available to holders of ADSs. We have no obligation to take any other action to permit distribution on the ADSs, 
ordinary shares, rights or anything else to holders of the ADSs. This means that holders of our ADSs may not receive the 
distributions we make on our ordinary shares or any value from them if it is unlawful or impractical to make them available. 
These restrictions may have an adverse effect on the value of our ADSs.
Because we do not anticipate paying any cash dividends on our ADSs in the foreseeable future, capital appreciation, if 
any, will be the sole source of gains to the holders of our ADSs and such holders may never receive a return on their 
investment.
Under current English law, a company’s accumulated realized profits must exceed its accumulated realized losses (on a non-
consolidated basis) before dividends can be declared and paid. Therefore, we must have distributable profits before declaring 
and paying a dividend. We have not paid dividends in the past on our ordinary shares. We intend to retain earnings, if any, 
for use in our business and do not anticipate paying any cash dividends in the foreseeable future. As a result, capital 
appreciation, if any, on our ADSs will be the sole source of gains to the holders of our ADSs for the foreseeable future, and 
such holders may suffer a loss on their investment if they are unable to sell their ADSs at or above the price at which such 
holders purchased the ADSs.

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Sales of a substantial number of our ADSs in the public market by our existing shareholders could cause the market price 
of our ADSs to drop significantly.
Sales of a substantial number of our ADS in the public market, or the perception that holders of a large number of ADSs 
intend to sell, could reduce the market price of our ADSs. As of December 31, 2022, we had outstanding 126,947,225 voting 
shares. The holders of 8,611,375 shares of our ordinary shares are entitled to rights with respect to the registration of their 
ordinary shares under the Securities Act of 1933, as amended, or the Securities Act. Registration of these ordinary shares 
under the Securities Act would result in the ADSs representing them becoming freely tradable without restriction, except for 
ADSs purchased by affiliates. In addition, our directors, executive officers and other affiliates may establish, and certain 
executive officers, directors and affiliates have established, programmatic selling plans under Rule 10b5-1 of the Exchange 
Act, for the purpose of effecting sales of our ADSs. Generally, sales under such plans by our executive officers and directors 
require public filings. Any sales of securities by these shareholders, or the perception that those sales may occur, under such 
programmed selling plans, could have a material adverse effect on the trading price of our ADSs. In addition, as of December 
31, 2022, 18,488,043 ordinary shares reserved for issuance upon the exercise of existing options outstanding and issuance of 
performance-based and time-based restricted shares under our current equity incentive plans will become eligible for sale in 
the public market in the future, subject to certain legal and contractual limitations. 
We will continue to incur increased costs as a result of operating as a company whose ADSs are publicly traded in the 
United States, and our management is required to devote substantial time to new compliance initiatives.
As a public company listed on a U.S. Exchange, we have incurred and will continue to incur significant legal, accounting and 
other expenses that we did not incur as a private company. In addition, the Sarbanes-Oxley Act and rules subsequently 
implemented by the SEC and Nasdaq have imposed various requirements on public companies, including establishment and 
maintenance of effective disclosure and financial controls and corporate governance practices. Our management and other 
personnel are required to devote a substantial amount of time to these compliance initiatives. Moreover, these rules and 
regulations have increased and will continue to increase our legal and financial compliance costs and make some activities 
more time-consuming and costly.
Pursuant to Section 404 of the Sarbanes-Oxley Act, or Section 404, we are required to furnish a report by our management on 
our internal control over financial reporting and, once we are no longer a “smaller reporting company”, we will be required to 
furnish an attestation report on internal control over financial reporting issued by our independent registered public 
accounting firm. In order to achieve and maintain compliance with Section 404, we have documented and evaluated our 
internal control over financial reporting, which is both costly and challenging. In this regard, we continue to dedicate internal 
resources, have engaged outside consultants and adopted a detailed work plan to continually assess and document the 
adequacy of internal control over financial reporting, taken steps to improve control processes as appropriate, validated 
through testing that controls are functioning as documented and have implemented a continuous reporting and improvement 
process for internal control over financial reporting. Despite our efforts, there is a risk in any given year that we will not be 
able to conclude within the prescribed time frame that our internal control over financial reporting is effective as required by 
Section 404. This could result in an adverse reaction in the financial markets due to a loss of confidence in the reliability of 
our financial statements. Moreover, if in the future we are required to obtain an opinion as to the effectiveness of our internal 
control over financial reporting and if our independent registered public accounting firm is unable to express an opinion as to 
the effectiveness of our internal control over financial reporting, investors may lose confidence in the accuracy and 
completeness of our financial reports and the market price of our ADSs could be negatively affected, and we could become 
subject to investigations by the SEC or other regulatory authorities or to shareholder litigation, which could have an adverse 
impact on the market price or our ADSs and cause us to incur additional expenses.
Shareholder protections and restrictions found in provisions under The City Code on Takeovers and Mergers do not apply 
to us.
In February 2020, the UK Takeover Panel confirmed that we are not considered to be subject to The City Code on Takeovers 
and Mergers, or The Takeover Code, and, as a result, our shareholders are not entitled to the benefit of certain takeover offer 
protections provided under The Takeover Code. The Takeover Code provides a framework within which takeovers of 
companies are regulated and conducted and which may operate to prohibit certain arrangements and courses of conduct 
considered customary in the United States. There are no provisions in our Articles of Association that replicate the provisions 
of The Takeover Code.
We believe that this position is unlikely to change at any time in the near future, but in accordance with good practice, we 
will review the situation on a regular basis and cooperate and consult with the UK Takeover Panel if there is any material 
change in our circumstances with respect to matters which the UK Takeover Panel might consider relevant in their 
determination of jurisdiction over us.

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The rights of our shareholders may differ from the rights typically offered to shareholders of a U.S. corporation.
We are incorporated under English law. The rights of holders of ordinary shares and, therefore, certain of the rights of holders 
of ADSs, are governed by English law, including the provisions of the UK Companies Act 2006, or the Companies Act, and 
by our Articles of Association. These rights differ in certain respects from the rights of shareholders in typical U.S. 
corporations.
The principal differences include the following:
•
Under English law and our Articles of Association, each shareholder present at a meeting has only one vote 
unless demand is made for a vote on a poll, in which case each holder gets one vote per share owned. Under U.S. 
law, each shareholder typically is entitled to one vote per share at all meetings.
•
Under English law, it is only on a poll that the number of shares determines the number of votes a holder may 
cast. The voting rights of ADSs are also governed by the provisions of a deposit agreement with our depositary 
bank.
•
Under English law, subject to certain exceptions and disapplications, each shareholder generally has preemptive 
rights to subscribe on a proportionate basis to any issuance of ordinary shares or rights to subscribe for, or to 
convert securities into, ordinary shares for cash. Under U.S. law, shareholders generally do not have preemptive 
rights unless specifically granted in the certificate of incorporation or otherwise.
•
Under English law and our Articles of Association, certain matters require the approval of 75% of the 
shareholders who vote (in person or by proxy) on the relevant resolution (or on a poll of shareholders 
representing 75% of the ordinary shares voting (in person or by proxy)), including amendments to the Articles of 
Association. This may make it more difficult for us to complete corporate transactions deemed advisable by our 
board of directors. Under U.S. law, generally only majority shareholder approval is required to amend the 
certificate of incorporation or to approve certain significant transactions.
•
In the United Kingdom, takeovers may be structured as takeover offers or as schemes of arrangement. Under 
English law, a bidder seeking to acquire us by means of a takeover offer would need to make an offer for all of 
our outstanding ordinary shares/ADSs. If acceptances are not received for 90% or more of the ordinary 
shares/ADSs under the offer, under English law, the bidder cannot complete a “squeeze out” to obtain 100% 
control of us. Accordingly, acceptances of 90% of our outstanding ordinary shares/ADSs will likely be a 
condition in any takeover offer to acquire us, not 50% as is more common in tender offers for corporations 
organized under Delaware law. By contrast, a scheme of arrangement, the successful completion of which would 
result in a bidder obtaining 100% control of us, requires the approval of a majority of shareholders voting at the 
meeting and representing 75% of the ordinary shares voting for approval.
•
Under English law and our Articles of Association, shareholders and other persons whom we know or have 
reasonable cause to believe are, or have been, interested in our shares may be required to disclose information 
regarding their interests in our shares upon our request, and the failure to provide the required information could 
result in the loss or restriction of rights attaching to the shares, including prohibitions on certain transfers of the 
shares, withholding of dividends and loss of voting rights. Comparable provisions generally do not exist under 
U.S. law.
If we fail to maintain an effective system of internal control over financial reporting, we may not be able to accurately 
report our financial results or prevent fraud. As a result, shareholders could lose confidence in our financial and other 
public reporting, which would harm our business and the trading price of our ADSs.
Effective internal controls over financial reporting are necessary for us to provide reliable financial reports and, together with 
adequate disclosure controls and procedures, are designed to prevent fraud. Any failure to implement required new or 
improved controls, or difficulties encountered in their implementation could cause us to fail to meet our reporting obligations. 
In addition, testing required to be conducted by us in connection with Section 404, and subsequent testing by our independent 
registered public accounting firm, may reveal deficiencies in our internal controls over financial reporting that are deemed to 
be material weaknesses or that may require prospective or retroactive changes to our financial statements or identify other 
areas for further attention or improvement. Inferior internal controls could also cause investors to lose confidence in our 
reported financial information, which could have a negative effect on the trading price of our ADSs.
We are required to disclose changes made in our internal controls and procedures on a quarterly basis, and our management is 
required to assess the effectiveness of these controls annually. However, for as long as we are a “smaller reporting company,” 
our independent registered public accounting firm will not be required to attest to the effectiveness of our internal control 

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over financial reporting pursuant to Section 404. We will qualify as a “smaller reporting company” if the market value of our 
ADSs held by non-affiliates is below $250 million (or $700 million if our annual revenue is less than $100 million) as of the 
last business day of our most recently completed second fiscal quarter. An independent assessment of the effectiveness of our 
internal control over financial reporting could detect problems that our management’s assessment might not. Undetected 
material weaknesses in our internal control over financial reporting could lead to financial statement restatements and require 
us to incur the expense of remediation.
Our disclosure controls and procedures may not prevent or detect all errors or acts of fraud.
We are subject to certain reporting requirements of the Exchange Act. Our disclosure controls and procedures are designed to 
reasonably assure that information required to be disclosed by us in reports we file or submit under the Exchange Act is 
accumulated and communicated to management, recorded, processed, summarized and reported within the time periods 
specified in the rules and forms of the SEC. We believe that any disclosure controls and procedures or internal controls and 
procedures, no matter how well conceived and operated, can provide only reasonable, not absolute, assurance that the 
objectives of the control system are met. These inherent limitations include the realities that judgments in decision-making 
can be faulty, and that breakdowns can occur because of simple error or mistake. Additionally, controls can be circumvented 
by the individual acts of some persons, by collusion of two or more people or by an unauthorized override of the controls. 
Accordingly, because of the inherent limitations in our control system, misstatements or insufficient disclosures due to error 
or fraud may occur and not be detected.
We are not currently in compliance with the minimum bid price rule of the Nasdaq Capital Market, and a delisting could 
limit the liquidity of our ADSs, increase their volatility and hinder our ability to raise capital.
We are not currently in compliance with The Nasdaq Stock Market’s minimum bid price rule because the closing bid price of 
our ADSs had been below $1.00 per share for 30 consecutive business days. On March 10, 2023, we effected a change to our 
ADS to ordinary share ratio from the previous ratio of one ADS to one ordinary share to a new ratio of one ADS to ten 
ordinary shares. We expect that we will regain compliance with the minimum bid price rule as a result of the ratio change. 
However, we may not be able to remain compliant in the future.
If we are not able to maintain compliance with the Nasdaq listing requirements, including the minimum bid price rule, we 
could receive a delisting notice from Nasdaq. Delisting from The Nasdaq Capital Market could make trading our ADSs more 
difficult for investors, potentially leading to declines in the trading price of our ADSs and decreased liquidity. We cannot 
ensure that our ADSs, if delisted from the Nasdaq Capital Market, will be listed on another national securities exchange or 
quoted on an over-the-counter system. Other consequences of delisting could include an adverse effect on our ability to 
obtain equity financing on acceptable terms or at all, an increase in volatility of our ADS trading price, and a loss of 
confidence by shareholders, employees and business partners.
Risks related to taxation
Changes in tax law could adversely affect our business and financial condition.
We conduct business globally. The tax treatment of the company or any of the group companies could be materially 
adversely affected by several factors, including, but not limited to: (i) changing tax laws, regulations and treaties, or the 
interpretation thereof; (ii) tax policy initiatives and reforms under consideration (such as those related to the Organization for 
Economic Co-Operation and Development’s, or OECD, Base Erosion and Profit Shifting, or BEPS, Project, the European 
Commission’s state aid investigations and other initiatives); (iii) the practices of tax authorities in jurisdictions in which we 
operate; and (iv) the resolution of issues arising from tax audits or examinations and any related interest or penalties. Such 
changes may include (but are not limited to) the taxation of operating income, investment income, dividends received or (in 
the specific context of withholding tax) dividends paid.
We are unable to predict what tax reform may be proposed or enacted in the future or what effect such changes would have 
on our business, but such changes, to the extent they are brought into tax legislation, regulations, policies or practices in 
jurisdictions in which we operate, could affect our financial position, future results of operations, cash flows in a particular 
period and overall or effective tax rates in the future in countries where we have operations, reduce post-tax returns to our 
shareholders and increase the complexity, burden and cost of tax compliance.
Taxing authorities could challenge our historical and future tax positions or our allocation of taxable income among our 
subsidiaries, and tax laws to which we are subject could change in a manner adverse to us.
We operate through various subsidiaries in a number of countries throughout the world. Consequently, we are subject to tax 
laws, treaties, and regulations in the countries in which we operate, and these laws and treaties are subject to interpretation. 
We have taken, and will continue to take, tax positions based on our interpretation of such tax laws. 

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Our transfer pricing arrangements are not generally binding on applicable tax authorities. The price charged for products, 
services, or the royalty rates and other amounts paid for intellectual property rights, could be challenged by the various tax 
authorities, resulting in additional tax liability, interest or penalties. There can be no assurance that a taxing authority will not 
have a different interpretation of applicable law and assess us with additional taxes. Similarly, a tax authority could assert 
that we are subject to tax in a jurisdiction where we believe we have not established a taxable connection, often referred to as 
a ‘‘permanent establishment’’ under international tax treaties, and such an assertion, if successful, could increase our 
expected tax liability in one or more jurisdictions. If we are assessed with additional taxes, this may result in a material 
adverse effect on our results of operations and financial condition. 
A tax authority may take the position that material income tax liabilities, interest and penalties are payable by us, for example 
where there has been a technical violation of contradictory laws and regulations that are relatively new and have not been 
subject to extensive review or interpretation, in which case we expect that we might contest such assessment. Contesting such 
an assessment may be lengthy and costly and if we were unsuccessful in disputing the assessment, the implications could 
increase our anticipated effective tax rate, where applicable, or result in other liabilities. 
If we are a controlled foreign corporation, there could be adverse U.S. federal income tax consequences to certain U.S. 
holders.
Each “Ten Percent Shareholder” (as defined below) in a non-U.S. corporation that is classified as a “controlled foreign 
corporation,” or a CFC, for U.S. federal income tax purposes generally is required to include in income for U.S. federal tax 
purposes such Ten Percent Shareholder’s pro rata share of the CFC’s “Subpart F income” and investment of earnings in U.S. 
property, even if the CFC has made no distributions to its shareholders. Subpart F income generally includes dividends, 
interest, rents, royalties, global intangible low-taxed income, gains from the sale of securities and income from certain 
transactions with related parties. In addition, a Ten Percent Shareholder that realizes gain from the sale or exchange of shares 
in a CFC may be required to classify a portion of such gain as dividend income rather than capital gain. A non-U.S. 
corporation generally will be classified as a CFC for U.S. federal income tax purposes if Ten Percent Shareholders own, 
directly or indirectly, more than 50% of either the total combined voting power of all classes of stock of such corporation 
entitled to vote or of the total value of the stock of such corporation. A “Ten Percent Shareholder” is a United States person 
(as defined by the Code) who owns or is considered to own 10% or more of the total combined voting power of all classes of 
stock entitled to vote of such corporation. The determination of CFC status is complex and includes attribution rules, the 
application of which is not entirely certain.
We believe that we were not a CFC in the 2022 taxable year, but we may become a CFC in a subsequent taxable year. If we 
are classified as both a CFC and a passive foreign investment company, or PFIC (as discussed below), we generally will not 
be treated as a PFIC with respect to those U.S. holders that meet the definition of a Ten Percent Shareholder during the period 
in which we are a CFC. 
If we are a PFIC there could be adverse U.S. federal income tax consequences to U.S. holders.
Under the Code, we will be a PFIC, for any taxable year in which (i) 75% or more of our gross income consists of passive 
income or (ii) 50% or more of the average quarterly value of our assets consists of assets that produce, or are held for the 
production of, passive income. For purposes of these tests, passive income includes dividends, interest, gains from the sale or 
exchange of investment property and certain rents and royalties. In addition, for purposes of the above calculations, a non-
U.S. corporation that directly or indirectly owns at least 25% by value of the shares of another corporation is treated as 
holding and receiving directly its proportionate share of assets and income of such corporation. If we are a PFIC for any 
taxable year during which a U.S. holder holds our ordinary shares or ADSs, the U.S. holder may be subject to adverse tax 
consequences regardless of whether we continue to qualify as a PFIC, including ineligibility for any preferred tax rates on 
capital gains or on actual or deemed dividends, interest charges on certain taxes treated as deferred and additional reporting 
requirements.
Based on the current and expected composition of our income and assets and the value of our assets, we believe that we were 
a PFIC for U.S. federal income tax purposes for our taxable year ended December 31, 2022. The determination of whether 
we are a PFIC is a fact-intensive determination made on an annual basis applying principles and methodologies that in some 
circumstances are unclear and subject to varying interpretation. The value of our assets would also be determined differently 
for the purposes of this determination if we were treated as a CFC, as discussed above. As a result, there can be no assurance 
regarding if we currently are treated as a PFIC or may be treated as a PFIC in the future. In addition, for our current and 
future taxable years, the total value of our assets for PFIC testing purposes may be determined in part by reference to the 
market price of our ordinary shares or ADSs from time to time, which may fluctuate considerably. Under the income test, our 
status as a PFIC depends on the composition of our income which will depend on the transactions we enter into in the future 

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and our corporate structure. The composition of our income and assets is also affected by the spending of the cash we raise in 
any offering.
In certain circumstances, a U.S. holder of shares in a PFIC may alleviate some of the adverse tax consequences described 
above by making either a “qualified electing fund,” or QEF, election or a mark-to-market election (if our ordinary shares or 
ADSs constitute “marketable” securities under the Code), which each require the inclusion of a pro rata share of our income 
on a current basis. Because it was possible we were a PFIC for the 2022 taxable year, we currently expect that we will 
provide the information necessary for U.S. holders to make a QEF Election. We may elect to provide such information on our 
website (www.ORTX.com). A U.S. holder would also be able to make a mark-to-market election with respect to our ordinary 
shares or ADSs as long as those shares or ADSs constitute marketable securities under the Code.
We may be unable to use UK net operating loss and tax credit carryforwards and certain built-in losses to reduce future 
tax payments or benefit from favorable UK tax legislation.
As a UK incorporated and tax resident entity, we are subject to UK corporate taxation on tax-adjusted trading profits. Due to 
the nature of our business, we have generated losses since inception and therefore have not paid any UK corporation tax. As 
of December 31, 2022, we had cumulative carryforward tax losses of $633.4 million. Subject to numerous utilization criteria 
and restrictions (including those that limit the percentage of profits that can be reduced by carried forward losses and those 
that can restrict the use of carried forward losses where there is a change of ownership of more than half the ordinary shares 
of the Company and a major change in the nature, conduct or scale of the trade), we expect these to be eligible for carry 
forward and utilization against future operating profits. The use of loss carryforwards in relation to UK profits incurred on or 
after April 1, 2017 will be limited each year to £5.0 million plus, broadly, an incremental 50% of UK taxable profits. In 
addition, if we were to have a major change in the nature of the conduct of our trade, loss carryforwards may be restricted or 
extinguished.
As a company that carries out extensive research and development activities, we seek to benefit from two UK research and 
development tax relief programs, the Small and Medium-sized Enterprises R&D Tax Credit Program, or SME Program, and 
the Research and Development Expenditure Credit program, or RDEC Program. Where available, we may be able to 
surrender the trading losses that arise from our qualifying research and development activities for cash or carried forward for 
potential offset against future profits (subject to relevant restrictions). The majority of our pipeline research, clinical trials 
management and manufacturing development activities are currently eligible for inclusion within these tax credit cash rebate 
claims. 
In the future we will continue to seek to benefit from these programs; however, the United Kingdom Government’s Autumn 
Statement on November 17, 2022 announced reductions in the level of credits offered under the SME Program that will take 
effect from April 2023, along with other changes outlined further below. Under the SME Program, we are currently in 
principle able to surrender some of our trading losses that arise from our qualifying research and development activities for a 
cash rebate of up to 33.35% of such qualifying research and development expenditures. The majority of our research, clinical 
trials management and manufacturing development activities are currently eligible for inclusion within these tax credit cash 
rebate claims. The cash rebate available from April 2023 is expected to reduce to up to 18.6% of qualifying research and 
development expenditures, which (if we continue to qualify as a SME) would represent a significant reduction in cash 
receivable from the United Kingdom Government. Furthermore, we may not be able to continue to claim payable research 
and development tax credits in the future if we cease to qualify as a SME, based on size criteria concerning employee 
headcount, turnover and gross assets. There is also a cap on payable credit claims under the SME Program in excess of 
£20,000 by reference to, broadly, three times the total PAYE and NICs liability of the company, subject to an exception 
which prevents the cap from applying. That exception requires the company to be creating, taking steps to create or managing 
intellectual property, as well as having qualifying research and development expenditure in respect of connected parties 
which does not exceed 15% of the total claimed. If such exception does not apply, this could restrict the amount of payable 
credit that we claim. If we cease to be eligible for the SME Program, we may be able to claim alternative credits under the 
RDEC Program (in addition to credits that we currently claim under that Program).  The RDEC Program does not entitle us 
to cash rebates in the same way as the SME Program, but instead (broadly) functions as a taxable credit against United 
Kingdom corporation tax (although the credit may be repayable to a loss-making company in certain circumstances).  The 
United Kingdom Government has announced an increase to the rate of the RDEC credit from 13% to 20% from April 2023 
(although the RDEC Program on the whole is less advantageous than the SME Program).
Additional changes to the R&D tax relief legislation, expected to take effect from April 2023, introduce restrictions on relief 
that may be claimed for expenditure on sub-contracted R&D activity, broadly requiring either that workers carrying on such 
activity are subject to UK PAYE or, where work is undertaken outside the UK, that this must be due to geographical, 
environmental or social conditions not replicable in the UK.  These restrictions may impact the quantum of R&D relief that 
we are able to claim in the future.  In addition, the UK government is currently consulting on the potential replacement of the 
SME Program and RDEC Program with a single program, operating similarly to the RDEC Program, which may, inter alia, 

93
change the present treatment of sub-contracted R&D work and introduce different thresholds and caps on expenditure and 
relief.  If enacted, the new program would be expected to have effect for expenditure incurred from April 2024 onward, and 
could have a material impact on the quantum of R&D relief that we are eligible to claim.
We may benefit in the future from the United Kingdom’s “patent box” regime, which allows certain profits attributable to 
revenue from patented products (and other qualifying income) to be taxed at an effective rate of 10%. We are the exclusive 
licensee or owner of several patent applications which, if issued, would cover our product candidates, and accordingly, future 
upfront fees, milestone fees, product revenue and royalties could be taxed at this tax rate. When taken in combination with 
the enhanced relief available on our research and development expenditures, we expect a long-term lower rate of corporation 
tax to apply to us. If, however, there are unexpected adverse changes to the UK research and development tax credit regime 
or the “patent box” regime, or for any reason we are unable to qualify for such advantageous tax legislation, or we are unable 
to use net operating loss and tax credit carryforwards and certain built-in losses to reduce future tax payments then our 
business, results of operations and financial condition may be adversely affected.
Our ability to use our U.S. tax attributes may be limited.
Under Section 382 and 383 of the Internal Revenue Code of 1986, as amended, or the Code, if a corporation undergoes an 
“ownership change,” generally defined as a greater than 50% change (by value) in its equity ownership by certain 
stockholders over a three-year period, the corporation’s ability to use its pre-change tax attributes (such as research and 
development tax credits) to offset its post-change tax liabilities may be limited. We have completed several financings since 
our inception, which we believe have resulted in an ownership change as defined by Section 382 of the Code. We may also 
experience ownership changes in the future as a result of subsequent shifts in our share ownership. As a result, if we incur 
U.S. federal tax liability, our ability to use our pre-change tax attributes to offset U.S. federal tax liability may be subject to 
limitations, which could potentially result in increased future tax liability to us. 
Risks related to our Domicile
Exchange rate fluctuations may materially affect our results of operations and financial condition.
Owing to the international scope of our operations, fluctuations in exchange rates, particularly between the pound sterling 
and the U.S. dollar, may adversely affect us. Although we are headquartered in the United Kingdom, we also source research 
and development, manufacturing, consulting and other services from the United States and the European Union. Further, 
potential future revenue may be derived from abroad, particularly from the United States. As a result, our business and the 
price of our ADSs may be affected by fluctuations in foreign exchange rates not only between the pound sterling and the U.S. 
dollar, but also the euro, which may have a significant impact on our results of operations and cash flows from period to 
period. Currently, we do not have any exchange rate hedging arrangements in place.
Claims of U.S. civil liabilities may not be enforceable against us.
We are incorporated under English law. Certain members of our board of directors and senior management are non-residents 
of the United States, and a substantial portion of our assets and the assets of such persons are located outside the United 
States. As a result, it may not be possible to serve process on such persons or us in the United States or to enforce judgments 
obtained in U.S. courts against them or us based on civil liability provisions of the securities laws of the United States. As a 
result, it may not be possible for investors to effect service of process within the United States upon such persons or to 
enforce judgments obtained in U.S. courts against them or us, including judgments predicated upon the civil liability 
provisions of the U.S. federal securities laws. 
The United States and the United Kingdom do not currently have a treaty providing for recognition and enforcement of 
judgments (other than arbitration awards) in civil and commercial matters. Consequently, a final judgment for payment given 
by a court in the United States, whether or not predicated solely upon U.S. securities laws, would not automatically be 
recognized or enforceable in the United Kingdom. In addition, uncertainty exists as to whether U.K. courts would entertain 
original actions brought in the United Kingdom against us or our directors or senior management predicated upon the 
securities laws of the United States or any state in the United States. Any final and conclusive monetary judgment for a 
definite sum obtained against us in U.S. courts would be treated by the courts of the United Kingdom as a cause of action in 
itself and sued upon as a debt at common law so that no retrial of the issues would be necessary, provided that certain 
requirements are met. Whether these requirements are met in respect of a judgment based upon the civil liability provisions 
of the U.S. securities laws, including whether the award of monetary damages under such laws would constitute a penalty, is 
an issue for the court making such decision. If an English court gives judgment for the sum payable under a U.S. judgment, 
the English judgment will be enforceable by methods generally available for this purpose. These methods generally permit 
the English court discretion to prescribe the manner of enforcement.

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As a result, U.S. investors may not be able to enforce against us or our senior management, board of directors or certain 
persons named herein who are residents of the United Kingdom or countries other than the United States any judgments 
obtained in U.S. courts in civil and commercial matters, including judgments under the U.S. federal securities laws.
General Risk Factors
We have debt service obligations and may incur additional indebtedness in the future, which could adversely affect our 
financial condition, our results of operations and our ability to react to changes in our business.
We currently have $32.2 million of principal indebtedness outstanding under our senior term facilities agreement, or the 
amended Credit Facility, with MidCap Financial (Ireland) Limited. We have the ability to borrow up to an additional $67.0 
million in the future under the Amended Credit Facility upon satisfaction of certain conditions. Our existing indebtedness and 
any additional indebtedness we may incur could require us to divert funds identified for other purposes for debt service and 
impair our liquidity position.
The fact that a portion of our cash, cash equivalents and marketable securities could be required to make payments on our 
indebtedness could have important consequences, including:
•
increasing our vulnerability to general adverse economic and industry conditions or increased interest rates;
•
restricting our ability to use our cash, cash equivalents and marketable securities for other purposes;
•
limiting our flexibility in planning for or reacting to changes in our business and the markets in which we 
operate, which would place us at a competitive disadvantage compared to our competitors that may have less 
debt;
•
limiting our ability to borrow additional funds for working capital, capital expenditures and other investments; 
and
•
failing to comply with the covenants in our debt agreements could result in all of our indebtedness becoming 
immediately due and payable.
If our business does not generate sufficient cash flow from operations or if future borrowings are not available to us under the 
Amended Credit Facility or otherwise in amounts sufficient to enable us to fund our liquidity needs, our financial condition 
and results of operations may be adversely affected. Our inability to make scheduled payments on our debt obligations in the 
future would require us to refinance all or a portion of our indebtedness on or before maturity, sell assets or seek additional 
equity investment. We may not be able to take any of such actions on a timely basis on terms satisfactory to us or at all.
The Amended Credit Facility contains customary restrictive covenants relating to the operation of our business, including 
restrictions on our ability to:
•
incur or guarantee additional indebtedness;
•
incur or permit to exist certain liens;
•
undergo a change in control;
•
amend material agreements and organizational documents;
•
effect certain mergers, consolidations, asset sales and acquisitions; and
•
pay dividends on, or redeem or repurchase, share capital, enter into transactions with affiliates, or materially 
change our business.
Such restrictions could affect our ability to take certain actions from time to time.
We may be adversely affected by natural disasters, and our business continuity and disaster recovery plans may not 
adequately protect us.
Natural disasters, including earthquakes, fires, flooding, and health epidemics and pandemics, among other things, could 
severely disrupt our business. If a natural disaster occurred, we may be unable to use all or a significant portion of our 
facilities, which could make it difficult or impossible for us to continue our business or a portion of our business for a 
substantial period of time. A natural disaster could also damage critical infrastructure and affect our third-party contract 
manufacturers. Our disaster recovery and business continuity plans are currently limited and may not prove adequate in the 
event of a serious natural disaster or similar event. As such, we could incur substantial expenses if a natural disaster occurs, 
which could have a material impact on our business.

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Our business may be affected by public health crises, including the COVID-19 pandemic.
Public health crises such as pandemics or similar outbreaks can adversely impact our business. For example, the COVID-19 
global pandemic caused significant disruptions to the U.S. and global economies, contributed to volatility in the financial 
markets, and led to measures that impacted various aspects of our business, including our clinical and regulatory efforts as 
well as our supply chain. Renewed outbreaks, including different variants of the virus, could negatively impact our business 
operations. 
In addition, in response to the COVID-19 pandemic, we implemented a hybrid work policy for many employees, whereby 
eligible employees spend only part of their time working in the office. Remote working creates risks to our business, 
including increased cybersecurity risks. We may also experience difficulty in recruiting and onboarding new employees as a 
result of remote working. 
The extent to which pandemics, including the COVID-19 pandemic, may impact our business, and our clinical development 
and regulatory efforts, as well as our supply chain, will depend on future developments that are highly uncertain and cannot 
be predicted with confidence, such as the geographic spread of a disease, the duration of the outbreak, government actions, 
such as travel restrictions, quarantines and social distancing requirements in the U.S. and in other countries, business closures 
or business disruptions and the effectiveness of actions taken in the U.S. and in other countries to contain and treat the 
disease. Accordingly, we cannot predict the impact of pandemics, including the COVID-19 pandemic, with any certainty. 
However, these effects could materially and adversely affect our business, financial condition, results of operations and 
growth prospects, which may in turn also have the effect of heightening many of the other risks and uncertainties described 
elsewhere in this “Risk Factors” section.
Any changes to existing accounting pronouncements or taxation rules or practices may cause adverse fluctuations in our 
reported results of operations or affect how we conduct our business.
A change in accounting pronouncements or taxation rules or practices could have a significant effect on our reported results 
and may affect our reporting of transactions completed before the change is effective. New accounting pronouncements, 
taxation rules and varying interpretations of accounting pronouncements or taxation rules have occurred in the past and may 
occur in the future. We could be required to modify a current tax or accounting position as a result of any such change, and 
this could adversely affect our reported financial results and could change the way we conduct our business.
We could be subject to securities class action litigation.
We could be the subject of a securities class action litigation. The risk is especially relevant to us because such litigation is 
often brought against companies following a decline in the market price of their securities, and biotechnology and 
pharmaceutical companies have experienced significant securities price volatility in recent years. If such a litigation were 
brought against us, it could result in substantial costs and could divert management’s attention and resources, which would be 
harmful to our business.
Item 1B. Unresolved Staff Comments. 
None.
Item 2. Properties. 
Facilities 
Our principal office is located at 245 Hammersmith Road, 3rd Floor, London W6 8PW, United Kingdom. We lease 
approximately 17,400 square feet of office space at this location and our lease for this location extends through February 
2032. We also lease approximately 14,000 square feet of office space in Boston, Massachusetts, our U.S. Headquarters. 
In December 2018, we entered into an agreement to lease approximately 153,000 square feet of manufacturing and office 
space in Fremont, California. This lease extends through May 2030. We have abandoned plans to build-out the facility and 
have subleased the facility to a third-party for the remainder of the lease term. 
We believe that suitable additional or substitute space will be available as needed to accommodate any future expansion of 
our operations.

96
Item 3. Legal Proceedings. 
From time to time, we may be a party to litigation or subject to claims incident to the ordinary course of business. Although 
the results of litigation and claims cannot be predicted with certainty, we currently believe that the final outcome of these 
ordinary course matters will not have a material adverse effect on our business. Regardless of the outcome, litigation can 
have an adverse impact on us because of defense and settlement costs, diversion of management resources and other factors. 
As of December 31, 2022, we were not a party to any material legal proceedings.
Item 4. Mine Safety Disclosures.
Not applicable.

97
PART II
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity 
Securities. 
Market Information and Holders of Ordinary Shares and ADSs
Prior to March 10, 2023, our American Depositary Shares, or ADSs, each represented one ordinary share, nominal value 
£0.10 per share, of Orchard Therapeutics plc. On March 10, 2023, we effected a change to our ADS to ordinary share ratio 
such that one ADS is now represented by ten ordinary shares. An ADS may be evidenced by an American Depositary 
Receipt issued by Citibank, N.A. as depositary bank. Our ADSs have been listed and traded on The Nasdaq Capital Market 
since September 13, 2022 and were previously listed and traded on The Nasdaq Global Select Market since October 31, 
2018. Our ADSs are listed and trade under the symbol “ORTX”. As of March 10, 2023, there were 55 holders of record of 
our ordinary shares and one holder of record of our ADSs. 
The closing sale price of our ADS on March 10, 2023 was $4.80, which reflects the above-mentioned ratio change.
Sales of Unregistered Securities
Not applicable.
Dividends
Since our inception, we have not declared or paid any dividends on our ordinary shares. We intend to retain any earnings for 
use in our business and do not currently intend to pay dividends on our ordinary shares.
The payment of dividends by us is governed by English law. The declaration and payment of any future dividends will be at 
the discretion of our board of directors and will depend upon our results of operations, cash requirements, financial condition, 
contractual restrictions, restrictions imposed by our indebtedness, any future debt agreements or applicable laws and other 
factors that our board of directors may deem relevant.
Information about Our Equity Compensation Plans
Information regarding our equity compensation plans is incorporated by reference in Item 12 of Part III of this Annual 
Report.
Item 6. Reserved. 
Not applicable.

98
Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations. 
The following discussion of our financial condition and results of operations should be read in conjunction with our 
consolidated financial statements and related notes included elsewhere in this report. Some of the information contained in 
this discussion and analysis and set forth elsewhere in this report, including information with respect to our plans and 
strategy for our business, includes forward-looking statements that involve risks and uncertainties. You should review the 
section titled “Risk Factors” in Part I—Item 1A of this report for a discussion of important factors that could cause actual 
results to differ materially from the results described in or implied by the forward-looking statements contained in the 
following discussion and analysis. 
Business Overview 
Orchard Therapeutics is a global gene therapy company dedicated to transforming the lives of people affected by severe 
diseases through the development of innovative, potentially curative gene therapies. Our ex vivo autologous hematopoietic 
stem cell (“HSC”) gene therapy approach harnesses the power of genetically modified blood stem cells and seeks to correct 
the underlying cause of disease in a single administration. We have one of the most advanced gene therapy pipelines in the 
industry spanning multiple therapeutic areas where the disease burden on children, families and caregivers is immense and 
current treatment options are limited or do not exist. 
Since our inception in 2015, we have devoted substantially all of our resources to conducting research and development of 
our product candidates, in-licensing and acquiring rights to our product candidates, commercializing Libmeldy in Europe, 
business planning, raising capital and providing general and administrative support for our operations. To date, we have 
financed our operations primarily with proceeds from the sale of equity securities, including American Depositary Shares 
(“ADSs”) in our initial public offering (“IPO”) and follow-on offering, ordinary shares in our private placement, and 
convertible preferred shares. We have also financed our operations through proceeds from our senior term facilities 
agreement (the “Amended Credit Facility”) with MidCap Financial (Ireland) Limited (“MidCap Financial”), research grants 
from the California Institute of Regenerative Medicine (“CIRM”), upfront payments from our collaboration agreement with 
Pharming Group N.V., and proceeds associated two UK research and development tax relief programs, the Small and 
Medium-sized Enterprises research and development tax credit (“SME”) program and the Research and Development 
Expenditure (“RDEC”) program.
We have incurred significant operating losses since our inception. With the approval of Libmeldy in Europe, we are now 
transitioning from a primarily clinical development stage company to a commercial stage company. We plan to continue the 
implementation of our commercialization plan for Libmeldy and our near-term plans for commercialization include: 
•
Enabling patient identification via multi-pronged diagnostics initiatives and newborn screening in Europe and the 
U.S.;
•
Expanding global footprint by qualifying leading centers with transplant and disease area expertise;
•
Leveraging cross-border and treatment abroad reimbursement pathways in Europe, Middle East, and Turkey;
•
Securing market access via multi-stakeholder engagement with various payment models.
Our net losses were $150.7 million for the year ended December 31, 2022. As of December 31, 2022, we had an accumulated 
deficit of $900.9 million. As of December 31, 2022, we had cash, cash equivalents and marketable securities of $143.8 
million. Our losses have resulted primarily from costs incurred in connection with research and development activities and 
general and administrative costs associated with our operations. We expect to continue to incur significant expenses and 
increasing operating losses for the foreseeable future. 
As a result, we will need substantial additional funding to support our continuing operations and pursue our growth strategy. 
Until such time as we can generate significant revenue from product sales, if ever, we expect to finance our operations 
through a combination of equity offerings, debt financings, collaborations, government contracts or other strategic 
transactions. We may be unable to raise additional funds or enter into such other agreements or arrangements when needed 
on favorable terms, or at all.
Recent Developments
In March 2022, we announced our decision to focus on severe neurometabolic diseases and early research programs, and to 
discontinue our investment in and seek strategic alternatives for our programs in rare primary immune deficiencies, including 
OTL-103 for treatment of WAS, OTL-102 for treatment of X-CGD and Strimvelis. In connection with this new strategic 
focus, we reduced our workforce by approximately 30%.

99
In March 2023, the Company announced a private placement pursuant to which the Company agreed to sell ordinary shares, 
non-voting ordinary shares, and warrants to purchase ordinary shares or non-voting ordinary shares. The private placement 
consists of two closings. The Company completed the initial closing in March 2023 and sold 56,666,900 ordinary shares and 
non-voting ordinary shares, nominal value £0.10 per share, and warrants to purchase an aggregate of 62,333,590 ordinary 
shares or non-voting ordinary shares, at a purchase price of $6.00 per ten shares and accompanying warrant. The completion 
of the initial closing resulted in gross proceeds of approximately $34.0 million. Refer to the Liquidity section below for 
further information on the private placement.
Business update regarding COVID-19
The COVID-19 pandemic presented substantial public health and economic challenges around the world, and it will likely 
continue to affect our business.
 In addition to general macro-economic effects of the pandemic, our business faced several specific challenges. For example, 
many of our clinical sites devoted, and continue to devote, significant resources to patients with COVID-19. If there is a 
future rise in hospitalizations, our clinical sites may need to dedicate additional resources to treating these people, which 
could limit their ability to enroll additional patients in clinical trials, if necessary. 
In addition, during the pandemic, many of our employees spent time working from home due to limitations on travel and 
other social distancing measures. Currently, a majority of employees are on a hybrid-working model, meaning they perform 
part of their work in the office and part of their work outside of the office. This could increase our cybersecurity risk and 
hinder our ability to onboard new employees. 
It is possible that if additional variants of the virus proliferate, our third party vendors and contract manufacturers could face 
delays and may struggle to operate at expected levels. While we don’t currently anticipate any interruptions to our business, 
we cannot predict this.
Finally, if there are future disruptions to the capital markets as a result of the pandemic, it could impact our ability to raise 
capital. 
For additional information on the various risks posed by the COVID-19 pandemic, please see the section titled “Item 1A. 
Risk Factors” included in this Annual Report.
Components of our results of operations 
Product revenue
We recognize product revenue, net, from sales of Libmeldy and Strimvelis in Europe. Product revenue is recorded net of 
estimates of variable consideration. Please read Note 2, Product revenue, net, to the consolidated financial statements 
included in this Form 10-K for further details of the reserves recorded for variable consideration. We expect that future sales 
of Libmeldy will fluctuate quarter over quarter. Strimvelis is distributed exclusively at the San Raffaele Hospital in Milan, 
Italy. We announced in March 2022 that we would discontinue our investment in and seek alternatives for Strimvelis. 
Collaboration revenue
We recognize collaboration revenue under our collaboration agreement with Pharming. Under revenue recognition guidance, 
we account for our obligations to provide the license and research, development, and manufacturing services under the 
agreement as a series of distinct services that are accounted for as a single performance obligation. We recognize revenue 
using the cost-to-cost input method, which we believe best depicts the transfer of control to the customer. Under the cost-to-
cost input method, the extent of progress towards completion is measured based on the ratio of actual costs incurred to the 
total estimated costs expected upon satisfying the identified performance obligation. Revenue is recorded as a percentage of 
the estimated transaction price based on the extent of progress towards completion. The impact of  any adjustment related to 
the estimated transaction price on revenue recorded to date is recognized in the period the adjustment is identified. 
Reimbursement for research, development, and manufacturing services are recognized as the costs are incurred. Refer to Note 
2 and Note 16 to the consolidated financial statements included in this Form 10-K for further discussion on our revenue 
recognition around this agreement.
Cost of product revenue
Cost of sales consists of costs to manufacture, including raw materials, distribute and administer Libmeldy and Strimvelis 
and royalty payments due to third parties that are tied to sales.

100
A portion of our inventory includes raw materials that were expensed prior to approval of Libmeldy, referred to as zero cost 
inventories. Cost of sales for newly launched products will not include the full cost of manufacturing until the initial pre-
launch inventory is depleted, and additional inventory is purchased, manufactured, and sold. Therefore, the cost of product 
revenue reflects a portion but not all of the manufacturing costs of our products. 
Operating expenses 
Research and development expenses 
Research and development expenses consist primarily of costs incurred for our research activities, including our discovery 
efforts and the development of our product candidates, and include: 
•
expenses incurred under agreements with third parties, including contract research organizations (CROs) that 
conduct research, pre-clinical activities and clinical trials on our behalf as well as contract manufacturing 
organizations that manufacture lentiviral vectors and cell-based drug products for use in our pre-clinical and 
clinical trials; 
•
expenses to acquire technologies to be used in research and development; 
•
salaries, benefits and other related costs, including share-based compensation expense, for personnel engaged in 
research and development functions; 
•
costs related to research and development performed associated with the Company’s collaboration arrangement;
•
costs of outside consultants, including their fees, share-based compensation and related travel expenses; 
•
the costs of laboratory supplies and acquiring, developing and manufacturing pre-clinical study and clinical trial 
materials; 
•
costs related to compliance with regulatory requirements; 
•
facility-related expenses, which include direct depreciation costs and allocated expenses for rent and maintenance 
of facilities, costs related to our collaboration agreements, and other operating costs; 
•
upfront, milestone and management fees for maintaining licenses under our third-party licensing agreements; and
•
grant awards or other government incentives unrelated to income taxes that we earn that are recorded as an offset 
to the related research and development costs incurred.
We expense research and development costs as incurred. We recognize external development costs based on an evaluation of 
the progress to completion of specific tasks using information provided to us by our service providers. Payments for these 
activities are based on the terms of the individual agreements, which may differ from the pattern of costs incurred, and are 
reflected in our financial statements as prepaid expenses or accrued research and development expenses. United Kingdom 
research and development tax credits are recorded as an offset to research and development expense. Amortization of the 
Strimvelis loss provision is also recorded as an offset to research and development expense. 
Our direct external research and development expenses are tracked on a program-by-program basis and consist of costs, such 
as fees paid to consultants, contractors and contract manufacturing organizations in connection with our pre-clinical and 
clinical development activities. License fees and other costs incurred after a product candidate has been designated and that 
are directly related to the product candidate are included in direct research and development expenses for that program. 
License fees and other costs incurred prior to designating a product candidate for development are included in unallocated 
costs. We do not allocate employee costs, costs associated with our early-stage discovery efforts, laboratory supplies, and 
facilities, including depreciation or other indirect costs, to specific product development programs because these costs are 
deployed across multiple product development programs and, as such, are not separately classified. 
Research and development activities are central to our business model. Product candidates in later stages of clinical 
development generally have higher development costs than those in earlier stages of clinical development, primarily due to 
the increased size and duration of later-stage clinical trials or the manufacturing requirements to conduct those clinical trials. 
We expect that our research and development expenses will continue to decline due to the portfolio updates and workforce 
reduction we undertook in 2022 as well as the completion of certain activities to support an OTL-200 BLA submission.
Selling, general and administrative expenses 
Selling, general and administrative expenses consist primarily of salaries and other related costs, including share-based 
compensation, for personnel in our executive, finance, commercial, corporate and business development, and administrative 

101
functions. Selling, general and administrative expenses also include professional fees for legal, patent, accounting, auditing, 
tax and consulting services, travel expenses and facility-related expenses, which include direct depreciation costs and 
allocated expenses for rent and maintenance of facilities and other operating costs. 
Other income (expense), net 
Interest income
Interest income consists of income earned on our cash and cash equivalents and marketable securities.
Interest expense
Interest expense consists of interest associated with our credit facility with MidCap Financial, which we entered into in May 
2019 and amended and restated in May 2021. During 2022, this credit facility bore a variable interest rate of 5.95% above 
LIBOR, plus a final payment equal to 3.5% of the principal borrowed under the credit facility. 
In January 2023, we again amended and restated the credit facility to change from LIBOR to SOFR. The newly amended 
facility bears a variable interest rate of 5.95% above SOFR plus 0.10% per annum, plus a final payment equal to 3.5% of the 
principal borrowed under the Amended Credit Facility.
Other income (expense)
Other income (expense), net consists primarily of realized and unrealized foreign currency transaction gains and losses.
Results of operations 
Comparison of the years ended December 31, 2022 and 2021
The following table summarizes our results of operations for the years ended December 31, 2022 and 2021 (in thousands): 
Year Ended December 31,
2022
2021
Change
Product revenue, net
$
20,610
$
700
$
19,910
Collaboration revenue
2,045
975
1,070
Total revenues
$
22,655
$
1,675
$
20,980
Costs and operating expenses
Cost of product revenue
6,771
226
6,545
Research and development
93,847
86,977
6,870
Selling, general and administrative
49,125
54,905
(5,780)
Total costs and operating expenses
149,743
142,108
7,635
Loss from operations
(127,088)
(140,433)
13,345
Other (expense) income:
Interest income
1,543
412
1,131
Interest expense
(3,079)
(2,497)
(582)
Other (expense) income, net
(24,410)
(1,238)
(23,172)
Total other (expense) income, net
(25,946)
(3,323)
(22,623)
Net loss before income tax
(153,034)
(143,756)
(9,278)
Income tax (expense) benefit
2,374
(828)
3,202
Net loss attributable to ordinary shareholders
$
(150,660)
$
(144,584)
$
(6,076)
Product revenue, net
The table below summarizes our revenue earned by product (in thousands):
Year Ended December 31,
2022
2021
Change
Libmeldy
$
18,796
$
—
$
18,796
Strimvelis
1,814
700
1,114
Total product revenue, net
$
20,610
$
700
$
19,910

102
Libmeldy received approval from the European Commission in December 2020 and we made our first commercial sale in the 
first quarter of 2022.  In March 2022, we announced that we would discontinue our investment in and seek alternatives for 
Strimvelis. 
Collaboration revenue 
During the years ended December 31, 2022 and 2021, we recognized revenue of $2.0 million and $1.0 million, respectively, 
under our collaboration agreement with Pharming. We recognize revenue using the cost-to-cost input method. Under this 
method, revenue is recorded as a percentage of the estimated transaction price based on the extent of progress towards 
completion. Reimbursement for research, development, and manufacturing services are recognized as the costs are incurred.
Cost of product revenue
Cost of product revenue for the year ended December 31, 2022, consisted of costs to manufacture, distribute and administer 
Libmeldy and Strimvelis and royalty payments due to third parties related to these sales. The gross margin on our product 
revenue, net was enhanced by our use of zero cost inventories. Utilizing the per unit average cost of materials that were 
purchased prior to approval and expensed that were utilized in the manufacturing process for our products sold during the 
period, cost of product revenue for the year ended December 31, 2022, would have been approximately $8.4 million.
Research and development expenses
The table below summarizes our research and development expenses by therapeutic area (in thousands): 
Year Ended December 31,
2022
2021
Change
Direct research and development expenses by therapeutic area:
Neurometabolic disorders
$
28,813
$
22,443
6,370
Primary immune deficiencies
9,777
17,801
(8,024)
Blood disorders
3,041
743
2,298
Other research and pre-clinical programs under development
3,927
5,636
(1,709)
Total direct research and development expenses
45,558
46,623
(1,065)
Research and discovery and unallocated costs
Personnel related (excluding share-based compensation)
31,108
31,897
(789)
Share-based compensation
6,791
9,214
(2,423)
Restructuring costs
1,448
524
924
Accretion of Strimvelis loss provision
(274)
(1,037)
763
Research and development tax credit
(8,243)
(13,920)
5,677
Facility and other
17,459
13,676
3,783
Total indirect research and development expenses
48,289
40,354
7,935
Total research and development expenses
$
93,847
$
86,977
6,870
Total direct research and development expenses decreased from $46.6 million for the year ended December 31, 2021, to 
$45.5 million for the year ended December 31, 2022. The $1.1 million decrease, or -2%, was primarily the result of:
•
an $8.0 million decrease in costs associated with primary immune deficiencies programs and a $1.7 million 
decrease in other research and pre-clinical programs due to due to de-prioritization of and decreased investment 
in these programs after our restructuring efforts; 
•
a $6.4 million increase in spending on neurometabolic disorder programs, specifically driven by spending on 
OTL-200 for MLD, as we ramp up our efforts to file a BLA with the FDA; and
•
a $2.3 million increase in spending on blood disorder program which was driven by the accruing of long-term 
follow up cost associated with returning the program to the licensee and other wind-down costs related to de-
prioritization of the program after our restructuring efforts. 
Total indirect research and development expenses increased from $40.4 million for the year ended December 31, 2021, to 
$48.3 million for the year ended December 31, 2022. The $7.9 million increase, or 20%, was the result of:

103
•
a $5.7 million decrease in the amount received from the UK research and development tax credit, which is an 
offset to research and development expenses incurred for qualifying programs. This decrease was driven by a 
decrease in qualifying costs; 
•
a $3.8 million increase in facility and other expenses due to increases in platform development costs;
•
a $0.9 million increase in restructuring costs driven by re-prioritization of our goals and changes in our corporate 
strategy and associated employee terminations;
•
a $0.8 million decrease in the accretion of the Strimvelis loss provision, which is an offset to research and 
development expenses. This decrease was driven by our decision to no longer invest in the development of our 
commercial program for Strimvelis and seek an alternative future for the program; and 
•
a $2.4 million decrease in share-based compensation and a $0.8 million decrease in personnel related costs due to 
our strategic restructuring efforts and headcount reduction. 
Selling, general and administrative expenses 
The table below summarizes our selling, general and administrative expenses by functional area (in thousands):
Year Ended December 31,
2022
2021
Change
Selling, general and administrative expenses:
Personnel (excluding share-based compensation)
$
16,868
$
18,227
(1,359)
Share-based compensation
9,219
13,322
(4,103)
Restructuring costs
333
484
(151)
Consulting, professional, and insurance-related costs
11,754
12,679
(925)
Marketing, promotions, and advocacy
4,135
5,259
(1,124)
Facilities and other costs
6,816
4,934
1,882
Total selling, general, and administrative expenses:
$
49,125
$
54,905
$
(5,780)
Selling, general and administrative expenses decreased from $54.9 million for the year ended December 31, 2021, to $49.1 
million for the year ended December 31, 2022. The $5.8 million decrease, or -11%, was a result of:
•
a $1.4 million decrease in personnel related expenses and a $4.1 million decrease in share-based compensation 
expenses due to decreased headcount as a result of our strategic restructuring; 
•
a $0.9 million decrease in consulting, professional, and insurance-related costs as well as a $1.1 million decrease 
in marketing, promotions, and advocacy costs due to a de-emphasis and discontinuation of investment in certain 
clinical and research programs as a result of our strategic restructuring; and
•
a $1.9 million increase in facilities and other costs driven by increased shareholder and ADS administration 
costs.
Other (expense) income, net 
Other (expense) income, net decreased from a $3.3 million loss for the year ended December 31, 2021, to a $25.9 million loss 
for the year ended December 31, 2022. During the year ended December 31, 2022, we had net realized and unrealized losses 
on foreign currency transactions of $24.4 million, comprised primarily of unrealized losses, compared to net realized and 
unrealized losses of $1.2 million for year ended December 31, 2021. Unrealized losses are driven primarily by intercompany 
balances denominated in currencies other than the functional currency of the entity with the intercompany balance, and 
typically fluctuates concurrently with fluctuations in the U.S. Dollar, Pounds sterling, and Euro exchange rates. Interest 
expense was $3.1 million and $2.5 million for the years ended December 31, 2022 and 2021, respectively. Interest income 
was $1.5 million and $0.4 million in the years ended December 31, 2022 and 2021, respectively. The increase to both interest 
expense and interest income is attributable to interest rate increases throughout 2022 driven by anti-inflationary measures 
born from the current economic environment.

104
Liquidity and capital resources
From our inception through December 31, 2022, we have not generated significant revenue from product sales and incurred 
significant operating losses and negative cash flows from our operations. We acquired our commercial product Strimvelis 
and the program that is now Libmeldy from GSK in April 2018, and our product candidates are in various phases of pre-
clinical and clinical development. In December 2020, the European Commission granted standard marketing authorization 
for Libmeldy. We launched Libmeldy in Europe and generated product revenue during the year ended December 31, 2022. 
To date, we have financed our operations primarily with proceeds from the sale of ADSs in our IPO and follow-on offering, 
proceeds from the sale of ordinary shares in our private placement, proceeds from the sale of convertible preferred shares, 
reimbursements associated with two UK research and development tax relief programs, the Small and Medium-sized 
Enterprises research and development tax credit (“SME”) program and the Research and Development Expenditure 
(“RDEC”) program, reimbursements from our research agreement with UCLA and, following transfer of the ADA-SCID 
research program sponsorship from UCLA to us in July 2018, a grant from the California Institute of Regenerative Medicine 
(“CIRM”), upfront payments from our collaboration agreement with Pharming Group N.V., our Original Credit Facility and 
our Amended Credit Facility with MidCap, and through proceeds from sales of Libmeldy in Europe beginning in 2022. 
On February 27, 2020, we entered into a Sales Agreement with Cowen and Company, LLC (“Cowen”), as agent, relating to 
an “at the market offering,” pursuant to which we may issue and sell ADSs representing our ordinary shares, having an 
aggregate offering price of up to $100.0 million. On March 24, 2022, we delivered written notice to Cowen to terminate the 
Sales Agreement, effective as of March 30, 2022, pursuant to Section 11(b) thereof. Prior to termination, we had not sold any 
ADSs pursuant to the Sales Agreement. As a result of the termination of the Sales Agreement, we will not offer or sell any 
ADSs under the Sales Agreement. On October 6, 2022 we entered into a Sales Agreement with Guggenheim Securities, LLC, 
as agent, relating to an “at the market offering,” pursuant to which we may issue and sell ADSs representing our ordinary 
shares, having an aggregate offering price of up to $30.0 million. As of December 31, 2022, we have not sold any shares 
under the Guggenheim Sales Agreement.
On March 6, 2023, we announced a private placement pursuant to which the Company agreed to sell up to an aggregate of 
99,166,900 ordinary shares and non-voting ordinary shares, nominal value of £0.10 per share, and warrants to purchase an 
aggregate of 109,083,590 ordinary shares or non-voting ordinary shares. The private placement consists of two closings. At 
each closing, the shares will be sold in fixed combinations with the warrants and units, with each purchaser receiving one 
warrant to purchase eleven shares per ten shares purchased. The Company received approximately $34 million at the initial 
closing on March 10, 2023. The Company may receive an additional $34 million from the second closing of the private 
placement. This second closing is conditioned upon (i) the Company’s announcement of its intention to file a biologics 
license application (“BLA”) submission following receipt of the minutes from the U.S. Food and Drug Administration 
(“FDA”) in connection with the Company’s pre-BLA (Type B) meeting for OTL-200, provided such minutes do not 
expressly advise the Company not to proceed with a BLA submission, and (ii) receipt of approval from the Company's 
shareholders, to be provided at a meeting of shareholders no later than 120 days after the initial closing, to give the 
Company's directors authority to issue the securities to be issued and sold in the second closing of the private placement and 
the shares issuable upon exercise of the warrants to be issued and sold in the private placement. 
We currently have no ongoing material financing commitments, such as lines of credit or guarantees, that are expected to 
affect our liquidity over the next five years, other than our manufacturing, lease, and debt obligations described below in the 
footnotes to our consolidated financial statements. 
Cash flows 
The following table summarizes our cash flows for each of the periods presented (in thousands): 
For the Year Ended December 31,
2022
2021
Net cash used in operating activities
$
(75,987)
$
(125,097)
Net cash provided by (used in) investing activities
90,560
(32,165)
Net cash provided by (used in) financing activities
(693)
158,066
Effect of exchange rate changes on cash
(1,419)
(27)
Net increase in cash, cash equivalents, and restricted cash
$
12,461
$
777
Operating activities 
Net cash used in operating activities for the year ended December 31, 2022, was $76.0 million and was primarily driven by 
our net loss of $150.7 million, partially offset by non-cash charges consisting of depreciation and amortization of $2.7 
million, share based compensation of $16.0 million, and unrealized foreign currency transaction losses on  intercompany 

105
accounts of $23.2 million. Our net cash used in operating activities also included a net source of cash of $36.2 million related 
to changes in operating assets and liabilities as follows:
•
a net source of cash of $22.6 million related to the receipt of funds from our UK research and development tax 
credit for claims submitted for the year ended December 31, 2021; 
•
a net source of cash of $13.6 million related to changes in accounts payable, accrued expenses, and other current 
liabilities primarily driven to timing of invoices as compared to when services are provided by our vendors as 
well as the accrual of remaining costs for discontinued clinical and research expenses for which we have 
discontinued further investment due to our corporate restructuring activities; 
•
a net source of cash of $2.2 million related to increased other long-term liabilities due to timing of payments of 
certain accrued royalties;
•
a net source of cash of $5.1 million from a decrease in prepaid expenses, other current assets, and other assets 
primarily due to services being performed on amounts already paid to vendors; and
•
a net use of cash of $7.4 million related increased accounts receivable due to timing of cash receipt on our 
revenues.
During 2021, operating activities used $125.1 million of cash, primarily resulting from our net loss of $144.6 million. Cash 
usage from changes in our operating assets and liabilities was $17.1 million. There was cash usage of $13.9 million from our 
UK research and development tax credit receivable, consisting of claims that were filed in December 2021 that we expect to 
receive in 2022. Further, payment of accruals and accounts payable resulted in cash outflows of $9.5 million. These were 
offset by a $13.1 million increase in deferred revenue associated with our strategic collaboration with Pharming. Non-cash 
adjustments to operating activities of $36.6 million was primarily due to $22.5 million in non-cash share-based compensation 
expense, offset by $1.0 million in amortization of the Strimvelis loss provision as an offset to research and development 
expense. There were also unrealized foreign currency transaction losses on investments, intercompany accounts, and foreign-
currency denominated payables and receivables held by our UK subsidiary of $9.7 million. Finally, we had $1.1 million in 
deferred income tax expense during 2021.
Investing activities 
Net cash provided by investing activities for the year ended December 31, 2022, was $90.6 million. This net cash provided 
by investing activities was primarily driven by proceeds from the sales and maturities of marketable securities that we utilize 
for operating activities. We further received $8.0 million back from our Fremont lease construction deposit that was held in 
escrow and used $6.5 million to purchase property, plant, and equipment for our new Hammersmith office and lab space 
lease.
During 2021, we used $32.2 million of cash in investing activities. The change in cash from investing activity was primarily 
due to proceeds from sales and maturities of marketable debt securities that we utilize for operating activities. 
Financing activities 
Net cash used by financing activities for the year ended December 31, 2022, was $0.7 million and primarily consisted of 
repayments of the principal balance on our notes payable. 
During 2021, we generated $158.1 million in cash from financing activities. This is primarily due to $143.6 million in 
proceeds from the issuance of ordinary shares in our private placement, after payment of $6.4 million in offering costs. We 
also generated $7.4 million associated with our entrance into the Amended Credit Facility. Further, we generated $4.1 million 
in proceeds associated with the Securities Purchase Agreement with Pharming that was entered into as part of our 
collaboration agreement.  We generated $2.9 million in proceeds from the exercise of share options and issuance of ordinary 
shares as part of our ESPP.
Funding requirements 
We expect our expenses and capital expenditures will remain consistent in the near term in connection with our ongoing 
activities as we advance the pre-clinical activities and clinical trials of our product candidates and as we: 
•
seek marketing approvals for our product candidates that successfully complete clinical trials, if any; 
•
continue to grow a sales, marketing and distribution infrastructure for our commercialization of Libmeldy in 
Europe, and for any product candidates for which we may submit for and obtain marketing approval anywhere in 
the world; 

106
•
continue our development of our product candidates, including continuing our ongoing advanced registrational 
trials and supporting studies, and any other clinical trials that may be required to obtain marketing approval for 
our product candidates; 
•
perform research and development activities with respect to potential new product candidates; 
•
conduct investigational new drug application, or IND, and or clinical trial application, or CTA-enabling studies 
for our pre-clinical programs; 
•
initiate additional clinical trials and pre-clinical studies for our other product candidates; 
•
seek to identify and develop, acquire or in-license additional product candidates; 
•
develop the necessary processes, controls and manufacturing data to obtain marketing approval for our product 
candidates, to support technology and process innovations and to support manufacturing of product to 
commercial scale; 
•
develop and implement plans to establish and operate our own in-house manufacturing operations and facility; 
•
hire and retain additional personnel, such as non-clinical, clinical, pharmacovigilance, quality assurance, 
regulatory affairs, manufacturing, distribution, legal, compliance, medical affairs, finance, general and 
administrative, commercial and scientific personnel;
•
develop, maintain, expand and protect our intellectual property portfolio; and 
•
comply with our obligations as a public company. 
Because of the numerous risks and uncertainties associated with biopharmaceutical product development, we are unable to 
accurately predict the timing or amount of increased expenses or when, or if, we will be able to achieve or maintain 
profitability. Even though we started generating Libmeldy product sales in 2022, we may not become profitable. If we fail to 
become profitable or are unable to sustain profitability on a continuing basis, then we may be unable to continue our 
operations at planned levels and be forced to reduce or terminate our operations. 
We believe our existing cash, cash equivalents, and marketable securities on hand, together with expected proceeds from 
sales of Libmeldy and the $34 million received in March 2023 from the 2023 private placement, will enable us to fund our 
operating expenses and capital expenditure requirements into 2025. We have based this estimate on assumptions that may 
prove to be wrong, and we could exhaust our available capital resources sooner than we expect.
Critical Accounting Policies and Estimates
Our management’s discussion and analysis of financial condition and results of operations is based on our consolidated 
financial statements, which have been prepared in accordance with U.S. GAAP. The preparation of our consolidated financial 
statements and related disclosures requires us to make estimates and assumptions that affect the reported amounts of assets 
and liabilities, costs and expenses and the disclosure of contingent assets and liabilities in our consolidated financial 
statements. We base our estimates on historical experience, known trends and events and various other factors that we believe 
are reasonable under the circumstances, the results of which form the basis for making judgments about the carrying values 
of assets and liabilities that are not readily apparent from other sources. We evaluate our estimates and assumptions on an 
ongoing basis. Our actual results may differ from these estimates under different assumptions or conditions.
While our significant accounting policies are described in greater detail in Note 2 to our consolidated financial statements in 
this Annual Report, we believe that the following accounting policies are those most critical to the judgments and estimates 
used in the preparation of our consolidated financial statements.
United Kingdom research and development tax credit 
As a company that carries out research and development activities, we are able to submit tax credit claims from two UK 
research and development tax relief programs, the Small and Medium-sized Enterprises research and development tax credit 
(“SME”) program and the Research and Development Expenditure Credit (“RDEC”) program depending on eligibility. 
Qualifying expenditures largely comprise employment costs for research staff, consumables and certain internal overhead 
costs incurred as part of research projects for which we do not receive income.
Each reporting period, we evaluate which tax relief programs we are expected to be eligible for and record a reduction to 
research and development expense for the portion of the expense that we expect to qualify under the programs, that we plan 
to submit a claim for, and we have reasonable assurance that the amount will ultimately be realized. Based on criteria 
established by HM Revenue and Customs (“HMRC”), we expect a proportion of expenditures being carried in relation to our 

107
pipeline research, clinical trials management and manufacturing development activities to be eligible for the research and 
development tax relief programs for the years ended December 31, 2022 and 2021. 
The RDEC and SME credits are not dependent on us generating future taxable income or on our ongoing tax status or tax 
position. We have assessed our research and development activities and expenditures to determine whether the nature of the 
activities and expenditures will qualify for credit under the tax relief programs and whether the claims will ultimately be 
realized based on the allowable reimbursable expense criteria established by the UK government which are subject to 
interpretation. At each period end, we estimate the reimbursement available to us based on available information at the time.
We recognize credits from the research and development incentives when the relevant expenditure has been incurred and 
there is reasonable assurance that the reimbursement will be received. Such credits are accounted for as reductions in research 
and development expense. We make estimates of the research and development tax credit receivable as of each balance sheet 
date, based upon facts and circumstances known to us at the time. Although we do not expect our estimates to be materially 
different from amounts actually recognized, our estimates could differ from actual results. To date, there have not been any 
material adjustments to our prior estimates of the research and development tax credit receivable.
We may not be able to continue to claim research and development tax credits under the SME program in the future because 
it may no longer qualify as a small or medium-sized company.  In addition, as noted above, the benefits offered by the SME 
program are to be reduced from April 2023 and may be subject to further reduction (or even withdrawal) in future, which 
could have a material impact on future credits that we may be eligible to claim, when compared to those we have benefited 
from in prior years.  Furthermore, the UK government is currently consulting on the potential replacement of the R&D tax 
credit regime with a new regime, which may, inter alia, change the present treatment of sub-contracted R&D work and 
introduce different thresholds and caps on expenditure and relief.  If enacted, the new program would be expected to have 
effect for expenditure incurred from April 2024 onward, and could have a material impact on the quantum of R&D relief and 
credits that we are eligible to claim.
Accrued research and development expenses
As part of the process of preparing our consolidated financial statements, we are required to estimate our accrued research 
and development expenses. This process involves reviewing open contracts and purchase orders, communicating with our 
personnel to identify services that have been performed on our behalf and estimating the level of service performed and the 
associated cost incurred for the service when we have not yet been invoiced or otherwise notified of actual costs. The 
majority of our service providers invoice us in arrears for services performed, on a pre-determined schedule or when 
contractual milestones are met; however, some require advanced payments. We make estimates of our prepaid and accrued 
expenses as of each balance sheet date in the consolidated financial statements based on facts and circumstances known to us 
at that time. There may be instances in which payments made to our vendors will exceed the level of services provided and 
result in a prepayment of the expense.
We base our expenses related to pre-clinical studies and clinical trials on our estimates of the services received and efforts 
expended pursuant to quotes and contracts with multiple CROs, research institutions and other vendors that supply, conduct 
and manage pre-clinical studies and clinical trials on our behalf. The financial terms of these agreements are subject to 
negotiation, vary from contract to contract and may result in uneven payment flows. There may be instances in which 
payments made to our vendors will exceed the level of services provided and result in a prepayment of the expense. 
Payments under some of these contracts depend on factors such as the successful enrollment of patients and the completion 
of clinical trial milestones. In accruing service fees, we estimate the time period over which services will be performed and 
the level of effort to be expended in each period. If the actual timing of the performance of services or the level of effort 
varies from the estimate, we adjust the accrual or the amount of prepaid expenses accordingly. Although we do not expect 
our estimates to be materially different from amounts actually incurred, our understanding of the status and timing of services 
performed relative to the actual status and timing of services performed may vary and may result in reporting amounts that 
are too high or too low in any particular period. To date, there have not been any material adjustments to our prior estimates 
of accrued research and development expenses.
Valuation of share-based compensation
We measure share-based awards granted to employees, non-employees and directors based on the fair value on the date of the 
grant and recognize compensation expense for those awards over the requisite service period, which is generally the vesting 
period of the respective award. Forfeitures are accounted for as they occur. Generally, we issue share-based awards in the 
form of stock options with only service-based vesting conditions and record the expense for these awards using the straight-
line method. We have also issued share-based awards with performance-based vesting conditions for which the expense is 
recognized when achievement of such performance conditions becomes probable.

108
The fair value of each share option is estimated on the date of grant using the Black-Scholes option pricing model. Until the 
completion of our initial public offering in November 2018, we had been a private company and lacked company-specific 
historical and implied volatility information for our shares. Therefore, we estimate our expected share price volatility based 
on the historical volatility of publicly traded peer companies and expect to continue to do so until such time as we have 
adequate historical data regarding the volatility of our own traded share price. The expected term of our share options has 
been determined utilizing the “simplified method” for awards that qualify as “plain-vanilla” options. Prior to the adoption of 
ASU 2018-07, the expected term of share options granted to non-employees was the contractual term. After adoption of ASU 
2018-07, the expected term of share options granted to non-employees is determined in the same manner as share options 
granted to employees. The risk-free interest rate is determined by reference to the U.S. Treasury yield curve in effect at the 
time of grant of the award for time periods approximately equal to the expected term of the award. Expected dividend yield is 
based on the fact that we have never paid cash dividends on our ordinary shares and do not expect to pay any cash dividends 
in the foreseeable future.
Product revenue, net - Libmeldy
In January 2022, we began generating product revenue from sales of Libmeldy in Europe following the approval of Libmeldy 
by the European Commission in December 2020 for the treatment of early onset metachromatic leukodystrophy (“MLD”), 
characterized by biallelic mutations in the arylsulfatase-A (ARSA) gene leading to a reduction of the ARSA enzymatic 
activity in children with (i) late infantile or early juvenile forms, without clinical manifestations of the disease, or (ii) the 
early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk independently and 
before the onset of cognitive decline. 
We recognize revenue when control of promised goods is transferred to a customer at an amount that reflects the 
consideration to which we expect to be entitled in exchange for those goods. Control of the product transfers upon infusion of 
the product. To determine revenue recognition, we perform the following five steps: (i) identify the contract(s) with a 
customer; (ii) identify the performance obligations in the contract; (iii) determine the transaction price, including variable 
consideration, if any; (iv) allocate the transaction price to the performance obligations in the contract; and (v) recognize 
revenue when (or as) we satisfied the performance obligations. We only apply the five-step model to contracts when 
collectability of the consideration to which we are entitled in exchange for the goods we transfer to the customer is 
determined to be probable. In certain regions of Europe and the Middle East, we utilize distributors to act in an agent capacity 
including for patient identification and other related functions. We are exclusively responsible for product fulfillment and 
retain inventory risk and pricing discretion of the product.  Evaluation of these key indicators support our assertion that we 
maintain control over the product prior to delivery to the patient. We have concluded that we are the principal in these 
transactions and we record the associated revenue on a gross basis.  
Amounts are recorded as accounts receivable when the right to the consideration is unconditional. We do not assess whether 
a contract has a significant financing component if the expectation at contract inception is that the period between payment 
by the customer and the transfer of the promised goods or services to the customer will be one year or less. We expense 
incremental costs of obtaining a contract as and when incurred if the expected amortization period of the asset that would 
have been recognized is one year or less or the amount is immaterial. As of December 31, 2022, we have not capitalized any 
costs to obtain contracts. 
We recognize product revenue, net of variable consideration related to certain allowances and accruals, when the customer 
takes control of the product, which is at a point in time once the patient has been infused. Product revenue is recorded at the 
net sales price, or transaction price. We record product revenue reserves, which are classified as a reduction in product 
revenue, to account for the components of variable consideration. Variable consideration includes the following components: 
government rebates, including performance-based rebates, trade discounts and allowances, and other incentives, which are 
described below.
These reserves are based on estimates of the amounts earned or to be claimed on the related sales and are classified as a 
liability. Our estimates of reserves established for variable consideration are calculated based upon an application of the 
expected value method, which is the sum of probability-weighted amounts in a range of possible consideration amounts. 
These estimates reflect our historical experience, current contractual and statutory requirements, specific known market 
events and trends, industry data, and current expectations around final pricing. The amount of variable consideration that is 
included in the transaction price may be subject to constraint and is included in net product revenue only to the extent that it 
is probable that a significant reversal in the amount of the cumulative revenue recognized will not occur in a future period. 
Actual amounts of consideration received may ultimately differ from our estimates. If actual results vary, we adjust these 
estimates, which could have an effect on earnings in the period of adjustment. The following is a summary of the types of 
variable consideration the Company records:

109
Government rebates: We are subject to statutory government rebates on sales in certain European countries as well as 
estimated rebates in certain European countries because final pricing has not yet been negotiated. We record reserves 
for rebates in the same period the related product revenue is recognized, resulting in a reduction of product revenue and 
a current liability that is included in accrued expenses on our consolidated balance sheet. We are also subject to 
potential rebates in connection with performance criteria agreed upon with certain payors. The estimate for rebates is 
based on statutory discount rates, industry pricing data, current expectations around final pricing to be obtained, and 
historical experience of the performance of our products during clinical trials. 
Trade discounts and allowances: We may offer customers discounts, such as prompt pay discounts to remit payment in 
accordance with the stated terms of the invoice and fees for distribution services. These discounts are explicitly stated 
in the contracts and recorded in the period the related product revenue is recognized. Our payment terms can range 
from 30 days to under 1 year. We estimate which customers will earn these discounts and fees and deducts these 
discounts and fees in full from gross product revenue and accounts receivable at the time we recognize the related 
revenue.
Product returns: Based on the timing of revenue recognition upon treatment with the patient, we do not expect any 
returns of our products.  
Other incentives: While we do not currently have any other incentives that have been recorded to date, we may enter 
into future arrangements that have other incentives that will be recorded as a reduction of revenue.  
Off-balance sheet arrangements. 
We did not have during the periods presented, and we do not currently have, any off-balance sheet arrangements, as defined 
in the rules and regulations of the SEC.
Item 7A. Quantitative and Qualitative Disclosures About Market Risk. 
Interest rate sensitivity 
As of December 31, 2022, we had cash, cash equivalents, marketable securities, and restricted cash of $148.0 million. Our 
exposure to interest rate sensitivity is impacted by changes in the underlying UK and U.S. bank interest rates. Our surplus 
cash has been invested in corporate bonds, commercial paper, U.S. treasuries, and money market accounts. We have not 
entered into investments for trading or speculative purposes. Due to the conservative nature of our investment portfolio, 
which is predicated on capital preservation of investments with short-term maturities, we do not believe an immediate one 
percentage point change in interest rates would have a material effect on the fair market value of our portfolio, and therefore 
we do not expect our operating results or cash flows to be significantly affected by changes in market interest rates. 
We have borrowed $33.0 million under our credit facility. Amounts outstanding under the credit facility bear interest at a 
variable interest rate of 5.95% plus LIBOR. As of December 31, 2022, the carrying value of the term loans under the credit 
facility was $32.7 million.
In 2017, the United Kingdom’s Financial Conduct Authority announced that after 2021 it would no longer compel banks to 
submit the rates required to calculate the London Interbank Offered Rate (LIBOR) and other interbank offered rates, which 
have been widely used as reference rates for various securities and financial contracts, including loans, debt and derivatives. 
This announcement indicates that the continuation of LIBOR on the current basis is not guaranteed after 2021. Regulators in 
the U.S. and other jurisdictions have been working to replace these rates with alternative reference interest rates that are 
supported by transactions in liquid and observable markets, such as the Secured Overnight Financing Rate (SOFR). 
Currently, our credit facilities reference LIBOR-based rates. In January 2023, we amended and restated our credit facility to 
change from LIBOR to SOFR. The newly amended facility bears a variable interest rate of 5.95% above SOFR plus 0.10% 
per annum, plus a final payment equal to 3.5% of the principal borrowed under the Amended Credit Facility. 
Foreign currency exchange risk 
The Company is exposed to foreign currency exchange risk because it currently operates in the United Kingdom and the 
United States. The reporting currency of the Company is the U.S. dollar. The Company has determined the functional 
currency of the ultimate parent company, Orchard Therapeutics plc, is U.S. dollars because it predominantly raises finance 
and expends cash in U.S. dollars and expects to continue to do so in the future. Monetary assets and liabilities denominated in 
currencies other than the functional currency are translated into the functional currency of the relevant entity at rates of 
exchange prevailing at the balance sheet dates. Non-monetary assets and liabilities denominated in foreign currencies are 
translated into the functional currency at the exchange rates prevailing at the date of the transaction. Exchange gains or losses 
arising from foreign currency transactions are included in the determination of net income (loss) for the respective periods. 
We recorded realized and unrealized foreign currency losses of $24.3 million and $1.2 million for the years ended December 

110
31, 2022 and 2021. These foreign currency transaction gains and losses are included in other (expense) income in our 
consolidated statements of operations and comprehensive loss. 
Assets and liabilities have been translated at the exchange rates at the balance sheet dates, while revenue and expenses are 
translated at the average exchange rates over the reporting period and shareholders’ equity amounts are translated based on 
historical exchange rates as of the date of each transaction. Translation adjustments are not included in determining net loss 
but are included in our foreign currency translation adjustment to other comprehensive loss, a component of shareholders’ 
equity. 
We do not currently engage in currency hedging activities in order to reduce our currency exposure, but we may begin to do 
so in the future. Instruments that may be used to hedge future risks include foreign currency forward and swap contracts. 
These instruments may be used to selectively manage risks, but there can be no assurance that we will be fully protected 
against material foreign currency fluctuations.
Item 8. Financial Statements and Supplementary Data. 
Our consolidated financial statements are appended at the end of this Annual Report, starting at page F-1, and incorporated 
herein by reference.
Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure.
None.
Item 9A. Controls and Procedures. 
Evaluation of Disclosure Controls and Procedures
We maintain disclosure controls and procedures (as defined in Rules 13a-15(e) or 15d-15(e) under the Securities Exchange 
Act of 1934, as amended, or the Exchange Act) that are designed to ensure that information required to be disclosed in 
reports that we file or submit under the Exchange Act is (1) recorded, processed, summarized, and reported within the time 
periods specified in the SEC’s rules and forms and (2) accumulated and communicated to our management, including our 
principal executive officer and principal financial officer, as appropriate, to allow timely decisions regarding required 
disclosure.
Our management, with the participation of our principal executive officer and principal financial officer, evaluated the 
effectiveness of our disclosure controls and procedures as of the end of the period covered by this report. In designing and 
evaluating our disclosure controls and procedures, our management recognizes that any controls and procedures, no matter 
how well designed and operated, can provide only reasonable assurance of achieving their objectives, and management 
necessarily applies its judgment in evaluating the cost-benefit relationship of possible controls and procedures. Our principal 
executive officer and principal financial officer have concluded based upon the evaluation described above that, as of 
December 31, 2022, our disclosure controls and procedures were effective at the reasonable assurance level.
We continue to review and document our disclosure controls and procedures, including our internal controls and procedures 
for financial reporting, and may from time to time make changes aimed at enhancing their effectiveness and to ensure that our 
systems evolve with our business in accordance with the Exchange Act.
Management’s Annual Report on Internal Control Over Financial Reporting
Our management is responsible for establishing and maintaining adequate internal control over financial reporting as defined 
in Rules 13a-15(f) and 15d-15(f) under the Exchange Act. Our internal control over financial reporting is a process designed 
to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for 
external purposes in accordance with general accepted accounting principles. Because of its inherent limitations, internal 
control over financial reporting may not prevent or detect misstatements. Projections of any evaluation of effectiveness to 
future periods are subject to the risk that controls may become inadequate because of changes in conditions, or that the degree 
of compliance with the policies or procedures may deteriorate.
Under the supervision and with the participation of our management, including our principal executive officer and principal 
financial officer, we conducted an evaluation of the effectiveness of our internal control over financial reporting based on the 
2013 framework in Internal Control – Integrated Framework issued by the Committee of Sponsoring Organizations of the 
Treadway Commission. Based on our evaluation under that framework, our management concluded that our internal control 
over financial reporting was effective as of December 31, 2022.

111
Changes in Internal Control Over Financial Reporting
There were no changes in our internal control over financial reporting (as defined in Rules 13a-15(f) and 15d-15(f) under the 
Exchange Act) during the quarter ended December 31, 2022 that have materially affected, or are reasonably likely to 
materially affect, our internal control over financial reporting.
Item 9B. Other Information. 
The following summary contains a description of material U.S. federal income tax and UK tax consequences of the 
acquisition, ownership and disposition of our ordinary shares or ADSs. This summary should not be considered a 
comprehensive description of all the tax considerations that may be relevant to beneficial owners of ADSs.
Material U.S. federal income tax considerations for U.S. holders
The following is a description of the material U.S. federal income tax consequences to the U.S. Holders described below of 
owning and disposing of our ordinary shares or ADSs. It is not a comprehensive description of all tax considerations that may 
be relevant to a particular person’s decision to acquire securities. This discussion applies only to a U.S. Holder that holds our 
ordinary shares or ADSs as a capital asset for tax purposes (generally, property held for investment). In addition, it does not 
describe all of the tax consequences that may be relevant in light of a U.S. Holder’s particular circumstances, including state 
and local tax consequences, estate tax consequences, alternative minimum tax consequences, the potential application of the 
Medicare contribution tax, and tax consequences applicable to U.S. Holders subject to special rules, such as: 
•
banks, insurance companies, and certain other financial institutions; 
•
U.S. expatriates and certain former citizens or long-term residents of the United States; 
•
dealers or traders in securities who use a mark-to-market method of tax accounting; 
•
persons holding ordinary shares or ADSs as part of a hedging transaction, “straddle,” wash sale, conversion 
transaction or integrated transaction or persons entering into a constructive sale with respect to ordinary shares or 
ADSs; 
•
persons whose “functional currency” for U.S. federal income tax purposes is not the U.S. dollar; 
•
brokers, dealers or traders in securities, commodities or currencies; 
•
tax-exempt entities or government organizations; 
•
S corporations, partnerships, or other entities or arrangements classified as partnerships for U.S. federal income 
tax purposes; 
•
regulated investment companies or real estate investment trusts; 
•
persons who acquired our ordinary shares or ADSs pursuant to the exercise of any employee stock option or 
otherwise as compensation; and 
•
persons holding our ordinary shares or ADSs in connection with a trade or business, permanent establishment, or 
fixed base outside the United States. 
If an entity that is classified as a partnership for U.S. federal income tax purposes holds ordinary shares or ADSs, the U.S. 
federal income tax treatment of a partner will generally depend on the status of the partner and the activities of the 
partnership. Partnerships holding ordinary shares or ADSs and partners in such partnerships are encouraged to consult their 
tax advisers as to the particular U.S. federal income tax consequences of holding and disposing of ordinary shares or ADSs. 
The discussion is based on the Code, administrative pronouncements, judicial decisions, final, temporary and proposed 
Treasury Regulations, and the income tax treaty between the United Kingdom and the United States, or the Treaty, all as of 
the date hereof, changes to any of which may affect the tax consequences described herein—possibly with retroactive effect.  
A “U.S. Holder” is a holder who, for U.S. federal income tax purposes, is a beneficial owner of ordinary shares or ADSs and 
is: 
i.
An individual who is a citizen or individual resident of the United States; 
ii.
a corporation, or other entity taxable as a corporation, created or organized in or under the laws of the United 
States, any state therein or the District of Columbia; 

112
iii.
an estate the income of which is subject to U.S. federal income taxation regardless of its source; or 
iv.
a trust if (1) a U.S. court is able to exercise primary supervision over the administration of the trust and one or 
more U.S. persons have authority to control all substantial decisions of the trust or (2) the trust has a valid 
election to be treated as a U.S. person under applicable U.S. Treasury Regulations. 
The discussion below assumes that the representations contained in the deposit agreement are true and that the obligations in 
the deposit agreement and any related agreement will be complied with in accordance with their terms. Generally, a holder of 
an ADS should be treated for U.S. federal income tax purposes as holding the ordinary shares represented by the ADS. 
Accordingly, no gain or loss will be recognized upon an exchange of ADSs for ordinary shares. The U.S. Treasury has 
expressed concerns that intermediaries in the chain of ownership between the holder of an ADS and the issuer of the security 
underlying the ADS may be taking actions that are inconsistent with the beneficial ownership of the underlying security. 
Accordingly, the creditability of foreign taxes, if any, as described below, could be affected by actions taken by 
intermediaries in the chain of ownership between the holders of ADSs and our company if as a result of such actions the 
holders of ADSs are not properly treated as beneficial owners of the underlying ordinary shares. These actions would also be 
inconsistent with the claiming of the reduced tax rate, described below, applicable to dividends received by certain non-
corporate holders. 
PERSONS CONSIDERING AN INVESTMENT IN ORDINARY SHARES OR ADSs SHOULD CONSULT THEIR OWN 
TAX ADVISORS AS TO THE PARTICULAR TAX CONSEQUENCES APPLICABLE TO THEM RELATING TO THE 
ACQUISITION, OWNERSHIP AND DISPOSITION OF THE ORDINARY SHARES OR ADSs, INCLUDING THE 
APPLICABILITY OF U.S. FEDERAL, STATE AND LOCAL TAX LAWS. 
PFIC Rules 
If we are classified as a PFIC in any taxable year, a U.S. Holder will be subject to special rules generally intended to reduce 
or eliminate any benefits from the deferral of U.S. federal income tax that a U.S. Holder could derive from investing in a non-
U.S. company that does not distribute all of its earnings on a current basis. 
A non-U.S. corporation will be classified as a PFIC for any taxable year in which, after applying certain look-through rules, 
either: 
•
at least 75% of its gross income is passive income (such as interest income); or 
•
at least 50% of its gross assets (determined on the basis of a quarterly average) is attributable to assets that 
produce passive income or are held for the production of passive income. 
We will be treated as owning our proportionate share of the assets and earning our proportionate share of the income of any 
other corporation, the equity of which we own, directly or indirectly, 25% or more (by value).  
Based on the current and expected composition of our income and assets and the value of our assets, we believe that we were 
a PFIC for U.S. federal income tax purposes for our taxable year ended December 31, 2022. However, a separate 
determination must be made after the close of each taxable year as to whether we are a PFIC for that year. As a result, our 
PFIC status may change from year to year, and we may be classified as a PFIC currently or in the future. The total value of 
our assets for purposes of the asset test generally will be calculated using the market price of the ordinary shares or ADSs, 
which may fluctuate considerably. Fluctuations in the market price of the ordinary shares or ADSs may result in our being a 
PFIC for any taxable year. However, if we are a “controlled foreign corporation” for any taxable year (see discussion below 
in “Controlled foreign corporation considerations”), the value of our assets for purposes of the asset test will be determined 
based on the tax basis of such assets which could increase the likelihood that we are treated as a PFIC. Because of the 
uncertainties involved in establishing our PFIC status, there can be no assurance regarding if we currently are treated as a 
PFIC or may be treated as a PFIC in the future. 
If we are classified as a PFIC in any year with respect to which a U.S. Holder owns the ordinary shares or ADSs, we will 
continue to be treated as a PFIC with respect to such U.S. Holder in all succeeding years during which the U.S. Holder owns 
the ordinary shares or ADSs, regardless of whether we continue to meet the tests described above unless (i) we cease to be a 
PFIC and the U.S. Holder has made a “deemed sale” election under the PFIC rules, or (ii) the U.S. Holder makes a Qualified 
Electing Fund Election, or QEF Election, with respect to all taxable years during such U.S. Holders holding period in which 
we are a PFIC. If the “deemed sale” election is made, a U.S. Holder will be deemed to have sold the ordinary shares or ADSs 
the U.S. Holder holds at their fair market value and any gain from such deemed sale would be subject to the rules described 
below. After the deemed sale election, so long as we do not become a PFIC in a subsequent taxable year, the U.S. Holder’s 
ordinary shares or ADSs with respect to which such election was made will not be treated as shares in a PFIC and the U.S. 
Holder will not be subject to the rules described below with respect to any “excess distribution” the U.S. Holder receives 
from us or any gain from an actual sale or other disposition of the ordinary shares or ADSs. U.S. Holders should consult their 
tax advisors as to the possibility and consequences of making a deemed sale election if we cease to be a PFIC and such 
election becomes available. 

113
For each taxable year we are treated as a PFIC with respect to U.S. Holders, U.S. Holders will be subject to special tax rules 
with respect to any “excess distribution” such U.S. Holder receives and any gain such U.S. Holder recognizes from a sale or 
other disposition (including, under certain circumstances, a pledge) of ordinary shares or ADSs, unless (i) such U.S. Holder 
makes a QEF Election or (ii) our ordinary shares or ADSs constitute “marketable“ securities, and such U.S. Holder makes a 
mark-to-market election as discussed below. Distributions a U.S. Holder receives in a taxable year that are greater than 125% 
of the average annual distributions a U.S. Holder received during the shorter of the three preceding taxable years or the U.S. 
Holder’s holding period for the ordinary shares or ADSs will be treated as an excess distribution. Under these special tax 
rules: 
•
the excess distribution or gain will be allocated ratably over a U.S. Holder’s holding period for the ordinary 
shares or ADSs; 
•
the amount allocated to the current taxable year, and any taxable year prior to the first taxable year in which we 
became a PFIC, will be treated as ordinary income; and 
•
the amount allocated to each other year will be subject to the highest tax rate in effect for that year and the 
interest charge generally applicable to underpayments of tax will be imposed on the resulting tax attributable to 
each such year.
The tax liability for amounts allocated to years prior to the year of disposition or “excess distribution” cannot be offset by any 
net operating losses for such years, and gains (but not losses) realized on the sale of the ordinary shares or ADSs cannot be 
treated as capital, even if a U.S. Holder holds the ordinary shares or ADSs as capital assets. 
Because it was possible that we were a PFIC for the 2022 taxable year, we currently expect that we will provide the 
information necessary for U.S. holders to make a QEF Election. We may elect to provide such information on our website 
(www.ORTX.com). In addition, if we are a PFIC, a U.S. Holder will generally be subject to similar rules with respect to 
distributions we receive from, and our dispositions of the stock of, any of our direct or indirect subsidiaries that also are 
PFICs, as if such distributions were indirectly received by, and/or dispositions were indirectly carried out by, such U.S. 
Holder. U.S. Holders should consult their tax advisors regarding the application of the PFIC rules to our subsidiaries. 
U.S. Holders can avoid the interest charge on excess distributions or gain relating to the ordinary shares or ADSs by making 
a mark-to-market election with respect to the ordinary shares or ADSs, provided that the ordinary shares or ADSs are 
“marketable.” Ordinary shares or ADSs will be marketable if they are “regularly traded” on certain U.S. stock exchanges or 
on a foreign stock exchange that meets certain conditions. For these purposes, the ordinary shares or ADSs will be considered 
regularly traded during any calendar year during which they are traded, other than in de minimis quantities, on at least 15 
days during each calendar quarter. Any trades that have as their principal purpose meeting this requirement will be 
disregarded. Our ADSs will be listed on Nasdaq, which is a qualified exchange for these purposes. Consequently, if our 
ADSs remain listed on Nasdaq and are regularly traded, we expect the mark-to-market election would be available to U.S. 
Holders if we are a PFIC. Each U.S. Holder should consult its tax advisor as to the whether a mark-to-market election is 
available or advisable with respect to the ordinary shares or ADSs. 
A U.S. Holder that makes a mark-to-market election must include in ordinary income for each year an amount equal to the 
excess, if any, of the fair market value of the ordinary shares or ADSs at the close of the taxable year over the U.S. Holder’s 
adjusted tax basis in the ordinary shares or ADSs. An electing holder may also claim an ordinary loss deduction for the 
excess, if any, of the U.S. Holder’s adjusted basis in the ordinary shares or ADSs over the fair market value of the ordinary 
shares or ADSs at the close of the taxable year, but this deduction is allowable only to the extent of any net mark-to-market 
gains for prior years. Gains from an actual sale or other disposition of the ordinary shares or ADSs will be treated as ordinary 
income, and any losses incurred on a sale or other disposition of the shares will be treated as an ordinary loss to the extent of 
any net mark-to-market gains for prior years. Once made, the election cannot be revoked without the consent of the Internal 
Revenue Service, or the IRS, unless the ordinary shares or ADSs cease to be marketable. 
However, a mark-to-market election generally cannot be made for equity interests in any lower-tier PFICs that we own, 
unless shares of such lower-tier PFIC are themselves “marketable.” As a result, even if a U.S. Holder validly makes a mark-
to-market election with respect to our ordinary shares or ADSs, the U.S. Holder may continue to be subject to the PFIC rules 
(described above) with respect to its indirect interest in any of our investments that are treated as an equity interest in a PFIC 
for U.S. federal income tax purposes. U.S. Holders should consult their tax advisors to determine whether any of these 
elections would be available and if so, what the consequences of the alternative treatments would be in their particular 
circumstances. 
Unless otherwise provided by the U.S. Treasury, each U.S. shareholder of a PFIC is required to file an Annual Report 
containing such information as the U.S. Treasury may require. A U.S. Holder’s failure to file the Annual Report will cause 
the statute of limitations for such U.S. Holder’s U.S. federal income tax return to remain open with regard to the items 
required to be included in such report until three years after the U.S. Holder files the Annual Report, and, unless such failure 

114
is due to reasonable cause and not willful neglect, the statute of limitations for the U.S. Holder’s entire U.S. federal income 
tax return will remain open during such period. U.S. Holders should consult their tax advisors regarding the requirements of 
filing such information returns under these rules. 
WE STRONGLY URGE OUR INVESTORS TO CONSULT THEIR TAX ADVISOR REGARDING THE IMPACT OF 
OUR PFIC STATUS ON THEIR INVESTMENTS IN OUR ORDINARY SHARES OR ADSs AS WELL AS THE 
APPLICATION OF THE PFIC RULES TO THEIR INVESTMENT IN OUR ORDINARY SHARES OR ADSs. 
Controlled foreign corporation considerations 
Each “Ten Percent Shareholder” (as defined below) in a non-U.S. corporation that is classified as a “controlled foreign 
corporation,” or a CFC, for U.S. federal income tax purposes generally is required to include in income each year for U.S. 
federal tax purposes such Ten Percent Shareholder’s pro rata share of certain types of income earned by the CFC, including 
“Subpart F income,” “global intangible low-taxed income” and certain other income generated by the CFC, even if the CFC 
has made no distributions to its shareholders. In addition, a Ten Percent Shareholder that realizes gain from the sale or 
exchange of shares in the CFC may be required to classify a portion of such gain as dividend income rather than capital gain 
(see discussion below in “Taxation of distributions” regarding the tax treatment of dividend income). A non-U.S. corporation 
generally will be classified as a CFC for U.S. federal income tax purposes if Ten Percent Shareholders own, directly or 
indirectly, more than 50% of either the total combined voting power of all classes of stock of such corporation entitled to vote 
or of the total value of the stock of such corporation. A “Ten Percent Shareholder” is a United States person (as defined by 
the Code) who owns or is considered to own 10% or more of either the total combined voting power of all classes of stock of 
such corporation entitled to vote or of the total value of the stock of such corporation. 
We believe that we were not a CFC in the 2021 taxable year, though we have not made a determination regarding our CFC 
status in the current taxable year, and we may become a CFC in a subsequent taxable year. The determination of CFC status 
is complex and includes attribution rules, the application of which is not entirely certain. In addition, recent changes to the 
attribution rules relating to the determination of CFC status may make it difficult to determine our CFC status for any taxable 
year. It is possible that a shareholder treated as a U.S. person for U.S. federal income tax purposes will acquire, directly or 
indirectly, enough shares to be treated as a Ten Percent Shareholder. U.S. Holders should consult their own tax advisors with 
respect to the potential adverse U.S. tax consequences of becoming a Ten Percent Shareholder in a CFC. If we are classified 
as both a CFC and a PFIC, we generally will not be treated as a PFIC with respect to those U.S. Holders that meet the 
definition of a Ten Percent Shareholder during the period in which we are a CFC. 
Taxation of distributions 
Subject to the discussion above under “PFIC rules,” distributions paid on ordinary shares or ADSs, other than certain pro rata 
distributions of ordinary shares or ADSs, will generally be treated as dividends to the extent paid out of our current or 
accumulated earnings and profits (as determined under U.S. federal income tax principles). Because we may not calculate our 
earnings and profits under U.S. federal income tax principles, we expect that distributions generally will be reported to U.S. 
Holders as dividends. Subject to applicable limitations and the discussions above regarding concerns expressed by the U.S. 
Treasury, dividends paid to certain non-corporate U.S. Holders may be taxable at preferential rates applicable to “qualified 
dividend income” if we are a “qualified foreign corporation” and certain other requirements are met. However, the qualified 
dividend income treatment may not apply if we are treated as a PFIC with respect to the U.S. Holder. The amount of the 
dividend will be treated as foreign-source dividend income to U.S. Holders and will not be eligible for the dividends-received 
deduction generally available to U.S. corporations under the Code. Dividends will generally be included in a U.S. Holder’s 
income on the date of the U.S. Holder’s receipt of the dividend. The amount of any dividend income paid in foreign currency 
will be the U.S. dollar amount calculated by reference to the exchange rate in effect on the date of actual or constructive 
receipt, regardless of whether the payment is in fact converted into U.S. dollars. If the dividend is converted into U.S. dollars 
on the date of receipt, a U.S. Holder should not be required to recognize foreign currency gain or loss in respect of the 
dividend income. A U.S. Holder may have foreign currency gain or loss if the dividend is converted into U.S. dollars after the 
date of receipt. Such gain or loss would generally be treated as U.S.-source ordinary income or loss. The amount of any 
distribution of property other than cash (and other than certain pro rata distributions of ordinary shares or ADSs or rights to 
acquire ordinary shares or ADSs) will be the fair market value of such property on the date of distribution. 
For foreign tax credit limitation purposes, our dividends will generally be treated as passive category income. Because no UK 
income taxes will be withheld from dividends on ordinary shares or ADSs, there will be no creditable foreign taxes 
associated with any dividends that a U.S. Holder will receive. The rules governing foreign tax credits are complex and U.S. 
Holders should therefore consult their tax advisers regarding the effect of the receipt of dividends for foreign tax credit 
limitation purposes. 

115
Sale or other taxable disposition of ordinary shares and ADSs 
Subject to the discussion above under “PFIC rules,” gain or loss realized on the sale or other taxable disposition of ordinary 
shares or ADSs will be capital gain or loss and will be long-term capital gain or loss if the U.S. Holder held the ordinary 
shares or ADSs for more than one year. The amount of the gain or loss will equal the difference between the U.S. Holder’s 
tax basis in the ordinary shares or ADSs disposed of and the amount realized on the disposition, in each case as determined in 
U.S. dollars. This gain or loss will generally be U.S.-source gain or loss for foreign tax credit purposes. The deductibility of 
capital losses is subject to limitations. 
If the consideration received by a U.S. Holder is not paid in U.S. dollars, the amount realized will be the U.S. dollar value of 
the payment received determined by reference to the spot rate of exchange on the date of the sale or other disposition. 
However, if the ordinary shares or ADSs are treated as traded on an “established securities market” and you are either a cash 
basis taxpayer or an accrual basis taxpayer that has made a special election (which must be applied consistently from year to 
year and cannot be changed without the consent of the IRS), you will determine the U.S. dollar value of the amount realized 
in a non-U.S. dollar currency by translating the amount received at the spot rate of exchange on the settlement date of the 
sale. If you are an accrual basis taxpayer that is not eligible to or does not elect to determine the amount realized using the 
spot rate on the settlement date, you will recognize foreign currency gain or loss to the extent of any difference between the 
U.S. dollar amount realized on the date of sale or disposition and the U.S. dollar value of the currency received at the spot 
rate on the settlement date. 
Information reporting and backup withholding 
Payments of dividends and sales proceeds that are made within the United States or through certain U.S.-related financial 
intermediaries generally are subject to information reporting, and may be subject to backup withholding, unless (i) the U.S. 
Holder is a corporation or other exempt recipient or (ii) in the case of backup withholding, the U.S. Holder provides a correct 
taxpayer identification number and certifies that it is not subject to backup withholding on a duly executed Form W-9 or 
otherwise establishes an exemption. 
Backup withholding is not an additional tax. The amount of any backup withholding from a payment to a U.S. Holder will be 
allowed as a credit against the U.S. Holder’s U.S. federal income tax liability and may entitle the U.S. Holder to a refund, 
provided that the required information is timely furnished to the IRS. 
Information with respect to foreign financial assets 
Certain U.S. Holders who are individuals (and, under regulations, certain entities) may be required to report information 
relating to the ordinary shares or ADSs, subject to certain exceptions (including an exception for ordinary shares or ADSs 
held in accounts maintained by certain U.S. financial institutions), by filing IRS Form 8938 (Statement of Specified Foreign 
Financial Assets) with their federal income tax return. Such U.S. Holders who fail to timely furnish the required information 
may be subject to a penalty. Additionally, if a U.S. Holder does not file the required information, the statute of limitations 
with respect to tax returns of the U.S. Holder to which the information relates may not close until three years after such 
information is filed. U.S. Holders should consult their tax advisers regarding their reporting obligations with respect to their 
ownership and disposition of the ordinary shares or ADSs. 
UK Taxation
The following is intended as a general guide to current UK tax law and HMRC published practice (which is not binding) 
applying as at the date of this Annual Report on Form 10-K (both of which are subject to change at any time, possibly with 
retrospective effect) relating to the holding of ADSs. It does not constitute legal or tax advice and does not purport to be a 
complete analysis of all UK tax considerations relating to the holding of ADSs, or all of the circumstances in which holders 
of ADSs may benefit from an exemption or relief from UK taxation. It is written on the basis that the company is not (and 
will not) directly or indirectly at any time derive 75% or more of our qualifying asset value from UK land, and that it is and 
remains solely resident in the UK for tax purposes and will therefore be subject to the UK tax regime and not the U.S. tax 
regime save as set out above under “Material U.S. federal income tax considerations for U.S. Holders.”
Except to the extent that the position of non-UK resident persons is expressly referred to, this guide relates only to persons 
who are resident (and in the case of individuals, domiciled or deemed domiciled) for tax purposes solely in the UK and do 
not have a permanent establishment, branch or agency (or equivalent) in any other jurisdiction with which the holding of the 
ADSs is connected, or UK Holders, who are absolute beneficial owners of the ADSs (and do not hold the ADSs through an 
Individual Savings Account or a Self-Invested Personal Pension) and any dividends paid in respect of the ADSs or 
underlying ordinary shares (where the dividends are regarded for UK tax purposes as that person’s own income). It is 
assumed that for the purposes of this guide that a holder of an ADS is the beneficial owner of the underlying ordinary share 
and any dividend income for UK direct tax purposes. 

116
This guide may not relate to certain classes of UK Holders, such as (but not limited to): 
•
persons who are connected with the company;
•
financial institutions;
•
insurance companies; 
•
charities or tax-exempt organizations;
•
collective investment schemes;
•
pension schemes;
•
brokers or dealers in securities or persons who hold ADSs otherwise than as an investment;
•
persons who have (or are deemed to have) acquired their ADSs by virtue of an office or employment or who are 
or have been officers or employees of the company or any of its affiliates; and 
•
individuals who are subject to UK taxation on a remittance basis or to whom split year treatment applies. 
THESE PARAGRAPHS ARE A SUMMARY OF CERTAIN UK TAX CONSIDERATIONS AND ARE INTENDED AS A 
GENERAL GUIDE ONLY. IT IS RECOMMENDED THAT ALL HOLDERS OF ADSs OBTAIN ADVICE AS TO THE 
CONSEQUENCES OF THE ACQUISITION, OWNERSHIP AND DISPOSAL OF THE ADSs IN THEIR OWN 
PARTICULAR CIRCUMSTANCES FROM THEIR OWN TAX ADVISORS. IN PARTICULAR, NON-UK RESIDENT 
OR DOMICILED PERSONS OR PERSONS SUBJECT TO TAXATION IN ANY JURISDICTION OTHER THAN THE 
UK ARE ADVISED TO CONSIDER THE POTENTIAL IMPACT OF ANY RELEVANT DOUBLE TAXATION 
AGREEMENTS. 
Dividends 
Withholding Tax 
Dividends paid by the company will not be subject to any withholding or deduction for or on account of UK tax. 
Income Tax 
An individual UK Holder may, depending on his or her particular circumstances, be subject to UK tax on dividends received 
from the company. An individual holder of ADSs who is not resident for tax purposes in the United Kingdom should not be 
chargeable to UK income tax on dividends received from the company unless he or she carries on (whether solely or in 
partnership) a trade, profession or vocation in the UK through a permanent establishment, branch or agency to which the 
ADSs are attributable. There are certain exceptions for trading in the UK through independent agent, such as some brokers 
and investment managers.
Dividend income is treated as the top slice of the total income chargeable to UK income tax for an individual UK Holder. An 
individual UK Holder who receives a dividend in the 2022/2023 tax year will be entitled to a tax-free allowance of £2,000. 
Income within the dividend allowance counts towards an individual’s basic or higher rate limits and may, therefore, affect the 
level of personal allowance to which they are entitled. Dividend income in excess of this tax-free allowance will (subject to 
the availability of any income tax personal allowance) be charged at 8.75% to the extent the excess amount falls within the 
basic rate band, 33.75% to the extent the excess amount falls within the higher rate band, and 39.35% to the extent the excess 
amount falls within the additional rate band. The UK government has announced that the dividend tax-free allowance of 
£2,000 will be reduced to £1,000 with effect from April 2023 for the tax year 2023/2024 and to £500 with effect from April 
2024 for the tax year 2024/2025 and thereafter. 
Corporation tax 
A corporate holder of ADSs who is not resident for tax purposes in the United Kingdom should not be chargeable to UK 
corporation tax on dividends received from the company unless it carries on (whether solely or in partnership) a trade in the 
United Kingdom through a permanent establishment to which the ADSs are attributable. 
Corporate UK Holders should not be subject to UK corporation tax on any dividend received from the company so long as 
the dividends qualify for exemption, which should be the case, although certain conditions must be met. It should be noted 
that the exemptions, whilst of wide application, are not comprehensive and are subject to anti-avoidance rules in relation to a 
dividend. If the conditions for the exemption are not satisfied, or such anti-avoidance provisions apply, or such UK Holder 
elects for an otherwise exempt dividend to be taxable, UK corporation tax will be chargeable on the amount of any dividends 

117
(at the current rate of 19% for the tax year 2022/2023, rising to 25% in the tax year 2023/2024 for companies with profits of 
more than £250,000, whilst the rate of 19% will apply to companies with profits not exceeding £50,000 with a tapered rate 
applying to profits between £50,000 and £250,000). 
Chargeable gains 
A disposal or deemed disposal of ADSs by a UK Holder may, depending on the UK Holder’s circumstances and subject to 
any available exemptions or reliefs (such as the annual exemption), give rise to a chargeable gain or an allowable loss for the 
purposes of UK capital gains tax and corporation tax on chargeable gains. 
If an individual UK Holder who is subject to UK income tax at either the higher or the additional rate is liable to UK capital 
gains tax on the disposal of ADSs, the applicable rate will be 20% (for the tax year 2022/2023). For an individual UK Holder 
who is subject to UK income tax at the basic rate and liable to UK capital gains tax on such disposal, the applicable rate 
would be 10% (for the tax year 2022/2023), save to the extent that any capital gains when aggregated with the UK Holder’s 
other taxable income and gains in the relevant tax year exceed the unused basic rate tax band. In that case, the rate applicable 
to the excess would be 20% (for the tax year 2022/2023). 
If a corporate UK Holder becomes liable to UK corporation tax on the disposal (or deemed disposal) of ADSs, the main rate 
of UK corporation tax would apply (currently at 19% for the tax year 2022/2023, rising to 25% in the tax year 2023/2024 for 
companies with profits of more than £50,000, whilst the rate of 19% will apply to companies with profits not exceeding 
£250,000 with a tapered rate applying to profits between £50,000 and £250,000). 
A holder of ADSs which is not resident for tax purposes in the UK should not normally be liable to UK capital gains tax or 
corporation tax on chargeable gains on a disposal (or deemed disposal) of ADSs, unless the person is carrying on (whether 
solely or in partnership) a trade, profession or vocation UK through a branch or agency (or, in the case of a corporate holder 
of ADSs, through a permanent establishment) to which the ADSs are attributable. However, an individual holder of ADSs 
who has ceased to be resident for tax purposes in the UK for a period of less than five years and who disposes of ADSs 
during that period of temporary non-residence may be liable on his or her return to the UK (or upon ceasing to be regarded as 
resident outside the UK for the purposes of double taxation treaty) to UK tax on any capital gain realized (subject to any 
available exemption or relief). 
Stamp duty and stamp duty reserve tax 
The discussion below relates to the holders of our ordinary shares or ADSs wherever resident, however it should be noted 
that special rules may apply to certain persons such as market makers, brokers, dealers or intermediaries. 
Issue of Ordinary Shares  
As a general rule, no UK stamp duty or stamp duty reserve tax (or SDRT) is payable on the issue of underlying ordinary 
shares in the company. 
Transfers of Ordinary Shares 
An unconditional agreement to transfer ordinary shares will normally give rise to a charge to SDRT at the rate of 0.5% of the 
amount or value of the consideration payable for the transfer. The purchaser of the shares is liable for the SDRT. Transfers of 
ordinary shares in certificated form are generally also subject to stamp duty at the rate of 0.5% of the amount or value of the 
consideration given for the transfer (rounded up to the next £5.00). Stamp duty is normally paid by the purchaser. The charge 
to SDRT will be canceled or, if already paid, repaid (generally with interest), where a transfer instrument has been duly 
stamped within six years of the charge arising, (either by paying the stamp duty or by claiming an appropriate relief) or if the 
instrument is otherwise exempt from stamp duty. 
Clearance Services and Depositary Receipts
Under current UK legislation, an issue or transfer of ordinary shares or an unconditional agreement to transfer ordinary shares 
to a clearance service or a depositary receipt system (including, to a nominee or agent for, a person whose business is or 
includes the issue of depositary receipts or the provision of clearance services) will generally be subject to SDRT (and, in the 
case of transfers, where the transfer is effected by a written instrument, stamp duty) at a higher rate of 1.5% of the amount or 
value of the consideration given for the transfer unless the clearance service has made and maintained an election under 
section 97A of the UK Finance Act 1986, or a section 97A election. It is understood that HMRC regards the facilities of DTC 
as a clearance service for these purposes and we are not aware of any section 97A election having been made by the DTC. 

118
However, based on current published HMRC practice following European Union case law in respect of the European Council 
Directives 69/335/EEC and 2009/7/EC, or the Capital Duties Directives, no SDRT is generally payable in respect of such an 
issue of ordinary shares and no SDRT or stamp duty is generally payable in respect of such a transfer of ordinary shares 
where such transfer is an integral part of an issue of share capital. This position was reaffirmed by HMRC in their January 
2021 Newsletter where they confirmed that the SDRT 1.5% charge on issues (or transfers integral to capital raising) 
remained disapplied under the terms of the European Union (Withdrawal) Act 2018 following the end of the transition period 
and that this would remain the position unless stamp taxes on shares legislation was amended. 
Any stamp duty or SDRT payable on a transfer of ordinary shares to a depositary receipt system or clearance service will in 
practice generally be paid by the transferors or participants in the clearance service or depositary receipt system. Specific 
professional advice should be sought before incurring or reimbursing the costs of a 1.5% charge.
Transfers of ADSs 
No UK SDRT or stamp duty is required to be paid in respect of the issue of or an agreement to transfer ADS (including by 
way of a paperless transfer of ADSs through the facilities of DTC). 
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections.
Not applicable.

119
PART III 
Item 10. Directors, Executive Officers and Corporate Governance. 
The information required under this item is incorporated herein by reference to our definitive proxy statement for our 2023 
annual general meeting to be filed with the U.S. Securities and Exchange Commission. 
Item 11. Executive Compensation. 
The information required under this item is incorporated herein by reference to our definitive proxy statement for our 2023 
annual general meeting to be filed with the U.S. Securities and Exchange Commission.
Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters. 
The information required under this item is incorporated herein by reference to our definitive proxy statement for our 2023 
annual general meeting to be filed with the U.S. Securities and Exchange Commission.
Item 13. Certain Relationships and Related Transactions, and Director Independence. 
The information required under this item is incorporated herein by reference to our definitive proxy statement for our 2023 
annual general meeting to be filed with the U.S. Securities and Exchange Commission.
Item 14. Principal Accounting Fees and Services. 
The information required under this item is incorporated herein by reference to our definitive proxy statement for our 2023 
annual general meeting to be filed with the U.S. Securities and Exchange Commission.

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PART IV 
Item 15. Exhibits, Financial Statement Schedules. 
The following documents are filed as part of this Annual Report on Form 10-K:
(a) (1) Financial Statements:
The financial statements required by this item are submitted in a separate section beginning on page F-1 of this Report, as 
follows:
 
Page
Report of Independent Registered Public Accounting Firm
 
F-2
Consolidated Balance Sheets
 
F-4
Consolidated Statements of Operations and Comprehensive Loss
 
F-5
Consolidated Statements of Shareholders’ Equity
 
F-6
Consolidated Statements of Cash Flows 
 
F-7
Notes to Consolidated Financial Statements
 
F-8
(a) (2) Financial Statement Schedules:
Not applicable.
(a) (3) Exhibits:
The Exhibits which are filed as part of this Annual Report or which are incorporated by reference are set forth in the Exhibit 
Index hereto.
EXHIBIT INDEX
Exhibit
Number
Description
Incorporated by 
Reference herein 
from Form or 
Schedule
Exhibit
File Date
File Number
2.1†
Asset Purchase and License Agreement, among 
the registrant, Glaxo Group Limited and 
GlaxoSmithKline Intellectual Property 
Development Ltd., dated April 11, 2018 
(Schedules, exhibits, and similar supporting 
attachments are omitted pursuant to Item 
601(b)(2) of Regulation S-K. The registrant agrees 
to furnish a supplemental copy of any omitted 
schedule or similar attachment to the Securities 
and Exchange Commission upon request).
Form F-1
2.1
Oct. 4, 2018
333-227698
3.1
Articles of Association of Orchard Therapeutics 
plc
Form 8-K
3.1
Jun. 19, 2020
001-38722
4.1
Deposit Agreement
Form 20-F
2.1
Mar. 22, 2019
001-38722
4.2*
Amendment No. 1 to Deposit Agreement
001-38722
4.3
Form of American Depositary Receipt (included 
in Exhibit 4.1)
Form 20-F
2.2
Mar. 22, 2019
001-38722
4.4
Investment and shareholders’ agreement between 
the registrant and the shareholders named therein, 
dated August 2, 2018, as amended.
Form F-1
10.1
Jun. 3, 2019
333-231916

121
4.5*
Description of the registrant’s securities.
001-38722
4.6
At-the-Market Letter Agreement
Form F-6
(b)
Feb. 10, 2023
001-38722
4.7
Form of Warrant
Form 8-K
4.1
Mar. 6, 2023
001-38722
10.1#
2016 Employee Share Option Plan with Non-
Employee Sub-Plan and U.S. Sub-Plan, as 
amended.
Form F-1
10.2
Oct. 4, 2018
333-227698
10.2#
2018 Share Option and Incentive Plan.
Form 20-F
4.3
Mar. 22, 2019
001-38722
10.3#
2018 Employee Share Purchase Plan.
Form F-1/A
10.10
Oct. 23, 2018
333-227698
10.4#
Forms of award agreements under the 2018 Share 
Option and Incentive Plan.
Form 10-K
10.13
Feb. 27, 2020
001-38722
10.5#
2019 Short-Term Incentive Plan.
Form 10-Q
10.1
May 7, 2020
001-38722
10.6#
2020 Inducement Equity Plan and forms of award 
agreements thereunder.
Form S-8
99.2
Aug. 6 2020
333-241646
10.7#
Form of Deed of Indemnity between the registrant 
and each of its directors and executive officers.
Form F-1
10.6
Oct. 4, 2018
333-227698
10.8
Deed of Novation, among the registrant, Glaxo 
Group Limited, GlaxoSmithKline Intellectual 
Property Development Limited, GlaxoSmithKline 
S.p.A., Fondazione Telethon and Ospedale San 
Raffaele (in its own capacity and as successor in 
interest to Fondazione Centro San Raffaele Del 
Monte Tabor), dated April 5, 2018
Form F-1
10.4
Oct. 4, 2018
333-227698
10.9
Research and Development Collaboration and 
License Agreement, among Glaxo Group Limited, 
Fondazione Telethon and Fondazione Centro San 
Raffaele del Monte Tabor, dated October 15, 
2010, as amended
Form F-1
10.5
Oct. 4, 2018
333-227698
10.10
Securities Purchase Agreement dated February 4, 
2021, among Orchard Therapeutics plc and the 
Purchasers named therein
Form 10-Q
10.1
May 13, 2021
001-38722
10.11
Lease Agreement, dated April 5, 2022, among 245 
Hammersmith Road Nominee Limited, 245 
Hammersmith Road Nominee 2 Limited, 245 
Hammersmith Road Partnership and Orchard 
Therapeutics (Europe) Limited
Form 10-Q
10.1
Aug. 4, 2022
001-38722
10.12†
License and Development Agreement, between 
the registrant and Oxford BioMedica (UK) 
Limited, dated November 28, 2016, as amended.
Form F-1
10.8
Oct. 4, 2018
333-227698
10.13††
Amendment Nos. 5 and 6 to License and 
Development Agreement, between the registrant 
and Oxford BioMedica (UK) Limited, dated 
November 28, 2016.
Form 10-Q
10.2
May 7, 2020
001-38722
10.14*
Senior Term Facilities Agreement, dated May 24, 
2019, as amended and restated on January 30, 
2023, among Orchard Therapeutics plc, the 
entities listed as original guarantors therein, 
001-38722

122
MidCap Financial (Ireland) Limited, and the 
additional lenders party thereto from time to time.
10.15#
Amended and Restated Employment Agreement, 
dated October 4, 2022, among Orchard 
Therapeutics plc, Orchard Therapeutics North 
America and Frank Thomas
Form 8-K
10.1
Oct. 6, 2022
001-38722
10.16#
Contract of Employment between Orchard 
Therapeutics (Europe) Limited and Hubert 
Gaspar, dated January 8, 2018, as amended, 
effective May 24, 2019.
Form 10-K
10.16
Feb. 27, 2020
001-38722
10.17#
Variation to Contract of Employment, dated 
March 18, 2020, between Orchard Therapeutics 
(Europe) Limited and Hubert Gaspar, M.D., Ph.D.
Form 8-K
10.3
Mar. 20, 2020
001-38722
10.18††
Manufacturing and Technology Development 
Master Agreement, between Orchard Therapeutics 
(Europe) Limited and MolMed S.p.A., dated July 
2, 2020.
Form 10-Q
10.1
Aug. 6, 2020
001-38722
10.19*
Amendment 1 to the Manufacturing and 
Technology Development Master Agreement, 
between Orchard Therapeutics (Europe) Limited 
and AGC Biologics S.p.A. (formerly MolMed 
S.p.A), dated December 7, 2022
001-38722
10.20
Securities Purchase Agreement dated March 6, 
2023, by and among Orchard Therapeutics plc and 
the Purchasers named therein.
Form 8-K
10.1
Mar. 6, 2023
001-38722
21.1*
List of Subsidiaries.
23.1*
Consent of PricewaterhouseCoopers LLP, 
Independent Registered Public Accounting Firm
31.1*
Certification of Principal Executive Officer 
Pursuant to Rules 13a-14(a) and 15d-14(a) under 
the Securities Exchange Act of 1934, as Adopted 
Pursuant to Section 302 of the Sarbanes-Oxley Act 
of 2002.
31.2*
Certification of Principal Financial Officer 
Pursuant to Rules 13a-14(a) and 15d-14(a) under 
the Securities Exchange Act of 1934, as Adopted 
Pursuant to Section 302 of the Sarbanes-Oxley Act 
of 2002.
32.1*
Certification of Principal Executive Officer 
Pursuant to 18 U.S.C. Section 1350, as Adopted 
Pursuant to Section 906 of the Sarbanes-Oxley Act 
of 2002.
32.2*
Certification of Principal Financial Officer 
Pursuant to 18 U.S.C. Section 1350, as Adopted 
Pursuant to Section 906 of the Sarbanes-Oxley Act 
of 2002.
101.INS*
Inline XBRL Instance Document (the instance document does not appear in the Interactive Data File because 
XBRL tags are embedded within the Inline XBRL document)

123
101.SCH*
Inline XBRL Taxonomy Extension Schema Document
101.CAL*
Inline XBRL Taxonomy Extension Calculation Linkbase Document
101.DEF*
Inline XBRL Taxonomy Extension Definition Linkbase Document
101.LAB*
Inline XBRL Taxonomy Extension Label Linkbase Document
101.PRE*
Inline XBRL Taxonomy Extension Presentation Linkbase Document
104*
Cover Page Interactive Data File (embedded within the Inline XBRL document).
* Filed herewith.
† Confidential treatment has been granted for portions of this exhibit. These portions have been omitted from the registration 
statement and filed separately with the United States Securities and Exchange Commission.
†† Portions of this exhibit (indicated by asterisks) were omitted in accordance with the rules of the Securities and Exchange 
Commission
# Indicates a management contract or any compensatory plan, contract or arrangement.
Item 16. Form 10-K Summary
Not applicable. 

124
SIGNATURES
Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, as amended, the Registrant has 
duly caused this Report to be signed on its behalf by the undersigned, thereunto duly authorized.
ORCHARD THERAPEUTICS PLC
Date: March 14, 2023
By: /s/ Bobby Gaspar
Bobby Gaspar
Chief Executive Officer
POWER OF ATTORNEY
We, the undersigned officers and directors of Orchard Therapeutics plc, hereby severally constitute and appoint Bobby 
Gaspar and Frank E. Thomas, and each of them singly (with full power to each of them to act alone), our true and lawful 
attorneys-in-fact and agents, with full power of substitution and re-substitution in each of them for him and in his name, place 
and stead, and in any and all capacities, to sign for us and in our names in the capacities indicated below any and all 
amendments to this Annual Report on Form 10-K, and to file the same, with all exhibits thereto and other documents in 
connection therewith, with the U.S. Securities and Exchange Commission, granting unto said attorneys-in-fact and agents, 
and each of them, full power and authority to do and perform each and every act and thing requisite or necessary to be done 
in and about the premises, as full to all intents and purposes as he might or could do in person, hereby ratifying and 
confirming all that said attorneys-in-fact and agents or any of them, or their or his substitute or substitutes, may lawfully do 
or cause to be done by virtue hereof.
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, this Annual Report has been signed below 
by the following persons on behalf of the Registrant in the capacities and on the dates indicated.
Signature
Title
Date
 
 
 
/s/ Bobby Gaspar
Chief Executive Officer and Director 
(Principal Executive Officer)
March 14, 2023
Bobby Gaspar
 
/s/ Frank E. Thomas
President and Chief Operating Officer 
(Principal Financial Officer and Principal Accounting Officer)
March 14, 2023
Frank E. Thomas
 
/s/ James A. Geraghty
Chairman of the Board of Directors
March 14, 2023
James A. Geraghty
 
/s/ Steven M. Altschuler
Director
March 14, 2023
Steven M. Altschuler, M.D.
 
/s/ Joanne T. Beck
Director
March 14, 2023
Joanne T. Beck, Ph.D.
 
/s/ John Curnutte
Director
March 14, 2023
John Curnutte, M.D., Ph.D.
 
/s/ Marc Dunoyer
Director
March 14, 2023
Marc Dunoyer
/s/ Charles A. Rowland, Jr.
Director
March 14, 2023
Charles A. Rowland, Jr.
 
/s/ Alicia Secor
Director
March 14, 2023
Alicia Secor

F-1
INDEX TO THE FINANCIAL STATEMENTS
 
Page
Report of Independent Registered Public Accounting Firm (PCAOB ID 238)
 
F-2
Consolidated Balance Sheets
 
F-4
Consolidated Statements of Operations and Comprehensive Loss
 
F-5
Consolidated Statements of Shareholders’ Equity
 
F-6
Consolidated Statements of Cash Flows 
 
F-7
Notes to Consolidated Financial Statements
 
F-8

F-2
REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM
To the Board of Directors and Shareholders of Orchard Therapeutics plc 
 
Opinion on the Financial Statements
 
We have audited the accompanying consolidated balance sheets of Orchard Therapeutics plc and its subsidiaries 
(the “Company”) as of December 31, 2022 and 2021, and the related consolidated statements of operations and 
comprehensive loss, of shareholders equity and of cash flows for the years then ended, including the related notes 
(collectively referred to as the “consolidated financial statements”). In our opinion, the consolidated financial 
statements present fairly, in all material respects, the financial position of the Company as of December 31, 2022 
and 2021, and the results of its operations and its cash flows for the years then ended in conformity with 
accounting principles generally accepted in the United States of America. 
 
Basis for Opinion
 
These consolidated financial statements are the responsibility of the Company's management. Our responsibility 
is to express an opinion on the Company’s consolidated financial statements based on our audits. We are a public 
accounting firm registered with the Public Company Accounting Oversight Board (United States) (PCAOB) and 
are required to be independent with respect to the Company in accordance with the U.S. federal securities laws 
and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB. 
 
We conducted our audits of these consolidated financial statements in accordance with the standards of the 
PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about 
whether the consolidated financial statements are free of material misstatement, whether due to error or fraud. 
The Company is not required to have, nor were we engaged to perform, an audit of its internal control over 
financial reporting. As part of our audits we are required to obtain an understanding of internal control over 
financial reporting but not for the purpose of expressing an opinion on the effectiveness of the Company's internal 
control over financial reporting. Accordingly, we express no such opinion.
 
Our audits included performing procedures to assess the risks of material misstatement of the consolidated 
financial statements, whether due to error or fraud, and performing procedures that respond to those risks. Such 
procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the 
consolidated financial statements. Our audits also included evaluating the accounting principles used and 
significant estimates made by management, as well as evaluating the overall presentation of the consolidated 
financial statements. We believe that our audits provide a reasonable basis for our opinion.
 
Critical Audit Matters
 
The critical audit matter communicated below is a matter arising from the current period audit of the consolidated 
financial statements that was communicated or required to be communicated to the audit committee and that (i) 
relates to accounts or disclosures that are material to the consolidated financial statements and (ii) involved our 
especially challenging, subjective, or complex judgments. The communication of critical audit matters does not 
alter in any way our opinion on the consolidated financial statements, taken as a whole, and we are not, by 
communicating the critical audit matter below, providing a separate opinion on the critical audit matter or on the 
accounts or disclosures to which it relates.
Accrued External Research and Development Expenses
As described in Notes 2 and 8 to the consolidated financial statements, the Company has entered into various 
research and development contracts. When billing terms under these contracts do not coincide with the timing of 
when the work is performed, management is required to make estimates of outstanding obligations to those third 
parties. Within accrued expenses and other current liabilities, total accrued external research and development 
expenses amounted to $11.2 million as of December 31, 2022. Any accrual estimates are based on a number of 
factors, including management’s knowledge of the progress towards completion of the research and development 
activities, invoicing to date under the contracts, communication from the research institution or other entities of 
any actual costs incurred during the period that have not yet been invoiced, and the costs included in the 
contracts. Significant judgments and estimates are made in determining the accrued balances at the end of any 
reporting period.

F-3
The principal considerations for our determination that performing procedures relating to accrued external 
research and development expenses is a critical audit matter are (i) the significant judgment by management in 
developing the estimate and (ii) a high degree of auditor judgment, subjectivity, and effort in performing 
procedures and evaluating management’s factors related to the progress towards completion of the research and 
development activities, the related invoicing to date under the contracts and communication from the research 
institution or other entities of any actual costs incurred during the period that have not yet been invoiced.
Addressing the matter involved performing procedures and evaluating audit evidence in connection with forming 
our overall opinion on the consolidated financial statements. These procedures included, among others, (i) testing 
management’s process for developing the estimate of accrued external research and development expenses, and 
for a sample of contracts, (ii) evaluating the appropriateness of the methods used by management to develop the 
estimate; (iii) testing the completeness and accuracy of the underlying data used in the estimate; and (iv) 
evaluating the reasonableness of management’s factors related to the progress towards completion of the research 
and development activities. Evaluating the reasonableness of management’s factors related to the progress 
towards completion of the research and development activities involved testing, on a sample basis, invoicing to 
date under the contracts and communication from the research institution or other entities of any actual costs 
incurred during the period that have not yet been invoiced.
 
/s/PricewaterhouseCoopers LLP
 
Boston, Massachusetts 
March 14, 2023
 
We have served as the Company's auditor since 2019.

F-4
Orchard Therapeutics plc 
Consolidated Balance Sheets 
(In thousands, except share and per share amounts) 
December 31,
2022
2021
Assets
Current assets:
Cash and cash equivalents
$
68,424
$
55,912
Marketable securities
75,326
164,195
Accounts receivable
8,467
1,480
Prepaid expenses and other current assets
9,986
23,011
Research and development tax credit receivable
5,942
30,723
Total current assets
168,145
275,321
Non-current assets:
Operating lease right-of-use-assets
22,774
24,316
Property and equipment, net
8,138
4,767
Restricted cash
4,215
4,266
Intangible assets, net
3,560
4,149
Other assets
12,075
9,590
Total non-current assets
50,762
47,088
Total assets
$
218,907
$
322,409
Liabilities and shareholders’ equity
Current liabilities:
Accounts payable
$
9,318
$
10,008
Accrued expenses and other current liabilities
34,437
24,318
Deferred revenue
959
346
Operating lease liabilities
6,424
7,335
Notes payable, current
9,429
786
Total current liabilities
60,567
42,793
Notes payable, long-term
22,991
32,086
Deferred revenue, net of current portion
10,315
12,519
Operating lease liabilities, net of current portion
19,246
19,278
Other long-term liabilities
7,524
5,783
Total liabilities
120,643
112,459
Commitments and contingencies (Note 17)
Shareholders’ equity:
Ordinary shares, £0.10 par value, authority to allot up to a maximum nominal 
value of £13,023,851.50 of shares at December 31, 2022 and 2021, respectively;  
Issued and outstanding — 126,947,225 and 125,674,095 shares at December 31, 
2022 and 2021, respectively.
16,419
16,253
Additional paid-in capital
956,711
940,675
Accumulated other comprehensive income
26,018
3,246
Accumulated deficit
(900,884)
(750,224)
Total shareholders’ equity
98,264
209,950
Total liabilities and shareholders’ equity
$
218,907
$
322,409
The accompanying notes are an integral part of these consolidated financial statements.

F-5
Orchard Therapeutics plc 
Consolidated Statements of Operations and Comprehensive Loss 
(In thousands, except share and per share amounts) 
For the Year Ended December 31,
2022
2021
Product revenue, net
$
20,610
$
700
Collaboration revenue
2,045
975
Total revenues
22,655
1,675
Costs and operating expenses
Cost of product revenue
6,771
226
Research and development
93,847
86,977
Selling, general and administrative
49,125
54,905
Total costs and operating expenses
149,743
142,108
Loss from operations
(127,088)
(140,433)
Other (expense) income:
Interest income
1,543
412
Interest expense
(3,079)
(2,497)
Other (expense) income, net
(24,410)
(1,238)
Total other (expense) income, net
(25,946)
(3,323)
Net loss before income tax
(153,034)
(143,756)
Income tax (expense) benefit
2,374
(828)
Net loss attributable to ordinary shareholders
$
(150,660)
$
(144,584)
Net loss per share attributable to ordinary shareholders, basic and
  diluted
$
(1.18)
$
(1.17)
Weighted average number of ordinary shares outstanding—basic and
  diluted
127,975,062
123,963,762
Other comprehensive income (loss)
Foreign currency translation adjustment
22,838
3,124
Unrealized loss on marketable debt securities
(66)
(251)
Total other comprehensive income (loss)
22,772
2,873
Total comprehensive loss
$
(127,888)
$
(141,711)
The accompanying notes are an integral part of these consolidated financial statements.

F-6
Orchard Therapeutics plc 
Consolidated Statements of Shareholders’ Equity 
(In thousands, except share amounts) 
Ordinary shares
Shares
Amount
Additional
paid-in capital
Accumulated
other comprehensive
income (loss)
Accumulated
deficit
Total
Balance at December 31, 2020
98,283,603
$
12,507
$
771,194
$
373
$
(605,640)
$
178,434
Share-based compensation expense
—
—
22,536
—
—
22,536
Exercise of share options
1,727,254
224
2,515
—
—
2,739
Issuance of ESPP shares
232,340
30
534
—
—
564
Vesting of restricted share units, net of shares withheld for taxes
64,647
9
(401)
—
—
(392)
Sale of voting and non-voting ordinary shares, net of issuance 
costs of $6,355
24,115,755
3,310
140,335
—
—
143,645
Ordinary shares issued as part of consulting agreement
22,758
3
(3)
—
—
—
Ordinary shares issued as part of collaboration agreement
1,227,738
170
3,965
—
—
4,135
Foreign currency translation
—
—
—
3,124
—
3,124
Unrealized loss on marketable debt securities
—
—
—
(251)
—
(251)
Net loss
—
—
—
—
(144,584)
(144,584)
Balance at December 31, 2021
125,674,095
$
16,253
$
940,675
$
3,246
$
(750,224)
$
209,950
Share-based compensation expense
—
—
16,010
—
—
16,010
Exercise of share options
699,234
91
(90)
—
—
1
Issuance of ESPP shares
544,442
72
139
—
—
211
Vesting of restricted share units, net of shares withheld for taxes
24,202
3
(22)
—
—
(19)
Ordinary shares issued as part of consulting agreement
5,252
—
(1)
—
—
(1)
Foreign currency translation
—
—
—
22,838
—
22,838
Unrealized loss on marketable debt securities
—
—
—
(66)
—
(66)
Net loss
—
—
—
—
(150,660)
(150,660)
Balance at December 31, 2022
126,947,225
$
16,419
$
956,711
$
26,018
$
(900,884)
$
98,264
The accompanying notes are an integral part of these consolidated financial statements.

F-7
Orchard Therapeutics plc 
Consolidated Statements of Cash Flows 
(In thousands) 
Year Ended December 31,
2022
2021
Cash flows from operating activities
Net loss attributable to ordinary shareholders
$
(150,660)
$
(144,584)
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation and amortization
2,741
2,327
Share-based compensation
16,010
22,536
Non-cash interest expense
372
392
Amortization of provision on loss contract
(274)
(1,037)
Deferred income taxes
(3,283)
1,131
Amortization of premium (discount) on marketable securities
(305)
1,514
Unrealized foreign currency and other non-cash adjustments
23,208
9,687
Changes in operating assets and liabilities:
Accounts receivable
(7,420)
(624)
Research and development tax credit receivable
22,568
(13,920)
Prepaid expenses, other current assets, and other assets
5,053
(5,209)
Operating leases, right-of-use-assets
5,431
5,938
Accounts payable, accrued expenses, and other current liabilities
13,642
(9,452)
Deferred revenue
(272)
13,122
Other long-term liabilities
2,154
34
Operating lease liabilities
(4,952)
(6,952)
Net cash used in operating activities
$
(75,987)
$
(125,097)
Cash flows from investing activities
Proceeds from sales and maturities of marketable securities
201,389
234,732
Purchases of marketable securities
(112,281)
(263,878)
Receipt of funds from construction deposit
7,966
216
Payments on intangible assets
—
(887)
Purchases of property and equipment
(6,514)
(2,348)
Net cash provided by (used in) investing activities
$
90,560
$
(32,165)
Cash flows from financing activities
Proceeds from modification of credit facility, net of debt issuance costs paid
—
7,375
Proceeds from employee equity plans
212
3,303
Payment of taxes on restricted stock vesting
(19)
(392)
Proceeds from issuance of shares as part of collaboration agreement
—
4,135
Proceeds from the issuance of ordinary shares in private placement
—
150,000
Payment of placement agent fees and offering costs
(100)
(6,355)
Repayment of notes payable
(786)
—
Net cash (used in) provided by financing activities
$
(693)
$
158,066
Effect of exchange rate changes on cash
(1,419)
(27)
Net increase in cash, cash equivalents and restricted cash
$
12,461
$
777
Cash, cash equivalents, and restricted cash —beginning of year
60,178
59,401
Cash, cash equivalents, and restricted cash —end of year
$
72,639
$
60,178
Supplemental disclosure of non-cash activities
Intangible assets and property and equipment in accounts payable and accrued expenses
60
2,589
Supplemental disclosure of cash flow information
Lease assets obtained in exchange for new operating lease liabilities
4,912
552
Changes to operating lease right-of-use assets and liabilities from amendments
530
—
Cash paid for interest
2,648
2,103
Cash paid for taxes
157
1,651
The accompanying notes are an integral part of these consolidated financial statements.

F-8
Orchard Therapeutics plc
Notes to Consolidated Financial Statements
1. Nature of the Business and Liquidity
Orchard Therapeutics plc (the “Company”) is a global gene therapy company dedicated to transforming the lives of people 
affected by severe diseases through the development of innovative, potentially curative gene therapies. The Company’s ex 
vivo autologous hematopoietic stem cell (“HSC”) gene therapy approach utilizes genetically modified blood stem cells and 
seeks to correct the underlying cause of disease in a single administration. The Company has a portfolio that includes a 
commercial-stage product and research and development-stage product candidates.
The Company is a public limited company incorporated pursuant to the laws of England and Wales. The Company has 
American Depositary Shares (“ADSs”) registered with the U.S. Securities and Exchange Commission (the “SEC”). The 
ADSs were listed on the Nasdaq Global Select Market on October 31, 2018 and were transferred to the Nasdaq Capital 
Market on September 13, 2022. As of December 31, 2022, each holder of ordinary shares and ADSs is entitled to one vote 
per ordinary share and to receive dividends when and if such dividends are recommended by the board of directors and 
declared by the shareholders.  The Company did not declared any dividends in 2022 or 2021.
Effective March 10, 2023, the Company enacted a ratio change wherein each ADS listed on the Nasdaq Capital Market is 
worth ten ordinary shares. 
On February 9, 2021, the Company issued and sold (i) 20,900,321 ordinary shares, nominal value £0.10 per share, at a 
purchase price of $6.22 per share (the “Purchase Price”), which was the closing sale price of the Company’s ADSs on the 
Nasdaq Global Select Market on February 4, 2021, and (ii) 3,215,434 non-voting ordinary shares, nominal value £0.10 per 
share, at the Purchase Price (together (i) and (ii) the “2021 Private Placement”). The 2021 Private Placement resulted in net 
proceeds to the Company of $143.6 million after deducting placement agent fees of $6.0 million and other issuance costs of 
$0.4 million. As of December 31, 2021, all outstanding non-voting shares have been converted to voting ordinary shares.
In January 2022, the Company began to generate revenue from product sales of Libmeldy™ in Europe following the 
approval of Libmeldy by the European Commission in December 2020 for the treatment of early onset metachromatic 
leukodystrophy (“MLD”), characterized by biallelic mutations in the arylsulfatase-A ("ARSA") gene leading to a reduction 
of the ARSA enzymatic activity in children with (i) late infantile or early juvenile forms, without clinical manifestations of 
the disease, or (ii) the early juvenile form, with early clinical manifestations of the disease, who still have the ability to walk 
independently and before the onset of cognitive decline.
On March 6, 2023, the Company entered into a Securities Purchase Agreement pursuant to which the Company agreed to sell 
ordinary shares, non-voting ordinary shares, and warrants to purchase to purchase ordinary shares or non-voting ordinary 
shares in an unregisterd offering (the "2023 Private Placement"). The 2023 Private Placement consists of two closings. On 
March 10, 2023, the Company completed the initial closing and issued and sold (i) 56,666,900 ordinary shares and non-
voting ordinary shares, nominal value £0.10 per share and (ii) warrants to purchase an aggregate of 62,333,590 ordinary 
shares or non-voting ordinary shares, at a purchase price of $6.00 per unit, where each unit consists of ten (10) Shares and an 
accompanying Warrant to purchase eleven (11) Shares. The initial closing of the 2023 Private Placement resulted in gross 
proceeds of approximately $34.0 million. Refer to Footnote 19 for further discussion around the 2023 Private Placement.
The Company’s business is subject to risks and uncertainties common to development-stage companies in the biotechnology 
industry. There can be no assurance that the Company’s research and development will be successfully completed, that 
adequate protection for the Company’s technology will be obtained, that any products developed will obtain necessary 
government regulatory approval or that any products, if approved, will be commercially viable. The Company operates in an 
environment of rapid technological innovation and substantial competition from pharmaceutical and biotechnology 
companies. In addition, the Company is dependent upon the services of its employees, consultants and service providers. 
Even if the Company’s product development efforts are successful in gaining regulatory approval, it is uncertain when, if 
ever, the Company will realize significant revenue from product sales. The future developments of the COVID-19 pandemic 
may also directly or indirectly impact the Company’s business, including impacts due to travel restrictions, supply chain 
disruptions, business closures, and other measures.
Through December 31, 2022, the Company funded its operations with proceeds from the sale of equity securities, including 
ADSs in the Company’s initial public offering (“IPO”) and follow-on offering, ordinary shares in the private placement, and 
convertible preferred shares. The Company has also financed its operations through proceeds from the Company’s senior 
term facilities agreement with MidCap Financial (Ireland) Limited, research grants from the California Institute of 
Regenerative Medicine (“CIRM”), upfront payments from the Company’s collaboration agreement and share purchase 
agreement with Pharming Group N.V., proceeds from the sales of the Company's Libmeldy product, and reimbursements 
associated with two UK research and development tax relief programs, the Small and Medium-sized Enterprises research and 

F-9
development tax credit (“SME”) program and the Research and Development Expenditure (“RDEC”) program. The 
Company has incurred recurring losses since its inception and expects to continue to generate operating losses for the 
foreseeable future. 
The Company expects that its cash, cash equivalents, and marketable securities on hand as of December 31, 2022, of $143.8 
million, together with expected proceeds from sales of Libmeldy and the $34 million received in March 2023 from the 2023 
Private Placement, will be sufficient to fund its operations and capital expenditure requirements for at least twelve months 
from the date of filing of this Annual Report on Form 10-K. The Company will seek additional funding through private or 
public equity financings, debt financings, collaborations, strategic alliances, and marketing, distribution or licensing 
arrangements. The Company may not be able to obtain financing on acceptable terms, or at all, and may not be able to enter 
into collaborations or other arrangements. The terms of any financing may adversely affect the holdings or the rights of the 
Company's stockholders. The future viability of the Company is dependent on its ability to raise additional capital to finance 
its operations. If the Company is unable to obtain funding, the Company will be forced to delay, reduce or eliminate some or 
all of its research and development programs, product portfolio expansion or commercialization efforts, which could 
adversely affect its business prospects, or the Company may be unable to continue operations. Although management 
continues to pursue these plans, there is no assurance that the Company will be successful in obtaining sufficient funding on 
terms acceptable to the Company to fund continuing operations, if at all.
2. Summary of Significant Accounting Policies 
Basis of presentation
The accompanying consolidated financial statements have been prepared in conformity with U.S. generally accepted 
accounting principles ("GAAP") and include the accounts of the Company and its wholly owned subsidiaries, after 
elimination of all intercompany accounts and transactions. Any reference in these notes to applicable guidance is meant to 
refer to authoritative United States generally accepted accounting principles as found in the Accounting Standards 
Codification (“ASC”) and as amended by Accounting Standards Updates (“ASU”) of the Financial Accounting Standards 
Board (“FASB”). 
Amounts reported are based in thousands, except percentages, per share amounts or as otherwise noted. As a result, certain 
totals may not sum due to rounding.
Principles of consolidation
The accompanying consolidated financial statements include the accounts of the Company and its wholly owned subsidiaries. 
All intercompany balances and transactions have been eliminated in consolidation.
Use of estimates 
The preparation of consolidated financial statements in conformity with GAAP requires management to make estimates and 
assumptions that affect the reported amounts of assets and liabilities, the disclosure of contingent assets and liabilities at the 
date of the consolidated financial statements and the reported amounts of revenue and expenses during the reporting periods. 
Significant estimates and assumptions reflected in these consolidated financial statements include, but are not limited to, the 
accrual for research and development expenses, the research and development tax credit receivable, share-based 
compensation, collaboration agreement milestones, variable consideration in revenue recognition, operating lease assets and 
liabilities, and income taxes. Estimates are periodically reviewed in light of changes in circumstances, facts and experience. 
Actual results could differ from the Company’s estimates. 
Concentration of credit risk and of significant suppliers
The Company has no significant off-balance sheet risk, such as foreign currency contracts, options contracts, or other foreign 
hedging arrangements. Financial instruments that potentially expose the Company to concentrations of credit risk consist 
primarily of cash, cash equivalents, marketable securities, and receivables.
The Company invests its excess cash, in line with its investment policy, in money market funds and high credit quality debt 
instruments. The Company's cash is deposited in financial institutions that it believes have high credit quality and has not 
experienced any losses on such accounts and does not believe it is exposed to any unusual credit risk beyond the normal 
credit risk associated with commercial banking relationships or entities for which it has a receivable. 
The Company is dependent upon a third-party contract manufacturer to develop, manufacture, and supply certain raw 
materials and conduct manufacturing activities for certain research and development and commercial programs. The 
disruption of the supply of raw materials and manufacturing activities could adversely affect the Company's operations. The 

F-10
Company believes that its relationship with this manufacturer is satisfactory and has contingency plans in place to mitigate 
any adverse effects around the loss of this contract manufacturer. 
Foreign currency
The financial statements of the Company’s subsidiaries with functional currencies other than the U.S. Dollar are translated 
into U.S. Dollars using period-end exchange rates for assets and liabilities, historical exchange rates for shareholders’ equity 
and weighted average exchange rates for operating results. Unrealized losses are driven primarily by intercompany balances 
denominated in currencies other than the functional currency of the entity with the intercompany balance, and typically 
fluctuates concurrently with fluctuations in the U.S. Dollar, Pounds sterling, and Euro exchange rates. Translation gains and 
losses are included in accumulated other comprehensive income (loss) in shareholders’ equity. Foreign currency transaction 
gains and losses are included in other income (expense), net in the results of operations. The Company recorded realized and 
unrealized foreign currency transaction losses of $24.3 million and of $1.2 million for the years ended December 31, 2022 
and 2021, respectively, which is included in other income (expense) in the statements of operations and comprehensive loss. 
Segment information
The Company operates in a single segment focusing on researching, developing and commercializing potentially curative 
gene therapies. Consistent with its operational structure, its chief operating decision maker manages and allocates resources 
at a global, consolidated level. Therefore, the results of the Company's operations are reported on a consolidated basis for the 
purposes of segment reporting. 
All material long-lived assets of the Company reside in the United States or United Kingdom. The Company had property 
and equipment, net, of $7.5 million and $0.6 million located in the United Kingdom and United States, respectively, as of 
December 31, 2022. The Company had property and equipment, net, of $3.6 million and $1.2 million located in the United 
Kingdom and United States, respectively, as of December 31, 2021. The Company had right-of-use assets in the United 
States and United Kingdom of $11.2 million and $11.6 million, respectively, as of December 31, 2022. The Company had 
right-of-use assets in the United States and United Kingdom and European Union of $12.5 million and $11.8 million, 
respectively, as of December 31, 2021.
Cash equivalents 
The Company considers all highly liquid investments purchased with original maturities of 90 days or less at the date of 
acquisition to be cash equivalents. 
Marketable securities
Marketable securities consist of investments with original maturities greater than ninety days from the date of acquisition. 
The Company has classified its investments with maturities beyond one year as short term, based on their highly liquid nature 
and because such marketable securities represent the investment of cash that is available for current operations. The 
Company considers its investment portfolio of investments as available-for-sale. Accordingly, these investments are recorded 
at fair value, which is based on quoted market prices or other observable inputs. Unrealized gains and losses are recorded as a 
component of other comprehensive income (loss). Realized gains and losses are determined on a specific identification basis 
and are included in other income (loss). Amortization and accretion of discounts and premiums is also recorded in other 
income (loss).
When the fair value is below the amortized cost of the asset an estimate of expected credit losses is made, the estimate is 
limited to the amount by which fair value is less than amortized cost. The credit-related impairment amount is recognized in 
the consolidated statements of operations and the remaining impairment amount and unrealized gains are reported as a 
component of accumulated other comprehensive income (loss) in shareholders’ equity. Credit losses are recognized through 
the use of an allowance for credit losses account and subsequent improvements in expected credit losses are recognized as a 
reversal of the allowance account. If the Company has the intent to sell the security or it is more likely than not that the 
Company will be required to sell the security prior to recovery of its amortized cost basis the allowance for credit loss is 
written off and the excess of the amortized cost basis of the asset over its fair value is recorded in the consolidated statements 
of operations.
Accounts receivable
Accounts receivable arise from product revenue and amounts due from the Company's collaboration partners and have  
payment terms that generally require payment within 30 to 90 days. For some Libmeldy customers, our payment terms can 
range from 30 days to under one year. The amount from product revenue represents amounts due from distributors in Europe, 
which are recorded net of reserves for trade discounts and allowances, and other incentives to the extent such amounts are 
payable to the customer by the Company. The Company monitors economic conditions to identify facts or circumstances that 

F-11
may indicate that its receivables are at risk of collection. The Company provides reserves against accounts receivable for 
estimated losses, if any, that may result from a customer's inability to pay based on the composition of its accounts 
receivable, current economic conditions, and historical credit loss activity. Amounts determined to be uncollectible are 
charged or written-off against the reserve. The Company did not record any expected credit losses related to outstanding 
accounts receivable in 2022 and 2021.
Fair Value Measurements 
Certain assets and liabilities of the Company are carried at fair value under GAAP. Financial assets and liabilities carried at 
fair value are to be classified and disclosed in one of the following three levels of the fair value hierarchy, of which the first 
two are considered observable and the last is considered unobservable: 
Level 1—Valuations based on quoted prices in active markets for identical assets or liabilities that the Company has 
the ability to access at the measurement date. 
Level 2—Valuations based on quoted prices for similar assets or liabilities in markets that are not active or for which 
all significant inputs are observable, either directly or indirectly, such as quoted market prices, interest rates, and yield 
curves. 
Level 3—Valuations that require inputs that reflect the Company’s own assumptions that are both significant to the fair 
value measurement and unobservable. 
To the extent a valuation is based on models or inputs that are less observable or unobservable in the market, the 
determination of fair values requires more judgment. Accordingly, the degree of judgment exercised by the Company in 
determining fair value is greatest for instruments categorized as Level 3. A financial instrument’s level within the fair value 
hierarchy is based on the lowest level of any input that is significant to the fair value measurement. 
The Company believes that the carrying amount reflected on the consolidated balance sheets for research and development 
tax incentive receivable, trade receivables, accounts payable, and accrued expenses approximate fair value due to their short-
term maturities. The carrying value of the Company’s outstanding notes payable approximates fair value (a Level 2 fair value 
measurement), reflecting interest rates currently available to the Company
Restricted cash and construction deposits
Cash and cash equivalents that are restricted as to withdrawal or use under the terms of certain contractual agreements are 
recorded as restricted cash on the Company's consolidated balance sheets. The Company has an outstanding letter of credit 
for $3.0 million associated with a lease and is required to hold this amount in a standalone bank account as of December 31, 
2022 and 2021. The Company is also contractually required to maintain a cash collateral account associated with corporate 
credit cards and other leases in the amount of $1.3 million as of December 31, 2022 and 2021. 
The Company includes the restricted cash balance in cash and cash equivalents when reconciling beginning-of-period and 
end-of-period total amounts shown on the consolidated statements of cash flows. The following table provides a 
reconciliation of cash, cash equivalents, and restricted cash reported in the consolidated balance sheet that sum to the total of 
the amounts reported in the consolidated statement of cash flows (in thousands):
As of December 31,
2022
2021
Cash and cash equivalents
$
68,424
$
55,912
Restricted cash
4,215
4,266
Total cash, cash equivalents and restricted cash shown in the statement of cash 
flows
$
72,639
$
60,178
Inventory
The Company began capitalizing inventory manufactured or purchased after the acquisition of Strimvelis in April 2018 and 
EMA approval of Libmeldy in December 2020. Inventory is stated at the lower of cost or estimated net realizable value with 
cost determined on a first-in, first-out basis. Inventory costs include raw materials, third-party contract manufacturing, third-
party packaging services, and freight. Raw and intermediate materials that may be utilized for either research and 
development or commercial purposes are classified as inventory. Amounts in inventory that are used for research and 
development purposes are charged to research and development expense when the product enters the research and 
development process and can no longer be used for commercial purposes and, therefore, does not have an “alternative future 
use” as defined in authoritative guidance. The Company performs an assessment of the recoverability of capitalized inventory 
during each reporting period and, if needed, writes down any excess and obsolete inventory to its estimated net realizable 

F-12
value in the period it is identified. If they occur, such impairment charges are recorded as a component of cost of goods sold 
in the consolidated statements of operations and comprehensive income (loss). Inventory is included in prepaid expenses and 
other current assets on the consolidated balance sheets as its balance was not significant as of December 31, 2022 or 2021 
(refer to Footnote 4).
Prior to the initial date that regulatory approval is received, costs related to the production of inventory are recorded as 
research and development expense on the Company’s consolidated statements of operations and comprehensive income 
(loss) in the period incurred. 
Intangible assets, net
Intangible assets consist of milestones associated with the Company’s approved products net of accumulated amortization. 
The Company amortizes its intangible assets using the straight-line method over their estimated economic lives and 
periodically reviews for impairment. The Company has not recognized any impairment charges related to intangible assets to 
date.
Property and equipment 
Property and equipment are recorded at cost and depreciated or amortized using the straight-line method over the following 
estimated useful lives. 
Asset Type:
Estimated useful life
Lab equipment
5-10 years
Leasehold improvements
Shorter of lease term or estimated useful life
Furniture and fixtures
4 years
Office and computer equipment
3-5 years
Repairs and maintenance expenditures, which are not considered improvements and do not extend the useful life of property 
and equipment, are expensed as incurred. Upon retirement or sale, the cost of assets disposed of and the related accumulated 
depreciation are removed from the accounts, and any resulting gain or loss is included in the consolidated statements of 
operations and other comprehensive loss. 
Impairment of long-lived assets 
Long-lived assets consist of property and equipment and operating lease right-of-use assets. Long-lived assets to be held and 
used are tested for recoverability whenever events or changes in business circumstances indicate that the carrying amount of 
the assets or asset group may not be fully recoverable. Factors that the Company considers in deciding when to perform an 
impairment review include significant under performance of the business in relation to expectations, significant negative 
industry or economic trends and significant changes or planned changes in the use of the assets. If an impairment review is 
performed to evaluate a long-lived asset group for recoverability, the Company compares forecasts of undiscounted cash 
flows expected to result from the use and eventual disposition of the long-lived asset or asset group to its carrying value. An 
impairment loss would be recognized when the estimated undiscounted future cash flows expected to result from the use of 

F-13
an asset group are less than its carrying amount. The impairment loss would be based on the excess of the carrying value of 
the impaired asset group over its fair value. 
Research and development costs 
Research and development costs are expensed as incurred. Research and development expenses consist of costs incurred in 
performing research and development activities including salaries and benefits, share-based compensation, facilities costs, 
depreciation, third-party license fees, certain milestone payments, external costs incurred by outside vendors engaged to 
conduct clinical development activities and clinical trials, the purchase of in-process research and development assets, and 
costs incurred to develop a manufacturing process, perform analytical testing and manufacture clinical trial materials. Non-
refundable prepayments for goods or services that will be used or rendered for future research and development activities are 
recorded as prepaid expenses. Such amounts are recognized as an expense as the goods are delivered, the related services are 
performed, or until it is no longer expected that the goods will be delivered or the services rendered. In addition, funding 
from research grants is recognized as an offset to research and development expenses on the basis of costs incurred on the 
research program. Royalties to third parties associated with our research grants will be accrued when they become probable.
Accrued external research and development expenses
The Company has entered into various research and development contracts. These agreements are cancelable, and related 
costs are recorded as research and development expenses as incurred. When billing terms under these contracts do not 
coincide with the timing of when the work is performed, the Company is required to make estimates of outstanding 
obligations to those third parties. Any accrual estimates are based on a number of factors, including the Company’s 
knowledge of the progress towards completion of the research and development activities, invoicing to date under the 
contracts, communication from the research institution or other entities of any actual costs incurred during the period that 
have not yet been invoiced, and the costs included in the contracts. Significant judgments and estimates may be made in 
determining the accrued balances at the end of any reporting period. There may be instances in which payments made to our 
vendors will exceed the level of services provided and result in a prepayment of the expense. Actual results could differ from 
the estimates made by the Company. The historical accrual estimates made by the Company have not been materially 
different from the actual costs.
Share-based compensation 
The Company measures all stock options and other stock-based awards granted based on the fair value of the award on the 
date of the grant and recognizes stock-based compensation expense for those awards over the requisite service period, which 
is generally the vesting period of the respective award. The Company has elected to recognize forfeitures as they occur. 
Therefore, the reversal of compensation cost previously recognized for an award that is forfeited because of a failure to 
satisfy a service or performance condition is recognized in the period of the forfeiture. The Company classifies stock-based 
compensation expense in its consolidated statements of operations and comprehensive loss in the same manner in which the 
award recipient’s payroll costs are classified or in which the award recipients’ service payments are classified.
The fair value of each stock option grant is estimated on the date of grant using the Black-Scholes option pricing model, 
which requires inputs based on certain subjective assumptions, including the fair value of the Company’s common stock, 
expected stock price volatility, the expected term of the stock option, the risk-free interest rate for a period that approximates 
the expected term of the stock option, and the Company’s expected dividend yield. The risk-free interest rate is based on a 
U.S. treasury instrument whose term is consistent with the expected term of the stock options. The expected term of the 
Company’s options has been determined utilizing the “simplified” method for awards that qualify as “plain-vanilla” options. 
The expected volatility is based on the historical volatility of a representative group of companies with similar characteristics 
to the Company, including those in the early stages of product development with a similar and therapeutic focus. For these 
analyses, the Company selects companies with comparable characteristics to its own including enterprise value, risk profiles, 
position within the industry, and with historical share price information sufficient to meet the expected term of the options/ 
The closing sale price per share of the Company’s common stock as reported on The Nasdaq Global Market on the date of 
grant is used to determine the fair value, which is then used to establish the exercise price per share of share-based awards to 
purchase common stock.
Comprehensive loss 
Comprehensive loss is composed of net loss and other comprehensive income (loss). Other comprehensive income (loss) 
consists of unrealized gains and losses on marketable securities and foreign currency translation gains and losses. 
Leases

F-14
At the inception of an arrangement, the Company determines whether the arrangement is or contains a lease based on specific 
facts and circumstances, the existence of an identified asset(s), if any, and the Company’s control over the use of the 
identified asset(s), if applicable. Operating lease assets represent a right to use an underlying asset for the lease term and 
operating lease liabilities represent an obligation to make lease payments arising from the lease. Operating lease liabilities 
with a term greater than one year and their corresponding right-of-use assets are recognized on the balance sheet at the 
commencement date of the lease based on the present value of lease payments over the expected lease term. The Company 
recognizes a corresponding right-of-use (“ROU”) asset, initially measured as the amount of lease liability, adjusted for any 
initial lease costs or lease payments made before or at the commencement of the lease, and reduced by any lease incentives. 
The Company made an accounting policy election to not record a right-of-use asset or lease liability for leases with a term of 
one year or less. To date, the Company has not identified any material short-term leases, either individually or in the 
aggregate.
The lease liability is measured at the present value of future lease payments, discounted using the discount rate as of the lease 
commencement date. Future lease payments may include payments that depend on an index or a rate (such as the consumer 
price index or other market index). The Company initially measures payments based on an index or rate by using the 
applicable rate at lease commencement and subsequent changes in such rates are recognized as variable lease costs. Variable 
payments that do not depend on a rate or index are not included in the lease liability and are recognized as they are incurred. 
The Company’s contracts typically do not have variable payments based on index or rate. 
When readily determinable, the discount rate used to calculate the lease liability is the rate implicit in the lease. As the 
Company’s leases do not typically provide an implicit rate, the Company utilizes an incremental borrowing rate, which is the 
rate incurred to borrow an amount on a collateralized basis over a similar term as the associated lease in a similar economic 
environment. The Company estimated the incremental borrowing rate based on the Company’s currently outstanding credit 
facility as inputs to the analysis to calculate a spread, adjusted for factors that reflect the profile of secured borrowing over 
the expected term of the lease. The lease term used to calculate the lease liability includes options to extend or terminate the 
lease when it is reasonably certain that the Company will exercise that option. With limited exceptions, the nature of the 
Company's facility leases is such that there are no economic or other conditions that would indicate that it is reasonably 
certain at lease commencement that the Company will exercise options to extend the term.
The components of a lease should be split into three categories: lease components (e.g., land, building, etc.), non-lease 
components (e.g., common area maintenance, utilities, performance of manufacturing services, purchase of inventory, etc.), 
and non-components (e.g., property taxes, insurance, etc.). Then the fixed contract consideration (including any related to 
non-components) must be allocated based on fair values to the lease components and non-lease components. Although 
separation of lease and non-lease components is required, certain accounting policy elections are available to entities. Entities 
can elect accounting policies that would not separate lease and non-lease components. Rather, they would account for each 
lease component and the related non-lease component together as a single component. The Company has elected not to apply 
the accounting policy with respect to its lease of manufacturing space at a contract manufacturing organization, and as a 
result, the Company has allocated the consideration between the lease and non-lease components of the contract based on the 
respective fair values of the lease and non-lease components. The Company calculated the fair value of the lease and non-
lease components using financial information readily available as part of its master services arrangement and other 
representative data indicative of fair value.
The Company’s leases consist of only operating leases. Operating leases are recognized on the balance sheet as ROU assets, 
operating lease liabilities, and operating lease liabilities non-current. Fixed payments are included in the calculation of the 
lease balances while certain variable costs paid for certain operating and pass-through costs are excluded. Lease expense is 
recognized over the expected lease term on a straight-line basis. 
The Company accounts for sublease income on a straight-line basis over the respective lease period and records an unbilled 
rent receivable for sublease income incurred but not yet paid. The Company periodically performs a collectability assessment 
associated with any unbilled rent receivables. The Company recognizes the sublease income as a reduction to the related 
operating expense associated with the head lease.
Strimvelis loss provision
As part of the GSK transaction, the Company is required to maintain commercial availability of Strimvelis in the European 
Union until such time that an alternative gene therapy is available. Strimvelis is not currently expected to generate sufficient 
cash flows to overcome the costs of maintaining the product and certain regulatory commitments; therefore, the Company 
initially recorded a liability associated with the loss contract of $18.4 million in 2018. The Company recognizes the 
amortization of the loss provision on a diminishing balance basis based on the actual net loss incurred associated with the 
Strimvelis program and the expected future net losses to be generated until such time as Strimvelis is no longer commercially 
available. The amortization of the provision is recorded as a reduction to research and development expense. The Company 

F-15
has made an estimate of the expected future losses associated with Strimvelis and will adjust this estimate as facts and 
circumstances change regarding the commercial availability and costs of maintaining and selling Strimvelis. The Company 
does not update the accrued loss provision for any subsequent adjustment of future losses, however, the timing of recognizing 
the amortization of what was originally recorded is adjusted for updated future losses. 
The following table below outlines the changes to the Strimvelis loss provision for the periods ended December 31, 2022 and 
2021 (in thousands):
Year Ended December 31,
2022
2021
Balance at beginning of period
$
3,419
$
4,482
Amortization of loss provision
(274)
(1,037)
Foreign currency translation
(326)
(26)
Balance at end of period
$
2,819
$
3,419
As of December 31, 2022, the entire balance of the Strimvelis loss provision was categorized as current. As of December 31, 
2021, $0.7 million of the loss provision was classified as current, and $2.7 million was classified as non-current.
United Kingdom Research and development income tax credits 
As the Company carries out research and development activities, it is able to submit tax credit claims from two UK research 
and development tax relief programs: the Small and Medium-Sized Enterprises research and development tax credit (“SME”) 
program and the Research and Development Expenditure Credit (“RDEC”), depending on eligibility. Qualifying 
expenditures largely comprise employment costs for research staff, consumables, and certain internal overhead costs incurred 
as part of research projects for which the Company does not receive income. 
The RDEC and SME credits are not dependent on the Company generating future taxable income or on the ongoing tax status 
or tax position of the Company. Each reporting period, the Company assesses its research and development activities and 
expenditures to determine whether the nature of these costs will qualify for credit under the tax relief programs and whether 
the claims will ultimately be realized based on the allowable reimbursable expense criteria established by the UK 
government. The Company expects a proportion of expenditures incurred in relation to its pipeline research, clinical trials 
management, and manufacturing development activities to be eligible for the research and development tax relief programs 
for the year ended December 31, 2022. The Company has qualified under the more favorable SME regime for the year ended 
December 31, 2021 and expects to qualify under the SME regime for the year ending December 31, 2022.
The Company recognizes credits from the research and development incentives when the relevant expenditure has been 
incurred and there is reasonable assurance that the reimbursement will be received. Such credits are accounted for as 
reductions in research and development expenses. The following table outlines the changes to the research and development 
tax credit receivable, including amount recognized as an offset to research and development expense during the years ended 
December 31, 2022 and 2021 (in thousands):
Year Ended December 31,
2022
2021
Balance at beginning of period
$
30,723
$
17,344
Recognition of credit claims as offset to research and development expense
8,243
13,920
Receipt of credit claims
(30,811)
-
Foreign currency translation
(2,213)
(541)
Balance at end of period
$
5,942
$
30,723
As of December 31, 2022 and 2021, the Company’s tax credit receivable was classified as current with receipt of the credit 
expected within twelve months of the balance sheet date.
Income taxes 
The Company is primarily subject to corporation taxes in the United Kingdom, the United States, and certain European 
Union countries in which it has legal subsidiaries. The calculation of the Company’s tax provision involves the application of  
country applicable tax law and requires judgment and estimates. 
The Company accounts for income taxes in accordance with ASC Topic 740, Accounting for Income Taxes, which provides 
for deferred taxes using an asset and liability approach. The Company recognizes deferred tax assets and liabilities for the 
expected future tax consequences of events that have been included in the financial statements or tax returns. The Company 
determines its deferred tax assets and liabilities based on differences between financial reporting and tax bases of assets and 

F-16
liabilities, which are measured using the enacted tax rates and laws that will be in effect when the differences are expected to 
reverse. Valuation allowances are provided if, based upon the weight of available evidence, it is more likely than not that 
some or all of the net deferred tax assets will not be realized. 
The Company accounts for uncertainty in income taxes by applying a two-step process to determine the amount of tax benefit 
to be recognized. First, the tax position must be evaluated to determine the likelihood that it will be sustained upon external 
examination by the taxing authorities. If the tax position is deemed more-likely-than-not-to be sustained, the tax position is 
then assessed as the amount of benefit to recognize in the consolidated financial statements. The amount of benefits that may 
be used is the largest amount that has a greater than 50% likelihood of being realized upon ultimate settlement. The provision 
for income taxes includes the effects of any resulting tax reserves, or unrecognized tax benefits, that are considered 
appropriate, as well as the related net interest and penalties. 
Product revenue, net
Libmeldy
In January 2022, the Company began generating product revenue from sales of Libmeldy in Europe following the approval of 
Libmeldy by the European Commission in December 2020 for the treatment of early onset MLD, characterized by biallelic 
mutations in the ARSA gene leading to a reduction of the ARSA enzymatic activity in children with (i) late infantile or early 
juvenile forms, without clinical manifestations of the disease, or (ii) the early juvenile form, with early clinical manifestations 
of the disease, who still have the ability to walk independently and before the onset of cognitive decline.
The Company recognizes revenue when control of promised goods is transferred to a customer at an amount that reflects the 
consideration to which the Company expects to be entitled in exchange for those goods. Control of the product transfers upon 
infusion of the product. 
To determine revenue recognition, the Company performs the following five steps: (i) identify the contract(s) with a 
customer; (ii) identify the performance obligations in the contract; (iii) determine the transaction price, including variable 
consideration, if any; (iv) allocate the transaction price to the performance obligations in the contract; and (v) recognize 
revenue when (or as) the Company satisfies the performance obligations. The Company only applies the five-step model to 
contracts when collectability of the consideration to which it is entitled in exchange for the goods the Company transfers to 
the customer is determined to be probable. 
In certain regions of Europe and the Middle East, the Company utilizes distributors to act in an agent capacity including for 
patient identification and other related functions. The Company is exclusively responsible for product fulfillment and retains 
inventory risk and pricing discretion of the product.  Evaluation of these key indicators supports the assertion that the 
Company maintains control over the product prior to delivery to the patient. The Company has concluded that it is the 
principal in these transactions and records the associated revenue on a gross basis with any payments to these entities being 
recorded as a selling expense. 
Amounts are recorded as accounts receivable when the right to the consideration is unconditional. The Company does not 
assess whether a contract has a significant financing component if the expectation at contract inception is that the period 
between payment by the customer and the transfer of the promised goods or services to the customer will be one year or less. 
The Company expenses incremental costs of obtaining a contract as and when incurred if the expected amortization period of 
the asset that would have been recognized is one year or less or the amount is immaterial. As of December 31, 2022, the 
Company has not capitalized any costs to obtain contracts.
The Company recognizes product revenue, net of variable consideration related to certain allowances and accruals, when the 
customer takes control of the product, which is at a point in time once the patient has been infused. Product revenue is 
recorded at the net sales price, or transaction price. The Company records estimated product revenue reserves, which are 
classified as a reduction in product revenue, to account for the components of variable consideration. Variable consideration 
includes the following components: government rebates, including performance-based rebates, trade discounts and 
allowances, and other incentives, which are described below.
These reserves are based on estimates of the amounts earned or to be claimed on the related sales and are classified as a 
liability. The Company's estimates of reserves established for variable consideration are calculated based upon an application 
of the expected value method, which is the sum of probability-weighted amounts in a range of possible consideration 
amounts. These estimates reflect the Company's historical experience, current contractual and statutory requirements, specific 
known market events and trends, industry data, and current expectations around final pricing. The amount of variable 
consideration that is included in the transaction price may be subject to constraint and is included in net product revenue only 
to the extent that it is probable that a significant reversal in the amount of the cumulative revenue recognized will not occur in 
a future period. The actual amounts of consideration received may ultimately differ from the Company's estimates. If actual 
results vary, the Company adjusts these estimates, which could have an effect on earnings in the period of adjustment. The 
following is a summary of the types of variable consideration the Company records:

F-17
Government rebates: The Company is subject to statutory government rebates on sales in certain European countries as 
well as estimated rebates in certain European countries because final pricing has not yet been negotiated. The Company 
records reserves for rebates in the same period the related product revenue is recognized, resulting in a reduction of 
product revenue and a current liability that is included in accrued expenses on the Company’s consolidated balance 
sheet. The Company is also subject to potential rebates in connection with performance criteria agreed upon with 
certain payors. The estimate for rebates is based on statutory discount rates, industry pricing data, current expectations 
around final pricing to be obtained, and historical experience of the performance of the Company’s products during 
clinical trials. The Company classifies rebates within accrued expenses in the accompanying consolidated balance 
sheets. 
Trade discounts and allowances: The Company may offer customers discounts, such as prompt pay discounts to remit 
payment in accordance with the stated terms of the invoice. These discounts are explicitly stated in the contracts and 
recorded in the period the related product revenue is recognized. The Company estimates which customers will earn 
these discounts and fees and deducts these discounts and fees in full from gross product revenue and accounts 
receivable at the time the Company recognizes the related revenue. The Company classifies trade discounts and 
allowances as a reduction of accounts receivable within the accompanying consolidated balance sheets.
Product returns: Based on the timing of revenue recognition upon treatment with the patient, the Company does not 
expect any returns of the Company’s products. 
Other incentives: While the Company does not currently have any other incentives that have been recorded to date, the 
Company may enter into future arrangements that have other incentives that will be recorded as a reduction of revenue.  
Strimvelis
The Company’s product sales of Strimvelis are currently distributed exclusively at the San Raffaele Hospital in Milan, Italy. 
The hospital will purchase and pay for the products and submit a claim to the payer. The Company’s contracted sales with the 
hospital contains a single performance obligation and the Company recognizes revenue from product sales when the 
Company has satisfied its performance obligation, which is upon transferring control of the products to the hospital. The 
Company evaluated the variable consideration under ASC 606 and there is currently no variable consideration included in the 
transaction price for the products. Costs to manufacture and deliver the product and those associated with administering the 
therapy are included in the cost of product sales. As the product is sold in direct relation to a scheduled treatment, the 
Company estimates there is limited risk of product return, including the risk of product expiration. 
Collaboration revenue
The terms of the Company’s collaboration agreements may include consideration such as non-refundable license fees, 
funding of research and development services, payments due upon the achievement of clinical and pre-clinical performance-
based development milestones, regulatory milestones, manufacturing services, sales-based milestones and royalties on 
product sales.
The Company first evaluates collaboration arrangements to determine whether the arrangement (or part of the arrangement) 
represents a collaborative arrangement pursuant to ASC Topic 808, Collaborative Arrangements, based on the risks and 
rewards and activities of the parties pursuant to the contractual arrangement. The Company accounts for any collaborative 
arrangement or elements within the contract that are deemed to be a collaborative arrangement, and not a customer 
relationship, in accordance with ASC 808. Through December 31, 2022, the Company entered into one agreement with 
Pharming Group N.V. (the “Pharming Agreement”, see Note 16) that is accounted for pursuant to ASC 606 five-step model.
The Company recognizes the transaction price allocated to upfront license payments as revenue upon delivery of the license 
to the customer and resulting ability of the customer to use and benefit from the license, if the license is determined to be 
distinct from the other performance obligations identified in the contract. If the license is considered to not be distinct from 
other performance obligations, the Company utilizes judgment to assess the nature of the combined performance obligation 
to determine whether the combined performance obligation is satisfied (i) at a point in time, but only for licenses determined 
to be distinct from other performance obligations in the contract, or (ii) over time, and, if over time, the appropriate method 
of measuring progress for purposes of recognizing revenue from license payments. The Company evaluates the measure of 
progress each reporting period and, if necessary, adjusts the measure of performance and related revenue recognition.
The Pharming Agreement entitles the Company to additional payments upon the achievement of performance-based 
milestones. These milestones are generally categorized into three types: development milestones, regulatory milestones, and 
sales-based milestones. The Company is also eligible to receive from Pharming tiered royalty payments on worldwide net 
sales. The Company evaluates whether it is probable that the consideration associated with each milestone will not be subject 
to a significant reversal in the cumulative amount of revenue recognized. Amounts that meet this threshold are included in the 

F-18
transaction price using the most likely amount method, whereas amounts that do not meet this threshold are considered 
constrained and excluded from the transaction price until they meet this threshold. Milestones tied to regulatory approval, and 
therefore not within the Company’s control, are considered constrained until such approval is received. Upfront and ongoing 
development milestones per the collaboration agreements are not subject to refund if the development activities are not 
successful. At the end of each subsequent reporting period, the Company re-evaluates the probability of a significant reversal 
of the cumulative revenue recognized for the milestones, and, if necessary, adjusts the estimate of the overall transaction 
price. Any such adjustments are recorded on a cumulative catch-up basis, which would affect revenues from collaborators in 
the period of adjustment. 
The Company may enter into an agreement that includes sales-based milestone payments and royalties in exchange for a 
license of intellectual property. The Company considers the underlying facts and circumstances of these agreements, noting 
whether the future payments are contingent upon future sales and whether they are dependent on a third party’s ability to 
successfully commercialize a product using the licensed intellectual property. The Company also considers whether the 
license is the only, or predominant, item to which the milestone payments and royalties relate. If the Company concludes the 
license is the predominant item in the agreement, therefore the primary driver of value, the Company excludes sales-based 
milestone payments and royalties from the transaction price until the sale occurs (or, if later, until the underlying performance 
obligation to which some or all of the royalty has been allocated has been satisfied or partially satisfied). Currently, the 
Company has not recognized any royalty revenue resulting from the Pharming Agreement.
ASC 606 requires the Company to allocate the arrangement consideration on a relative standalone selling price basis for each 
performance obligation after determining the transaction price of the contract and identifying the performance obligations to 
which that amount should be allocated. The relative standalone selling price is defined in ASC 606 as the price at which an 
entity would sell a promised good or service separately to a customer. If other observable transactions in which the Company 
has sold the same performance obligation separately are not available, the Company is required to estimate the standalone 
selling price of each performance obligation. Key assumptions to determine the standalone selling price may include 
forecasted revenues, development timelines, reimbursement rates for personnel costs, discount rates and probabilities of 
technical and regulatory success.
Whenever the Company determines that a contract should be accounted for as a combined performance obligation, which is 
recognized over time, it will utilize the cost-to-cost input method. Revenue will be recognized over time using the cost-to-
cost input method, based on the total estimated costs to fulfill the obligations. The Company will recognize revenue as 
services are delivered. Significant management judgment is required in determining the estimate of total costs required under 
an arrangement and the period over which the Company is expected to complete its performance obligations under an 
arrangement.
Consideration that does not meet the requirements to satisfy the above revenue recognition criteria is a contract liability and 
is recorded as deferred revenue in the consolidated balance sheets. Short-term deferred revenue consists of amounts that are 
expected to be recognized as revenue in the next 12 months. Amounts that the Company expects will not be recognized 
within the next 12 months are classified as long-term deferred revenue.
The Company recognizes as revenue the amount of the transaction price that is allocated to the respective performance 
obligation when (or as) each performance obligation is satisfied, either at a point in time or over time. In particular, for the 
Company’s collaborations with Pharming, revenue attributable to research services is recognized as those services are 
provided, based on the costs incurred to date.

F-19
Net loss per share 
Basic net loss per share is computed by dividing the net loss by the weighted average number of ordinary shares outstanding 
for the period. Diluted net loss is computed by adjusting net loss based on the potential impact of dilutive securities. Diluted 
net loss per share is computed by dividing the diluted net loss by the weighted average number of ordinary shares outstanding 
for the period, including potentially dilutive ordinary shares. For the purpose of this calculation, outstanding options and 
unvested restricted shares are considered potential dilutive ordinary shares. Since the Company was in a loss position for all 
periods presented, the basic net loss per share is the same as diluted net loss per share for all periods as the inclusion of all 
potential ordinary share equivalents outstanding would have been anti-dilutive. 
The following securities, presented based on amounts outstanding at each period end, are considered to be ordinary share 
equivalents, but were not included in the computation of diluted net loss per ordinary share because to do so would have been 
anti-dilutive: 
As of December 31,
2022
2021
Share options
13,076,959
14,042,781
Unvested restricted incentive shares
2,253,199
512,908
15,330,158
14,555,689
Recent accounting pronouncements
In November 2021, the FASB issued ASU No. 2021-10, Government Assistance (Topic 832): Disclosures by Business 
Entities about Government Assistance, which requires increased transparency in the disclosures about government assistance 
in the notes to the financial statements. This ASU is effective for the Company beginning January 1, 2022, and interim 
periods within that year, with early adoption permitted. The Company adopted and applied the amendments of this ASU to its 
disclosures. The application of this ASU did not have a material impact on the Company's financial position, results of 
operations or cash flows. 
In March 2020, the FASB issued ASU 2020-04, Reference Rate Reform (Topic 848): Facilitation of the Effects of Reference 
Rate Reform on Financial Reporting and issued two subsequent amendments: ASU 2021-01, issued in January 2021, refines 
the scope of ASU and clarifies some of its guidance as part of the FASB’s monitoring of global reference rate reform 
activities and ASU 2022-06, issued in December 2022, which extends the effective period of the ASU through December 31, 
2023 (collectively, including ASU 2020-04, “ASC 848”). ASC 848 provides temporary optional expedients and exceptions to 
the GAAP guidance on contract modifications and hedge accounting to ease the financial reporting burdens related to the 
expected market transition from the London Interbank Offered Rate (“LIBOR”) and other interbank offered rates to 
alternative reference rates. ASC 848 is effective for all entities as of March 12, 2020, through December 31, 2023, at which 
time transition is expected to be complete. The Company is currently reviewing the provisions of this pronouncement, 
specifically its impact on its notes payable, but does not expect this guidance will have a material impact on the Company's 
consolidated financial statements.  
3. Fair Value Measurements and Marketable Securities
The following tables present information about the Company’s financial assets that have been measured at fair value as of 
December 31, 2022 and 2021, and indicate the fair value of the hierarchy of the valuation inputs utilized to determine such 
fair value (in thousands):
Fair Value Measurements as of
December 31, 2022
Level 1
Level 2
Level 3
Total
Cash equivalents
Money market funds
$
1,239
$
—
$
—
$
1,239
U.S. treasuries
—
6,600
—
6,600
U.S. government securities
—
5,200
—
5,200
Commercial paper
—
14,122
—
14,122
Total cash equivalents
$
1,239
$
25,922
$
—
$
27,161
Marketable securities
U.S. government securities
$
—
$
1,984
$
—
$
1,984
Corporate bonds
—
25,475
—
25,475
Commercial paper
—
47,867
—
47,867
Total marketable securities
$
—
$
75,326
$
—
$
75,326
Total Assets
$
1,239
$
101,248
$
—
$
102,487

F-20
Fair Value Measurements as of
December 31, 2021
Level 1
Level 2
Level 3
Total
Cash equivalents
Money market funds
$
21,085
$
—
$
—
$
21,085
U.S. government securities
—
7,321
—
7,321
Commercial paper
—
13,198
—
13,198
Total cash equivalents
$
21,085
$
20,519
$
—
$
41,604
Marketable securities
Corporate bonds
$
—
$
94,794
$
—
$
94,794
Commercial paper
—
69,401
—
69,401
Total marketable securities
$
—
$
164,195
$
—
$
164,195
Total
$
21,085
$
184,714
$
—
$
205,799
The Company classifies its money market funds as Level 1 assets since it measures fair value using quoted prices in active 
markets for identical assets. The Level 2 assets include commercial paper, U.S. government securities, U.S. treasuries, and 
corporate bonds and are valued based on quoted prices for similar assets in active markets and inputs other than quoted prices 
that are derived from observable market data.  The Company did not hold any Level 3 assets during the periods presented.
The Company evaluates transfers between levels at the end of each reporting period. There were no transfers between Level 1 
and Level 2 assets during the periods presented. 
Marketable Securities
The following tables summarize the amortized cost and fair value of the Company's available-for-sale marketable debt 
securities (in thousands): 
December 31, 2022
Amortized
Cost
Gross
Unrealized
Gains
Gross
Unrealized
Losses
Credit 
Losses
Fair Value
U.S. government securities
$
7,188
$
1
$
(6) $
—
$
7,183
U.S. treasuries
6,599
1
—
—
6,600
Corporate bonds
25,656
—
(180)
—
25,476
Commercial paper
62,038
3
(52)
—
61,989
Total
$
101,481
$
5
$
(238) $
—
$
101,248
December 31, 2021
Amortized
Cost
Gross
Unrealized
Gains
Gross
Unrealized
Losses
Credit 
Losses
Fair Value
Corporate bonds
$
102,224
$
—
$
(109) $
—
$ 102,115
Commercial paper
82,657
—
(58)
—
82,599
Total
$
184,881
$
—
$
(167) $
—
$ 184,714
The following table summarizes the Company’s available-for-sale marketable debt securities by contractual maturity, as of 
December 31, 2022 and 2021 (in thousands):
2022
2021
Maturities in one year or less
$
98,277
$
172,575
Maturities between one and three years
2,971
12,139
Total
$
101,248
$
184,714
All investments in an unrealized loss position were in this position for less than 12 months. The Company evaluated its 
securities for potential other-than-temporary impairment and considered the decline in market value to be primarily 
attributable to current economic and market conditions. Additionally, the Company does not intend to sell the securities in an 
unrealized loss position and does not expect it will be required to sell the securities before recovery of the unamortized cost 
basis. Given the Company's intent and ability to hold such securities until recovery, and the lack of a significant change in 
credit risk for these investments, the Company does not consider these investments to be impaired as of December 31, 2022. 

F-21
There were no realized gains or losses recognized on investments for the years ended December 31, 2022 and 2021. 
 
4. Prepaid expenses and other current assets
Prepaid expenses and other current assets consist of the following (in thousands):
December 31,
2022
2021
Prepaid external research and development expenses
$
881
$
2,438
Inventories
3,400
2,016
Other prepayments
1,817
6,128
VAT receivable
1,077
1,169
Construction deposit - current
—
7,909
Non-trade receivables
1,851
3,351
Rent deposits
960
—
Total prepaid expenses and other current assets
$
9,986
$
23,011
5. Property and equipment 
Property and equipment consist of the following (in thousands):
December 31,
2022
2021
Property and equipment:
Lab equipment
$
6,722
$
5,937
Leasehold improvements
5,069
2,450
Furniture and fixtures
226
303
Office and computer equipment
2,153
2,023
Construction-in-progress
759
211
Property and equipment
14,929
10,924
Less: accumulated depreciation
(6,791)
(6,157)
Property and equipment, net
$
8,138
$
4,767
Depreciation expense for the years ended December 31, 2022 and 2021 was $2.4 million and $2.2 million, respectively.
6. Intangible assets, net
Intangible assets, net of accumulated amortization, consisted of the following (in thousands):
As of December 31, 2022
Cost
Accumulated 
Amortization
Net
License milestones
$
4,069
$
(509)
$
3,560
Total
$
4,069
$
(509)
$
3,560
As of December 31, 2021
Cost
Accumulated 
Amortization
Net
License milestones
$
4,329
$
(180)
4,149
Total
$
4,329
$
(180)
$
4,149
License intangibles consist of capitalized milestone payments or accruals of payments the Company has deemed probable 
upon receiving regulatory approval of Libmeldy in the EU. The license intangibles are being amortized on a straight-line 
basis over the remaining useful life of the related patents of approximately twelve years. Amortization of intangible assets 
was $0.3 million and $0.2 million for the years ended December 31, 2022 and 2021, respectively. The effect of foreign 
currency translation on the net carrying value of intangible assets during the year ended December 31, 2022 was $0.2 million. 
The effect of foreign currency translation on the net carrying value of intangible assets during 2021 was not material.

F-22
The following table summarizes the estimated future amortization for intangible assets for the next five years and thereafter 
(in thousands):
2023
$
343
2024
343
2025
343
2026
343
2027
343
Thereafter
1,845
Total
$
3,560
7. Other assets
Other assets consist of the following (in thousands):
December 31,
2022
2021
Deferred tax assets
$
7,369
$
4,086
Deposits
1,048
1,404
Deferred financing costs
462
693
Other non-current assets
3,196
3,407
Total other assets
$
12,075
$
9,590
8. Accrued expenses and other liabilities 
Accrued expenses and other current liabilities consisted of the following (in thousands): 
December 31,
2022
2021
Accrued external research and development expenses
$
11,230
$
9,273
Accrued payroll and related expenses
12,312
8,521
Accrued milestone payments
85
2,058
Accrued professional fees
2,263
854
Accrued other
2,562
2,941
Accrued governmental rebates
2,300
—
Strimvelis liability - current portion
3,685
671
Total accrued expenses and other current liabilities
$
34,437
$
24,318
9. Restructuring charges
On March 30, 2022, the Company announced its commitment to focus on severe neurometabolic diseases and early research 
programs, and to discontinue its investment in and seek strategic alternatives for the Company’s programs in rare primary 
immune deficiencies, including OTL-103 for treatment of Wiskott Aldrich syndrome (“WAS”), OTL-102 for treatment of X-
linked chronic granulomatous disease (“X-CGD”), and Strimvelis for adenosine deaminase severe combined 
immunodeficiency (“ADA-SCID”). During the year ended December 31, 2022, the Company recognized a one-time charge 
during of approximately $1.7 million, which relates to employee-related termination costs, of which $1.4 million and $0.3 
million was recognized in research and development expenses and selling, general, and administrative expenses, respectively, 
in the Company's consolidated statements of operations and comprehensive loss. Activity during the year ended December 
31, 2022, was as follows (in thousands):
Year Ended 
December 31,
2022
Balance at beginning of period
$
6
Charged to expense
2,481
Non-cash adjustments and foreign currency translation
(760)
Payments made
(1,727)
Balance at end of period
$
-

F-23
There were no restructuring costs incurred during the year ended December 31, 2021.
10. Leases
Operating leases- office and lab space
In January 2018, December 2018, and February 2022 the Company entered into lease agreements for office space in London, 
United Kingdom. The leases entered into in 2018 both terminate in January 2023 and there were no options to extend the 
lease term. The lease entered into in March 2022 expires in February 2032 and there are no options to extend the lease term. 
The combined annual rental payments, including variable payments, under the lease agreements were $1.7 million in 2022 
and $1.8 million in 2021. The Company also rented lab spaces in London in 2021, for which it made $0.2 million in 
payments in 2022 and 2021.
In March 2018, the Company entered into a lease agreement for office space in Boston, Massachusetts, United States, which 
terminated in September 2022. The annual rental payments, including variable payments, were $0.3 million in 2022 and $0.4 
million in 2021. The Company subleased the space starting in August 2021, and recognized $0.2 and $0.1 million in sublease 
income in 2022 and 2021, respectively.
In July 2019, the Company entered into a lease agreement for office space in Boston, Massachusetts, United States, which 
commenced in January 2020. The lease terminates in September 2026 and has no options for term extension. The annual 
rental payments, including variable payments, were $1.2 million and $1.1 million in 2022 and 2021, respectively. The lease 
agreement includes annual rent escalation provisions.
As of December 31, 2022, the carrying value of the operating lease right-of-use assets in Boston and London was $8.1 
million and the lease liabilities was $8.7 million. As of December 31, 2021, the carrying value of the operating lease right-of-
use assets in Boston and London was $4.1 million and the lease liabilities was $4.3 million.
Fremont operating lease and sublease agreements
In December 2018, the Company leased manufacturing, laboratory, and office space in Fremont, California (the “Fremont 
facility” and the “Head Lease”) which terminates in May 2030. In May 2020, the Company committed to a restructuring plan 
whereby it ceased construction and build-out of the Fremont facility. In December 2020, the Company entered into a sublease 
agreement (the “Sublease”) with an unrelated third-party (the “subtenant”) whereby the Company subleased the entire 
Fremont facility to the subtenant. The Company accounts for the Head Lease and Sublease as two separate contracts. Both 
the Head Lease and Sublease were determined to be operating leases.
The Head Lease annual rental payments, including variable payments, were $3.2 million in 2022 and $3.1 million in 2021. 
The Head Lease includes annual rent escalation provisions. The Company was provided with 8 months of free rent. Subject 
to the terms of the Head Lease agreement, the Company executed a $3.0 million letter of credit upon signing the lease, which 
may be reduced by 25% subject to reduction requirements specified therein. This amount is classified as restricted cash on 
the consolidated balance sheets.  
As of December 31, 2022, the carrying value of the Fremont Head Lease right-of-use asset was $8.8 million and the lease 
liability was $12.0 million. The Head Lease provides for up to $5.3 million in tenant improvement allowances to be 
reimbursed to the Company by the landlord. These tenant improvement allowances have been included in the calculation of 
the operating lease liability and are currently expected to be received in 2023. The Company continues to assess the expected 
receipt of the tenant improvement allowances and may remeasure the right-of-use asset and liability from time to time as 
facts and circumstances may change.
The Sublease commenced in December 2020 and is in force for the remainder of the Head Lease term. The Sublease 
provided for 12 months of free rent until December 2021. The sublease provides for cash base rent payments with an annual 
rent escalation provision. The subtenant is also responsible for paying all operating expenses associated with the Head Lease. 
The Sublease also includes pass-through of up to $5.3 million in tenant improvement allowances to the subtenant, subject to 
the Company being reimbursed for the allowances per the terms of the Head Lease. The Subtenant provided the Company 
with a $2.6 million security deposit, which may be converted to a letter of credit upon providing evidence of $2.6 million in 
construction expenditures. The Company accounts for the security deposit within other long-term liabilities.
Embedded operating lease arrangement
In July 2020, the Company entered into a manufacturing and technology development master agreement for research and 
development and commercial production with AGC Biologics, S.p.A. (formerly MolMed S.p.A.) (“AGC”) pursuant to which 
AGC will develop, manufacture and supply certain viral vectors and conduct cell processing activities for certain Company 
development and commercial programs ("AGC Agreement"). 

F-24
The Company determined that the AGC Agreement contains an embedded lease as it includes a provision for manufacturing 
suites designated for the Company’s exclusive use during the term of the agreement. The AGC Agreement has an initial term 
of five years, beginning on the Effective Date and ending July 2, 2025. The agreement may be extended for an additional two 
years by mutual agreement of the Company and AGC. The Company does not deem it probable that it will exercise the 
option to extend as of December 31, 2022. The Company paid $2.5 million and $3.1 million in rental payments in 2022 and 
2021, respectively. As of December 31, 2022, the carrying value of the embedded operating lease right-of-use asset was $5.8 
million and the lease liability was $5.3 million. As of December 31, 2021, the carrying value of the embedded operating lease 
right-of-use asset was $10.7 million and the lease liability was $9.3 million. 
Summary of all lease costs recognized under ASC 842
Our facility leases described above generally contain customary provisions allowing the landlords to terminate the leases if 
we fail to remedy a breach of any of our obligations under any such lease within specified time periods, or upon our 
bankruptcy or insolvency. The leases do not include any restrictions or covenants that had to be accounted for under the lease 
guidance. The following table contains a summary of the lease-related costs recognized within operating expenses, and other 
information pertaining to the Company’s operating leases as of December 31, 2022 and 2021 (in thousands, where 
applicable):
2022
2021
Fixed lease cost
$
7,693
$
7,701
Variable lease cost
1,602
1,696
Sublease income
(2,820)
(2,746)
Total lease cost
$
6,475
$
6,651
Other information
  Operating cash flows used for operating leases
$
7,442
$
7,989
  Weighted-average remaining lease term (years)
6.5
6.0
  Weighted-average discount rate
8.5%
8.7%
Fixed lease cost represents the ASC 842 rent expense associated with the amortization of our right-of-use assets and lease 
liabilities. Variable lease cost are the amounts owed by the Company to a lessor that are not fixed, such as reimbursement for 
common area maintenance and utilities costs and are not included in the calculation of the Company’s operating lease right of 
use assets or operating lease liabilities and are expensed when incurred. Sublease income represents the straight-line 
recognition of base rent sublease income over the term of the Sublease, and recognition of pass-through operating expense 
costs per the terms of the Sublease.
During the year ended December 31, 2022, the Company obtained right of use assets valued at $6.1 million in exchange for 
lease liabilities of $6.1 million. During the year ended December 31, 2021, the Company obtained $0.6 million in right of use 
assets in exchange for $0.6 million in lease liabilities.
As of December 31, 2022, future minimum base rent commitments under ASC 842 under the Company’s property leases 
were as follows (in thousands):
Due in:
Gross lease 
payments
Gross sublease 
receipts
Net lease payments
2023
$
6,517 $
(2,246) $
4,271
2024
6,972
(2,313)
4,659
2025
6,035
(2,382)
3,653
2026
4,809
(2,454)
2,355
2027
3,774
(2,527)
1,247
Thereafter
12,266
(6,432)
5,834
Total future minimum lease payments
$
40,373 $
(18,354) $
22,019
Less: imputed interest
(14,703)
Total operating lease payments
$
25,670
11. Notes payable

F-25
In May 2019, the Company entered into a senior term facilities agreement, which was amended in April 2020 (the “Original 
Credit Facility”) with MidCap Financial (Ireland) Limited (“MidCap Financial”), as agent, and additional lenders from time 
to time (together with MidCap Financial, the “Lenders”), to borrow up to $75.0 million in term loans. 
In May 2021, the Company amended and restated the Original Credit Facility (the “Amended Credit Facility”). Under the 
Amended Credit Facility, the Lenders agreed to make term loans available to the Company in the aggregate amount of 
$100.0 million, including increasing the principal on the initial term loan to $33.0 million, from $25.0 million. To date, the 
Company has borrowed $33.0 million under the amended initial term loan. The remaining $67.0 million under the Amended 
Credit Facility may be drawn down in the form of a second and third term loan, the second term loan being a $33.0 million 
term loan available no earlier than July 1, 2022  and no later than July 1, 2023 upon certain regulatory approvals and 
evidence of the Company having $100 million in cash and cash equivalent investments; and the third term loan being a $34.0 
million term loan available no earlier than July 1, 2023 and no later than July 1, 2024 upon evidence of the Company having 
$100 million in cash and cash equivalent investments and attaining a pre-specified trailing 12-month revenue target.          
Each term loan under the Amended Credit Facility bears interest at an annual rate equal to 5.95% plus LIBOR. The Company 
is required to make interest-only payments on the term loan for 18 months following the date of the Amended Credit Facility, 
unless the Company is eligible for the second tranche, in which case the Company may elect to make interest-only payments 
for 30 months following the date of the Amended Credit Facility. The term loans under to the Amended Credit Facility begin 
amortizing on either the 18-month or the 30-month anniversary of the Amended Credit Facility (as applicable), with equal 
monthly payments of principal plus interest to be made by the Company to the Lenders in consecutive monthly installments 
until the loan maturity date. In addition, a final payment of 3.5% is due on the loan maturity date. The Company is accruing 
the final payment amount of $1.2 million associated with the first term loan of the Amended Credit Facility, to outstanding 
debt by charges to interest expense using the effective-interest method from the date of issuance through the loan maturity 
date. 
The Amended Credit Facility includes affirmative and negative covenants. The affirmative covenants include, among others, 
covenants requiring the Company to maintain their legal existence and governmental approvals, deliver certain financial 
reports, maintain insurance coverage, maintain property, pay taxes, satisfy certain requirements regarding accounts and 
comply with laws and regulations. The negative covenants include, among others, restrictions on the Company transferring 
collateral, incurring additional indebtedness, engaging in mergers or acquisitions, paying dividends or making other 
distributions, making investments, creating liens, amending material agreements and organizational documents, selling 
assets, changing the nature of the business and undergoing a change in control, in some cases subject to certain exceptions. 
The Company is also subject to an ongoing minimum cash financial covenant in which the Company must maintain 
unrestricted cash in an amount not less than $20.0 million following the utilization of the second term loan and not less than 
$35.0 million following the utilization of the third term loan.
In January 2023, the Company again amended and restated the credit facility to change from LIBOR to SOFR. The newly 
amended facility bears a variable interest rate of 5.95% above SOFR plus 0.10% per annum, plus a final payment equal to 
3.5% of the principal borrowed under the Amended Credit Facility. 
Notes payable consisted of the following (in thousands):
December 31,
2022
2021
Notes payable, net of issuance costs
$
31,970
$
32,669
Less: current portion
(9,429)
(786)
Notes payable, net of current portion
22,541
31,883
Accretion related to final payment
450
203
Notes payable, long term
$
22,991
$
32,086
As of December 31, 2022, the future principal payments and final payment that are due are as follows (in thousands):

F-26
Aggregate
Minimum
Payments
2023
$
9,429
2024
9,429
2025
9,429
2026
5,084
Total
33,371
Less current portion
(9,429)
Less unamortized portion of final payment
(705)
Less unamortized debt issuance costs
(246)
Notes payable, long term
$
22,991
During the years ended December 31, 2022 and 2021, the Company recognized $3.0 million and $2.5 million of interest 
expense related to the term loan, respectively. The effective annual interest rate as of December 31, 2022 and 2021, on the 
outstanding debt under the Term Loan was approximately 9.2% and 8.4%, respectively.
12. Share-based compensation 
The Company maintains four equity compensation plans; the Orchard Therapeutics Limited Employee Share Option Plan 
with Non-Employee Sub-Plan and U.S. Sub-Plan (the “2016 Plan”), the Orchard Therapeutics plc 2018 Share Option and 
Incentive Plan (the “2018 Plan”), the 2018 Employee Share Purchase Plan (the “ESPP”), and the 2020 Inducement Equity 
Plan (the “Inducement Plan”). The board of directors has determined not to make any further awards under the 2016 plan. As 
of December 31, 2022, there were 5,341,768 shares available for grant under the 2018 Plan, 721,500 available for grant under 
the Inducement Plan, and 627,677 shares available for grant under the ESPP.
The numbers of options and restricted stock units, the weighted average grant date fair values per stock option and per share, 
and the weighted average exercise prices are all shown below on a per ordinary share basis. Effective March 10, 2023, The 
Company’s ADSs that are listed on the NASDAQ Capital Market each represent ten ordinary shares.
On October 4, 2022, the Company’s Compensation Committee approved a one-time stock option repricing for certain 
previously granted and still outstanding options held by the Company’s employees and certain independent contractors which 
had an exercise price above $1.25. As a result of the repricing, the exercise price for 7,946,139 vested and unvested options 
outstanding was lowered to $0.58. No other terms of the repriced options were modified and the repriced stock will continue 
to vest according to their original vesting schedules and will retain their original expiration dates. The repricing resulted in 
one-time stock-based compensation expense of $0.9 million related to vested options and incremental stock option expense 
of $0.8 million related to unvested options which will be amortized on a straight-line basis over the remaining vesting period 
of those options.
Share options
The fair value of each stock option award is estimated on the date of grant using the Black-Scholes option-pricing model 
using the range of assumptions for the years ended December 31, 2022 and 2021, as noted in the following table:
Year Ended December 31,
2022
2021
Risk-free interest rate
1.5% - 4.4%
0.5% - 1.3%
Expected term (in years)
2.0 - 6.1
5.3 - 6.1
Expected volatility
74.4% - 79.5%
74.2% - 78.7%
Expected dividend rate
0.0%
0.0%

F-27
The following table summarizes option activity under the plans for the year ended December 31, 2022:
Shares
Weighted
Average
Exercise Price
per Share
Weighted
Average
Remaining
Contractual
Life (Years)
Aggregate
Intrinsic
Value
(in thousands)
Outstanding at December 31, 2021
17,300,740
$
6.57
Granted
4,600,154
0.56
Exercised
(699,234)
-
Forfeited
(4,777,493)
6.81
Outstanding at December 31, 2022
16,424,167
$
1.56
7.38
$
-
Vested and expected to vest at December 31, 2022
16,424,167
$
1.56
7.38
$
-
Exercisable at of December 31, 2022
9,212,552
$
2.28
6.26
$
-
The aggregate intrinsic value of options is calculated as the difference between the exercise price of the options and the fair 
value of the Company’s ordinary shares for those options that had exercise prices lower than the fair value of the Company’s 
ordinary shares. During the years ended December 31, 2022 and 2021, the total intrinsic value of share options exercised was 
$0.4 million and $7.4 million, respectively. The weighted average grant date fair value per share of options granted during 
the years ended December 31, 2022 and 2021, was $0.32 and $3.10, respectively.
Restricted share units
CEO award
The Company granted 195,000 performance based RSUs with a total grant date fair value of $1.4 million to its Chief 
Executive Officer, Bobby Gaspar, M.D., Ph.D., in April 2020. The award vests on January 2, 2024 as to 1/3 of the award for 
each of the first three to occur of four milestones, if each such milestone is achieved by the Company on or before December 
31, 2023 and Dr. Gaspar remains continuously employed with the Company through January 2, 2024. The milestones relate 
to the achievement of specific clinical and regulatory milestones. No performance-based share unit performance conditions 
associated with the CEO award were deemed probable and none vested during the year ended December 31, 2022. 
Time-based restricted share units
Time-based restricted share units vest in equal annual installments over a three-year period.
The following table summarizes restricted share unit award activity for the year-end December 31, 2022:
Performance-based 
RSUs
Time-based RSUs
Total RSUs
Weighted Average 
Grant Date Fair 
Value per Share
Unvested at December 31, 2021
195,000
123,333
318,333
$
6.41
Granted
—
2,192,988
2,192,988
0.46
Vested
—
(55,001)
(55,001)
5.58
Forfeited
—
(392,444)
(392,444)
0.60
Unvested at December 31, 2022
195,000
1,868,876
2,063,876
$
0.55
During the years ended December 31, 2022 and 2021, the total fair value of time-based RSU’s that vested was $0.3 million 
and $0.3 million, respectively.
Share-based compensation 
Share-based compensation expense related to share options, restricted share unit awards, and the employee stock purchase 
plan was classified in the consolidated statements of operations and comprehensive loss as follows (in thousands): 
Year Ended December 31,
2022
2021
Research and development
$
6,791
$
9,214
Selling, general and administrative
9,219
13,322
Total
$
16,010
$
22,536
Total share-based compensation by award type was as follows (in thousands):

F-28
Year Ended December 31,
2022
2021
Restricted share units
$
838
$
550
Share options
15,172
21,986
Total
$
16,010
$
22,536
As of December 31, 2022, total unrecognized compensation cost related to options was $14.0 million. This amount is 
expected to be recognized over a weighted average period of 2.34 years. As of December 31, 2022, total unrecognized 
compensation cost related to time-based RSUs was $0.8 million. This amount is expected to be recognized over a weighted 
average period of 1.96 years. As of December 31, 2022, the total unrecognized compensation cost related to performance-
based RSUs is a maximum of $1.4 million, the timing of recognition will be dependent upon achievement of milestones.
13. License and research arrangements 
GSK asset purchase and license agreement 
In April 2018, the Company completed an asset purchase and license agreement (the “GSK Agreement”) with subsidiaries of 
GSK to acquire a portfolio of autologous ex vivo gene therapy assets and licenses for rare diseases and option rights on three 
additional programs in pre-clinical development from Telethon Foundation and San Raffaele Hospital (“Telethon-OSR”). 
The portfolio of programs and options acquired consisted of two late-stage clinical gene therapy programs in ongoing 
registrational trials for MLD and WAS, one earlier stage clinical gene therapy program for TDT, Strimvelis, and option rights 
exercisable upon completion of clinical proof of concept studies for three additional earlier-stage development programs, 
which option rights have all subsequently lapsed. 
The Company accounted for the GSK Agreement as an asset acquisition, since the asset purchase and licensing arrangement 
did not meet the definition of a business pursuant to ASC 805, Business Combinations, resulting in total consideration of 
$133.6 million, which was recorded in the second quarter of 2018.
The Company is required to use commercially reasonable efforts to obtain a Priority Review Voucher (“PRV”) from the 
United States Food and Drug Administration for each of the programs for MLD, WAS and TDT, the first of which GSK 
retained beneficial ownership over. GSK also has an option to acquire, at a price pursuant to an agreed upon formula, any 
PRV granted to the Company thereafter for MLD, WAS and TDT. If GSK does not exercise this option to purchase any 
PRV, the Company may sell the PRV to a third party and must share any proceeds in excess of a specified sale price equally 
with GSK. As part of the GSK Agreement the Company is also required to use its best endeavors to make Strimvelis 
commercially available in the European Union until such time as an alternative gene therapy is commercially available for 
patients in Italy, and at all times at the San Raffaele Hospital in Milan, provided that a minimum number of patients continue 
to be treated at this site. 
The Company will pay GSK non-refundable royalties and milestone payments in relation to the gene therapy programs 
acquired. The Company will pay a flat mid-single digit percentage royalty on the annual net sales of Strimvelis. The 
Company will also pay tiered royalty rates at a percentage beginning in the mid-teens up to twenty percent for the MLD and 
WAS products, upon marketing approval, calculated as percentages of aggregate cumulative net sales of the MLD and WAS 
products, respectively. The Company will pay a tiered royalty at a percentage from the high single-digits to low double-digit 
for the TDT product, upon marketing approval, calculated as percentages of aggregate annual net sales of the TDT product. 
These royalties owed to GSK are in addition to any royalties owed to other third parties under various license agreements for 
the GSK programs. In aggregate, the Company may pay up to £90.0 million in milestone payments upon achievement of 
certain sales milestones applicable to GSK. The Company’s royalty obligations with respect to MLD and WAS may be 
deferred for a certain period in the interest of prioritizing available capital to develop each product. The Company’s royalty 
obligations are subject to reduction on a product-by-product basis in the event of market control by biosimilars and will 
expire in April 2048. Other than Strimvelis, these royalty and milestone payments were not determined to be probable and 
estimable at the date of the acquisition or through December 31, 2022, and are not included as part of consideration.
Telethon-OSR research and development collaboration and license agreements
In connection with the Company’s entering into the GSK Agreement in April 2018, the Company also acquired and assumed 
agreements with Telethon Foundation and San Raffaele Hospital, together referred to as Telethon-OSR, for the research, 
development and commercialization of autologous ex vivo gene therapies for ADA-SCID, WAS, MLD and TDT. 

F-29
As consideration for the licenses, the Company will be required to make payments to Telethon-OSR upon achievement of 
certain product development milestones, up to an aggregate of approximately €31.0 million ($33.4 million at December 31, 
2022). Additionally, the Company will be required to pay to Telethon-OSR a tiered mid-single to low-double digit royalty 
percentage on annual sales of licensed products covered by patent rights on a country-by-country basis, as well as a low 
double-digit percentage of sublicense income received from any certain third-party sublicenses of the collaboration programs.
In May 2019, the Company entered into a license agreement with Telethon-OSR, under which Telethon-OSR granted to the 
Company an exclusive worldwide license for the research, development, manufacture and commercialization of Telethon-
OSR’s ex vivo autologous HSC lentiviral based gene therapy for the treatment of mucopolysaccharidosis type I, including the 
Hurler variant (“MPS-IH”). Under the terms of the agreement, Telethon-OSR received €15.0 million ($16.1 million at 
December 31, 2022) in upfront and milestone payments from the Company upon entering into the agreement, resulting in 
$17.2 million in in-process research and development expense. The Company is also required to pay up to €28.0 million 
($30.1 million at December 31, 2022) related to milestone payments contingent upon achievement of certain development, 
regulatory and commercial milestones. Additionally, the Company will be required to pay Telethon a tiered mid-single to 
low-double digit royalty percentage on annual net sales of licensed products. 
UCLB/UCLA license agreement 
In February 2016, and amended in July 2017, the Company completed the UCLB/UCLA license agreement, under which the 
Company has been granted exclusive and non-exclusive, sublicensable licenses under certain intellectual property rights 
controlled by UCLB and UCLA to develop and commercialize gene therapy products in certain fields and territories. 
In exchange for these rights, in 2016, the Company made upfront cash payments consisting of $0.8 million for the license to 
the joint UCLB/UCLA technology and $1.1 million for the license to the UCLB technology and manufacturing technology. 
The Company also issued an aggregate of 4,665,384 ordinary shares to UCLB, of which 1,224,094, and 3,441,290 ordinary 
shares were issued in 2017 and 2016, respectively. The Company recorded research and development expenses based on the 
fair value of the ordinary shares as of the time the agreement was executed or modified. 
Under the UCLB/UCLA License Agreement, the Company may become obligated to make payments to the parties of up to 
an aggregate of £19.9 million ($24.1 million at December 31, 2022) upon the achievement of specified regulatory milestones 
as well as royalties ranging from low to mid-single-digit percentage on net sales of the applicable gene therapy product. 
In June 2021, the Company terminated the license to its OTL-101 program for ADA-SCID, which was granted pursuant to 
the UCLB/UCLA license agreement. Except for the termination of such license, the UCLB/UCLA license agreement 
continues in full force and effect. Unless terminated earlier by either party, the UCLB/UCLA license agreement will expire 
on the 25th anniversary of the agreement. 
Oxford BioMedica license, development and supply agreement 
In November 2016, and amended in June 2017, May 2018, July 2018, September 2018, May 2019 and April 2020, the 
Company entered into an arrangement with Oxford BioMedica plc whereby Oxford BioMedica granted an exclusive 
intellectual property license to the Company for the purposes of research, development, and commercialization of 
collaboration products, and whereby Oxford BioMedica will provide process development services (“Oxford BioMedica 
Development Agreement”). As part of the consideration to rights and licenses granted under the Oxford BioMedica 
Development Agreement, the Company issued 588,220 ordinary shares to Oxford BioMedica. The Company is also obligated 
to make certain development milestone payments in the form of issuance of additional ordinary shares if the milestones are 
achieved. In November 2017, the first milestone was achieved, and the Company was committed to issue another 150,826 
ordinary shares, and issued these shares in 2018. In September 2018, the second and fourth milestones were achieved, and the 
Company issued 150,826 ordinary shares. In April 2020, the fifth milestone was deemed to have been met upon execution of 
the amended agreement in April 2020, and the Company issued another 75,413 ordinary shares to Oxford BioMedica with a 
total value of $0.8 million which was recorded to research and development expense. No milestones were met during the year 
ended December 31, 2022. The Company may also pay low single-digit percentage royalties on net sales of collaborated 
products generated under the Oxford BioMedica Agreement.

F-30
14. Income taxes 
The components of net loss before income taxes for the years ended December 31, 2022 and 2021 are as follows (in 
thousands):
December 31,
2022
2021
U.K.
$
(156,000)
$
(147,337)
Non-U.K.
2,966
3,581
Net loss before taxes
$
(153,034)
$
(143,756)
The provision for (benefit from) income taxes for the years ended December 31, 2022 and 2021 are as follows (in thousands): 
December 31,
2022
2021
Current (benefit) provision
Federal—United States
$
618
$
(1,025)
State—United States
144
334
Other foreign
147
388
United Kingdom
—
—
Total current (benefit) provision
909
(303)
Deferred provision (benefit)
Federal—United States
(3,066)
1,099
State—United States
(204)
(312)
United Kingdom
(13)
—
Other foreign
—
344
Total deferred provision (benefit)
(3,283)
1,131
Total provision (benefit) for income taxes
$
(2,374)
$
828
The following table presents a reconciliation of income tax expense (benefit) computed at the UK statutory income tax rate to 
the effective income tax rate as reflected in the consolidated financial statements (in thousands): 
December 31,
2022
2021
Income taxes at United Kingdom statutory rate
$
(29,072) $
(27,313)
Change in valuation allowance
34,333
59,691
Reduction in research expense for credits granted
1,805
6,674
Change in tax rates
(8,240)
(38,785)
Tax credits
(2,049)
(2,232)
U.S. Deduction for foreign derived intangible income
(1,489)
(196)
Permanent differences, including share-based compensation deduction shortfalls
2,387
2,863
U.S. state income taxes
(45)
17
Foreign rate differential
(4)
109
Total provision (benefit) for income taxes
$
(2,374) $
828
The Company’s income tax expense for the year ended December 31, 2022, compared to the year ended December 31, 2021, 
decreased primarily related to an increase of the U.S. deduction for foreign derived intangible income (“FDII”), a decrease to 
the amount of shortfalls related to share-based compensation that is not deductible for tax purposes, and a decrease in the 
non-U.K. profit before tax.
During 2021, the U.K. Government announced that from April 1, 2023, the corporation tax rate would increase to 25%. This 
new law was enacted on June 10, 2021. The overall effect of the change was an increase in net deferred tax assets of $38.8 
million and an increase in valuation allowance by an equal amount.  

F-31
The Company accounts for income taxes in accordance with ASC Topic 740. Deferred income tax assets and liabilities are 
determined based upon temporary differences between the financial reporting and tax bases of assets and liabilities and are 
measured using the enacted tax rates and laws that will be in effect when the differences are expected to reverse. The 
following table presents the principal components of the Company’s deferred tax assets and liabilities as of December 31, 
2022 and 2021 (in thousands): 
December 31,
2022
2021
Deferred tax assets
Net operating loss carryforwards
$
158,344
$
126,563
Amortization
11,215
25,206
Research and development credits
2,525
2,449
Capitalized research and development costs
2,285
—
Share-based compensation
9,282
9,353
Accruals
946
798
Lease liability
6,126
6,444
Property and equipment
—
1,022
Total deferred tax assets
190,723
171,835
Valuation allowance
(177,630)
(161,573)
Fixed assets and right-of-use asset
(5,724)
(6,176)
Other non-current assets (net deferred tax assets and liabilities)
$
7,369
$
4,086
For the years ended December 31, 2022 and 2021, the Company had cumulative U.K. net operating loss carryforwards of 
approximately $633.4 million and $506.2 million, respectively. U.K. losses not surrendered may be carried forward 
indefinitely, subject to numerous utilization criteria and restrictions and are fully offset by a valuation allowance.  For the 
years ended December 31, 2022 and 2021, the Company also had U.S. federal orphan drug tax credits of $0.7 million and 
$0.6 million, respectively, and U.S. state research and development tax credits of $2.2 million and $2.4 million.  The U.S. 
federal orphan drug tax credits expire in 2042, while the U.S. state research and development credits may be carried forward 
indefinitely and are offset by a valuation allowance.
In measuring the Company’s deferred tax assets, the Company considers all available evidence, both positive and negative, to 
determine whether, based on the weight of that evidence, a valuation allowance is needed for all or some portion of the 
deferred tax assets. Significant judgment is required in considering the relative impact of the negative and positive evidence, 
and weight given to each category of evidence is commensurate with the extent to which it can be objectively verified. The 
more negative evidence that exists, the more positive evidence is necessary, and the more difficult it is to support a 
conclusion that a valuation allowance is not needed. Additionally, the Company utilizes the "more likely than not" criteria 
established in FASB ASC Topic 740 to determine whether the future tax benefit from the deferred tax assets should be 
recognized. As a result, the Company has established valuation allowances on the deferred tax assets in jurisdictions that 
have incurred net operating losses and in which it is more likely than not that such losses will not be utilized in the 
foreseeable future.
As of each reporting date, the Company considers new evidence, both positive and negative, that could impact the 
Company’s view with regard to the future realization of our deferred tax assets. Management has considered the Company’s 
history of cumulative net losses in the U.K., along with estimated future taxable income and has concluded that it is more 
likely than not that the Company will not realize the benefits of its U.K. deferred tax assets and U.S. state research and 
development tax credits. Accordingly, the Company has maintained a full valuation allowance against these net deferred tax 
assets as of December 31, 2022 and 2021, respectively.  
Changes in the valuation allowance for deferred tax assets during the years ended December 31, 2022 and 2021 related 
primarily to the increase in UK net operating loss carryforwards as follows (in thousands):
December 31,
2022
2021
Valuation allowance as of beginning of year
$
(161,573)
$
(103,890)
Increases recorded to income tax provision
(34,248)
(59,691)
Effect of foreign currency translation
18,191
2,008
Valuation allowance as of end of year
$
(177,630)
$
(161,573)
The Company applies the authoritative guidance on accounting for and disclosure of uncertainty in tax positions, which 
requires the Company to determine whether a tax position of the Company is more likely than not to be sustained upon 

F-32
examination, including resolution of any related appeals of litigation processes, based on the technical merits of the position. 
For tax positions meeting the more likely than not threshold, the tax amount recognized in the financial statements is reduced 
by the largest benefit that has a greater than fifty percent likelihood of being realized upon the ultimate settlement with the 
relevant taxing authority. There were no material uncertain tax positions as of December 31, 2022 and 2021.  
The Company will recognize interest and penalties related to uncertain tax positions in income tax expense. As of December 
31, 2022, and 2021, the Company had no accrued interest or penalties related to uncertain tax positions and no amounts have 
been recognized in the Company’s statement of operations. 
The Company and its subsidiaries file income tax returns in the UK, the U.S., and various foreign jurisdictions. Generally, 
the tax years 2018 through 2022 remain open to examination by the major taxing jurisdictions to which the Company is 
subject. To the extent the Company has tax attribute carryforwards, the tax years in which the attribute was generated may 
still be adjusted upon examination by the federal, state, or foreign tax authorities, if such tax attributes are utilized in a future 
period. 
15. Product revenue, net
The following table presents the Company's net revenue by product (in thousands): 
Year Ended December 31,
2022
2021
Libmeldy
$
18,796
$
—
Strimvelis
1,814
700
Total
$
20,610
$
700
Net product revenue of Libmeldy by geography consisted of the following and is attributable to individual countries based on 
the location of the customer as of December 31, 2022 (in thousands): 
Year ended 
December 31, 2022
United Kingdom
$
6,322
Italy
5,544
France
3,883
Germany
3,047
Total Libmeldy revenue, net
$
18,796
As of December 31, 2022 and 2021, all Strimvelis revenue was generated in Italy. 
Activity in each of the product revenue allowance and reserve categories for Libmeldy is summarized as follows (in 
thousands): 
Trade Discounts and 
Allowances
Government 
rebates
Total
Balance as of December 31, 2021
$
—
$
—
$
—
Provision Related to sales in the current year
4,573
2,300
6,873
Credits and payments made during the period
(183)
—
(183)
Balance as of December 31, 2022
$
4,390
$
2,300
$
6,690
The total reserves described above are summarized as components of the Company's consolidated balance sheets as follows 
(in thousands):
December 31, 2022
Reduction of accounts receivable, net
$
4,390
Component of accrued expenses and other current liabilities
2,300
Balance as of December 31, 2022
$
6,690
There were no Libmeldy reserves or revenue allowances as of December 31, 2021. Strimvelis had no trade discounts and 
allowances or government rebates in the years ended December 31, 2022 and 2021.
16. Collaboration revenue

F-33
On July 1, 2021, the Company entered into a strategic collaboration with Pharming Group N.V. (“Pharming”) to research, 
develop, manufacture, and commercialize OTL-105, an investigational ex vivo autologous HSC gene therapy for the 
treatment of hereditary angioedema (HAE), a life-threatening rare disorder that causes recurring swelling attacks in the face, 
throat, extremities and abdomen (the “Collaboration Agreement”).
Under the terms of the Collaboration Agreement, Pharming was granted worldwide rights to OTL-105 and will be 
responsible for clinical development, regulatory filings and commercialization of the investigational gene therapy, including 
associated costs. The Company will lead the completion of IND-enabling activities and oversee manufacturing of OTL-105 
during pre-clinical and clinical development, which will be funded by Pharming. In addition, both the Company and 
Pharming will explore the application of non-toxic conditioning regimen for use with OTL-105 administration.
The Company received an upfront payment of $10.0 million in cash from Pharming. The Company is also eligible to receive 
up to $189.5 million in development, regulatory and sales milestones as well as mid-single to low double-digit percentage 
royalty payments on future worldwide sales.
The Company also entered into a Share Purchase Agreement with Pharming on July 1, 2021 (the “SPA”), pursuant to which 
the Company issued 1,227,738 ordinary shares to Pharming for total consideration of $7.5 million. The consideration is 
payment for the fair value of ordinary shares with a fair value of $4.1 million plus a $3.4 million premium on the fair value of 
the Company’s ordinary shares. The “Collaboration Agreement” and the “SPA” are referred to together as the “Pharming 
Agreements.”
Accounting analysis
At the commencement of the arrangement, two units of accounting were identified, which are the issuance of 1,227,738 of 
the Company’s ordinary shares as part of the SPA, and the license and collaboration agreement, which conveys the license 
and provides for the Company to provide research, development, manufacturing services for OTL-105. The Pharming 
Agreements were entered into concurrently as part of a single commercial objective and the Company considers them a 
single arrangement for accounting purposes. The total upfront payments of $17.5 million are comprised of $4.1 million 
attributed to the equity sold to Pharming and $13.4 million attributed to the Collaboration Agreement.
The Company has concluded that the conveyance of the license for the HAE program and the provision of research, 
development, and manufacturing services for the HAE program represent a series of distinct services that are accounted for as 
a single performance obligation within the Collaboration Agreement. 
The Company determined that the transaction price includes: the $13.4 million attributed to the Collaboration Agreement and 
the variable consideration for estimated reimbursement payments at agreed upon contractual rates to be received from 
Pharming for the Company’s on-going research, development, and manufacturing services. The potential future variable 
consideration is associated with the reimbursement for research, development, and manufacturing services provided by the 
Company to Pharming at agreed upon contractual rates which is the only remaining unsatisfied performance obligation. The 
milestone payments included in the Collaboration Agreement are fully constrained as a result of the uncertainty regarding 
whether any of the associated milestones will be achieved. The Company re-evaluates the transaction price as of the end of 
each reporting period.
The Company recognizes revenue associated with the performance obligation as the research, development, and 
manufacturing services are provided using an input method, based on the cumulative costs incurred compared to the total 
estimated costs expected to be incurred to satisfy the performance obligation. The transfer of control to the customer occurs 
over the time period that the research, development and manufacturing services are to be provided by the Company.  
Reimbursement for research, development, and manufacturing services are recognized as the costs are incurred consistent 
with the cost-to-cost method. The estimated costs associated with the remaining efforts required to complete the performance 
obligations may change which may materially impact revenue recognition and the Company regularly evaluates and, when 
necessary, updates the costs associated with the remaining efforts. Accordingly, revenue may fluctuate from period to period 
due to revisions to estimated costs resulting in a change in the measure of progress for the performance obligation or if the 
transaction price changes due to inclusion of any milestone payments that become unconstrained.
The following table summarizes research and development costs incurred and collaboration revenue recognized in connection 
with the Company’s performance under the Collaboration Agreement (in thousands):
Year Ended December 31,
2022
2021
Reimbursement revenue
$
1,776
$
843
Upfront and milestone payment revenue
269
132
Total
$
2,045
$
975

F-34
The Company had $0.5 million and $0.8 due from Pharming included in accounts receivable as of December 31, 2022 and 
2021, respectively.
As of December 31, 2022, the Company had contract liabilities of $11.3 million, of which $1.0 million was classified as 
current and $10.3 million was classified as long-term in the consolidated balance sheets. The deferred revenue balance 
represents the portion of the upfront payments received related to the performance obligation that remains partially 
unsatisfied as of December 31, 2022.
17. Commitments and contingencies 
Lease commitments
The Company leases office and laboratory space and has an embedded lease with AGC. Refer to Note 10 for further 
information on the terms of our lease agreements.
Manufacturing and technology development master agreement with AGC
On July 2, 2020, the Company entered into the AGC Agreement pursuant to which AGC will develop, manufacture, and 
supply certain viral vectors and conduct cell processing activities for certain Company development and commercial 
programs. Under the terms of the AGC Agreement, the Company is obligated to pay AGC for a minimum product 
manufacturing commitment, dedicated manufacturing and development resources, and for a lease component associated with 
the right of use of exclusive manufacturing suites within AGC’s existing facilities. The following table outlines the annual 
commitments associated with the contract as of December 31, 2022 (in thousands):
Due in:
Product 
manufacturing 
commitments 
(1)
Dedicated 
manufacturing 
and 
development 
resources (2)
Exclusive 
transduction 
suites (3)
Total AGC 
Commitment
2023
$
1,933 $
5,655 $
2,147 $
9,735
2024
1,933
5,655
2,147
9,735
2025
966
2,827
1,074
4,867
Total manufacturing commitments
$
4,832 $
14,137 $
5,368 $
24,337
The tabular disclosure above has been translated from Euros to U.S. Dollars using an exchange rate of €1.00 to $1.07.
(1) The minimum product manufacturing commitments may be increased to the mid-seven figures per contract year upon 
achievement of certain milestones.
(2) The Company may increase or decrease the usage of dedicated development services on a rolling basis with between six 
and 12-months’ prior written notice to AGC. The above table assumes continued usage of dedicated development services at 
current rates.
(3) Refer to Note 10 for further information on the embedded operating lease agreement
The Company incurred $13.7 million and $16.4 million in expenses related to the AGC Agreement in the years ended 
December 31, 2022 and 2021, respectively. The AGC Agreement has an initial term of five years, beginning on the Effective 
Date and ending July 2, 2025. The AGC Agreement may be extended for an additional two years by mutual agreement of the 
Company and AGC. The Company has the right to terminate the AGC Agreement at its discretion upon 12-month’s prior 
written notice to AGC, and beginning no earlier than July 2, 2022, AGC has the right to terminate the AGC Agreement at its 
discretion upon 24-month’s prior written notice to the Company. Each party may terminate the AGC Agreement upon prior 
notice to the other party for an uncured material breach that the breaching party does not cure within the notice period.
Other funding commitments
The Company has entered into several license agreements (see Note 13). In connection with these agreements the Company 
is required to make milestone payments and annual license maintenance payments or royalties on future sales of specified 
products. 
Legal proceedings 
The Company is not a party to any litigation and does not have contingency reserves established for any litigation liabilities. 

F-35
Indemnification agreements
In the ordinary course of business, the Company may provide indemnification of varying scope and terms to vendors, lessors, 
business partners, and other parties with respect to certain matters including, but not limited to, losses arising out of breach of 
such agreements or from intellectual property infringement claims made by third parties. In addition, the Company has 
entered into indemnification agreements with members of its board of directors and senior management that will require the 
Company, among other things, to indemnify them against certain liabilities that may arise by reason of their status or service 
as directors or officers. The maximum potential amount of future payments the Company could be required to make under 
these indemnification agreements is, in many cases, unlimited. To date, the Company has not incurred any material costs as a 
result of such indemnifications. The Company is not aware of any claims under indemnification arrangements, and it has not 
accrued any liabilities related to such obligations in its consolidated financial statements as of December 31, 2022 or 2021. 
18. Benefit plans
The Company makes contributions to private defined contribution pension plans on behalf of its employees. The Company 
matches its employee contributions up to six percent of each employee’s annual salary based on the jurisdiction in which the 
employees are located. The Company paid $1.6 million and $1.7 million, in matching contributions for the years ended 
December 31, 2022 and 2021, respectively.
19. Subsequent events 
Ratio change
On February 10, 2023, the Company announced that the Company's Board of Directors approved a change to the ratio of the 
Company's ADSs to ordinary shares (the "ADS Ratio") from the previous ADS Ratio of one ADS to one ordinary share to a 
new ADS Ratio of one ADS to ten ordinary shares. The ratio change became effective on March 10, 2023. The change in the 
ADS Ratio had the same effect as a one-for-ten reverse ADS split and is intended to enable the Company to regain 
compliance with the Nasdaq minimum bid price requirement. As all financial statement and disclosure information is 
presented in ordinary share amounts, not ADSs, there was no impact to the consolidated financial statements and footnote 
disclosures. 
Issuance of shares through 2023 Private Placement
On March 6, 2023, the Company entered into a Securities Purchase Agreement (the “Purchase Agreement”) pursuant to 
which the Company agreed to sell, in an unregistered offering, up to an aggregate of (i) 99,166,900 shares, consisting of a 
combination of Ordinary Shares, nominal value £0.10 per share (“Ordinary Shares”) and Non-Voting Ordinary Shares, 
nominal value £0.10 per share (“Non-Voting Ordinary Shares” and together with the Ordinary Shares, “Shares”) and (ii) 
warrants to purchase an aggregate of 109,083,590 Ordinary Shares or Non-Voting Ordinary Shares (the “Warrants”).
The 2023 Private Placement consists of two closings. The Company agreed to sell and issue in the initial closing of the 2023 
Private Placement (i) 56,666,900 Shares and (ii) Warrants to purchase an aggregate of 62,333,590 Shares, at a purchase price 
of $6.00 per unit, where each unit consists of ten (10) Shares and an accompanying Warrant to purchase eleven (11) Shares. 
The initial closing of the 2023 Private Placement occurred on March 10, 2023. The Company received gross proceeds of 
approximately $34.0 million from the initial closing of the 2023 Private Placement, before deducting fees to the placement 
agent and other offering expenses payable by the Company.
In addition, the Company agreed to sell and issue in the second closing of the 2023 Private Placement (i) 42,500,000 Shares 
and (ii) Warrants to purchase an aggregate of 46,750,000 Shares, at a purchase price of $8.00 per unit, where each unit 
consists of ten (10) Shares and an accompanying Warrant to purchase eleven (11) Shares. The second closing is conditioned 
upon (x) the Company’s announcement of its intention to file a biologics license application (“BLA”) submission following 
receipt of the minutes from the U.S. Food and Drug Administration (“FDA”) in connection with the Company’s pre-BLA 
(Type B) meeting for OTL-200, provided such minutes do not expressly advise the Company not to proceed with a BLA 
submission, and (y) receipt of Shareholder Approval (as defined below) (collectively, the “Second Closing Trigger”). 
In connection with the Private Placement, the Company has agreed to hold a meeting of its shareholders no later than 120 
days following the initial closing of the Private Placement to seek approval to give the Company’s directors authority under 
s551 Companies Act 2006 to issue the securities to be issued and sold in the second closing of the Private Placement and the 
Shares issuable upon exercise of the Warrants to be issued and sold in the Private Placement, and to disapply pre-emption 
rights in respect of such authority under s570 of the Companies Act 2006 (collectively, “Shareholder Approval”).
The second closing is expected to occur on the fifth trading day after the Company notifies the purchasing parties that the 
Second Closing Trigger has occurred and is subject to additional, customary closing conditions. If the Second Closing 
Trigger occurs, the Company anticipates receiving gross proceeds of approximately $34.0 million from the second closing of 

F-36
the 2023 Private Placement, before deducting fees to the placement agent and other offering expenses payable by the 
Company.
Each Warrant will have an exercise price equal to $1.10 per Share in the event the Vesting Event (as defined below) occurs 
on or prior to December 31, 2024, and $0.95 per Share in the event the Vesting Event occurs after December 31, 2024. The 
Warrants will be exercisable during the 30 days following the Company’s announcement of receipt of marketing approval of 
its BLA with respect to OTL-200 (the “Vesting Event”); provided that exercise of any Warrant is conditioned upon the 
receipt of Shareholder Approval. Commencement of the 30-day exercise period may be delayed as set forth in the Warrants 
in the event the Vesting Event occurs prior to Shareholder Approval. The Warrants will expire at the conclusion of the 30-
day exercise period or, if the Vesting Event does not occur, March 10, 2026.

ORCHARD THERAPEUTICS PLC  
CORPORATE AND OTHER INFORMATION 
Board of Directors 
Bobby Gaspar, M.D., Ph.D. 
Director and Chief Executive Officer  
Honorary Clinical Professor of Pediatrics and 
Immunology, the UCL Great Ormond Street Institute of 
Child Health 
John T. Curnutte, M.D., Ph.D. (c) (d) 
Director, Chair of the Science and Technology 
Committee 
Senior Advisor, Samsara BioCapital 
Alicia Secor (a) (b) (c) 
Director  
President, Chief Executive Officer of Atalanta 
Therapeutics, Inc. 
Steven M. Altschuler, M.D. (d) 
Director  
Managing Director, Ziff Capital Partners 
Marc Dunoyer (a) (c) 
Director 
Chief Executive Officer, Alexion, AstraZeneca Rare 
Disease 
James Geraghty (c) 
Director, Chairman of the Board of Directors, Chair of 
the Nominating and Corporate Governance Committee  
Joanne T. Beck, Ph.D. (b) (d) 
Director  
Chief Technology Officer, Aerium Therapeutics 
Charles A. Rowland, Jr. (a) (b) 
Director, Chair of the Audit Committee, Chair of the 
Compensation Committee 
Board Committees 
(a) Audit Committee
(b) Compensation Committee
(c) Nominating and Corporate Governance Committee
(d) Science and Technology Committee
Executive Officers 
Bobby Gaspar, M.D., Ph.D. 
Director and Chief Executive Officer  
Honorary Clinical Professor of Pediatrics and 
Immunology, the UCL Great Ormond Street 
Institute of Child Health 
Frank Thomas 
President and Chief Operating Officer 
Registrar and Depositary 
The registrar of our ordinary shares is Equiniti 
Limited, and the depositary is Citibank, N.A. 
Stock Exchange Listing 
Our American Depositary Shares, each 
representing ten ordinary shares, are listed on the 
Nasdaq Capital Market under the symbol 
“ORTX.” 
Annual Meeting 
Our Annual General Meeting of Shareholders will 
take place at 9 am London time (4 am Eastern 
time) on Wednesday, June 14, 2023, at 245 
Hammersmith Road, London W6 8PW.  
Form 10-K Report 
Our Annual Report on Form 10-K for the year 
ended December 31, 2022, as filed with the 
Securities and Exchange Commission, is printed 
as part of this Annual Report. Additional copies 
are available without charge upon written request 
to:  
Christopher York, Company Secretary 
Orchard Therapeutics plc 
245 Hammersmith Road London W6 8PW 
United Kingdom 
+44 (0) 203 808 8286