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, 2021
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 001-38978
FULCRUM THERAPEUTICS, INC.
(Exact name of registrant as specified in its Charter)
Delaware
(State or other jurisdiction of
incorporation or organization)
26 Landsdowne Street
Cambridge, Massachusetts
(Address of principal executive offices)
47-4839948
(I.R.S. Employer
Identification No.)
02139
(Zip Code)
Registrant’s telephone number, including area code: (617) 651-8851
Securities registered pursuant to Section 12(b) of the Act:
Title of each class
Common stock, par value $0.001 per share
Trading
Symbol(s)
FULC
Name of each exchange on which registered
Nasdaq Global 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. ☐
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 June 30, 2021, the last business day of the registrant’s most recently completed second fiscal quarter, the aggregate market value of the registrant’s common stock held by non-
affiliates of the registrant, based on the closing price of the shares of common stock on the Nasdaq Global Market on June 30, 2021, was approximately $248,910,889.
The number of shares of registrant’s common stock outstanding as of February 24, 2022 was 40,637,216.
The registrant intends to file a definitive proxy statement pursuant to Regulation 14A relating to the 2022 Annual Meeting of Stockholders within 120 days of the end of the
registrant’s fiscal year ended December 31, 2021. Portions of such definitive proxy statement are incorporated by reference into Part III of this Annual Report on Form 10-K to the
extent stated herein.
DOCUMENTS INCORPORATED BY REFERENCE
Table of Contents
Business
Risk Factors
Unresolved Staff Comments
Properties
Legal Proceedings
Mine Safety Disclosures
Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities
Reserved
Management’s Discussion and Analysis of Financial Condition and Results of Operations
Quantitative and Qualitative Disclosures About Market Risk
Financial Statements and Supplementary Data
Changes in and Disagreements With Accountants on Accounting and Financial Disclosure
Controls and Procedures
Other Information
Disclosure Regarding Foreign Jurisdictions that Prevent Inspections
Directors, Executive Officers and Corporate Governance
Executive Compensation
Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters
Certain Relationships and Related Transactions, and Director Independence
Principal Accountant Fees and Services
Exhibits and Financial Statement Schedules
Form 10-K Summary
PART I
Item 1.
Item 1A.
Item 1B.
Item 2.
Item 3.
Item 4.
PART II
Item 5.
Item 6.
Item 7.
Item 7A.
Item 8.
Item 9.
Item 9A.
Item 9B.
Item 9C.
PART III
Item 10.
Item 11.
Item 12.
Item 13.
Item 14.
PART IV
Item 15.
Item 16.
Page
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109
109
109
109
109
110
110
In this Annual Report on Form 10-K, unless otherwise stated or as the context otherwise requires, references to “Fulcrum,” “Fulcrum Therapeutics,” “the
Company,” “we,” “us,” “our” and similar references refer to Fulcrum Therapeutics, Inc. together with its consolidated subsidiary. The Fulcrum
Therapeutics logo, FulcrumSeek and other trademarks or service marks of Fulcrum Therapeutics, Inc. appearing in this Annual Report on Form 10-K are
the property of Fulcrum Therapeutics, Inc. This Annual Report on Form 10-K also contains registered marks, trademarks and trade names of other
companies. All other trademarks, registered marks and trade names appearing herein are the property of their respective holders.
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K contains forward-looking statements, which reflect our current views with respect to, among other things, our
operations and financial performance. All statements other than statements of historical facts contained in this Annual Report on Form 10-K, including
statements regarding our strategy, future operations, future financial position, future revenue, projected costs, prospects, plans, objectives of management
and expected market growth are forward-looking statements. The words "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may,"
"might," “outlook,” "plan," "potential," "predict," "project," "should," "target," "would," and the negative version of these words and other similar
expressions are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Such
forward-looking statements are subject to various risks and uncertainties. Accordingly, there are or will be important factors that could cause actual
outcomes or results to differ materially from those indicated in these statements. We believe these factors include but are not limited to those described
under the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections and include, among
other things:
•
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•
•
•
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•
•
•
•
•
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our ongoing clinical trials of losmapimod and FTX-6058;
the impact of the ongoing COVID-19 pandemic on our business and operations, including our clinical trials and development plans, as well as
our future financial results;
the initiation, timing, progress and results of our drug target discovery screening programs;
the initiation, timing, progress and results of our current and future preclinical studies and clinical trials and our research and development
programs;
our plans to develop and, if approved, subsequently commercialize losmapimod, FTX-6058 and any other product candidates, including in
combination with other drugs and therapies;
the timing of and our ability to submit applications for, and obtain and maintain regulatory approvals for losmapimod, FTX-6058 and any other
product candidates;
our expectations regarding our ability to fund our operating expenses and capital expenditure requirements with our cash, cash equivalents, and
marketable securities;
the potential advantages of our product candidates;
the rate and degree of market acceptance and clinical utility of our products, if our product candidates are approved;
our estimates regarding the potential market opportunity for our product candidates;
our commercialization, marketing and manufacturing capabilities and strategy;
our intellectual property position;
the progress and results of our collaborations with Acceleron Pharma Inc., or Acceleron, a wholly-owned subsidiary of Merck & Co., Inc., or
Merck, and MyoKardia, Inc., or MyoKardia, a wholly-owned subsidiary of Bristol-Myers Squibb Company;
our ability to identify additional products, product candidates or technologies with significant commercial potential that are consistent with our
commercial objectives;
our estimates regarding expenses, future revenue, timing of any future revenue, capital requirements and needs for additional financing;
the impact of government laws and regulations;
our competitive position;
developments relating to our competitors and our industry;
our ability to maintain and establish collaborations or obtain additional funding; and
our expectations regarding the time during which we will be an emerging growth company or a smaller reporting company as defined under the
federal securities laws.
i
We may not actually achieve the plans, intentions or expectations disclosed in our forward-looking statements, and you should not place undue
reliance on our forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the
forward-looking statements we make. We have included important factors in the cautionary statements included in this Annual Report on Form 10-K,
particularly in the "Risk Factors" section, that we believe could cause actual results or events to differ materially from the forward-looking statements that
we make. Our forward-looking statements do not reflect the potential impact of any future acquisitions, mergers, dispositions, collaborations, joint ventures
or investments we may make or enter into.
You should read this Annual Report on Form 10-K and the documents that we have filed as exhibits to Annual Report on Form 10-K completely and
with the understanding that our actual future results may be materially different from what we expect. The forward-looking statements contained in this
Annual Report on Form 10-K are made as of the date of this Annual Report on Form 10-K, and we do not assume any obligation to update any forward-
looking statements, whether as a result of new information, future events or otherwise, except as required by applicable law.
This Annual Report on Form 10-K includes statistical and other industry and market data that we obtained from industry publications and research,
surveys and studies conducted by third parties as well as our own estimates of potential market opportunities. All of the market data used in this Annual
Report on Form 10-K involves a number of assumptions and limitations, and you are cautioned not to give undue weight to such data. Industry publications
and third-party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they
do not guarantee the accuracy or completeness of such information. Our estimates of the potential market opportunities for our product candidates include
several key assumptions based on our industry knowledge, industry publications, third-party research and other surveys, which may be based on a small
sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source
has verified such assumptions.
Our business is subject to a number of risks that if realized could materially affect our business, financial condition, results of operations, cash
flows and access to liquidity. These risks are discussed more fully in the “Risk Factors” section of this Annual Report on Form 10-K. Our principal risks
include the following:
SUMMARY RISK FACTORS
• We have incurred significant losses since our inception. Our net loss was $80.8 million for the year ended December 31, 2021 and $70.8
million for the year ended December 31, 2020. We expect to incur losses over the next several years and may never achieve or maintain
profitability. As of December 31, 2021, we had an accumulated deficit of $302.5 million.
• We will need substantial additional funding. If we are unable to raise capital when needed, we could be forced to delay, reduce or eliminate our
product development programs or commercialization efforts. We expect to devote substantial financial resources to our ongoing and planned
activities, particularly as we continue our clinical trials of losmapimod and FTX-6058 and continue research and development and initiate
additional clinical trials of, and seek regulatory approval for, these and other product candidates.
• We are early in our development efforts, and we only have two product candidates in clinical trials. If we are unable to commercialize our
product candidates or experience significant delays in doing so, our business will be materially harmed.
• We may not be successful in our efforts to use FulcrumSeek, our proprietary product engine to build a pipeline of product candidates. A key
element of our strategy is to use FulcrumSeek to identify and validate cellular drug targets that can potentially modulate gene expression to
address the root cause of genetically-defined rare diseases, with an initial focus on identifying small molecules specific to the identified cellular
target.
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Clinical drug development involves a lengthy and expensive process, with an uncertain outcome. The results of preclinical studies and early
clinical trials may not be predictive of future results. We may incur additional costs or experience delays in completing, or ultimately be unable
to complete, the development and commercialization of our product candidates.
Because we are developing some of our product candidates for the treatment of diseases in which there is limited clinical experience and, in
some cases, using new endpoints or methodologies, the U.S. Food and Drug Administration, or FDA, or other regulatory authorities may not
consider the endpoints of our clinical trials to predict or provide clinically meaningful results.
ii
•
•
The ongoing COVID-19 pandemic has and may continue to affect our ability to initiate and complete current or future preclinical studies or
clinical trials, disrupt regulatory activities or have other adverse effects on our business and operations. In addition, this pandemic may
continue to adversely impact economies worldwide, which could result in adverse effects on our business and operations.
If serious adverse events or unacceptable side effects are identified during the development of our product candidates, we may need to abandon
or limit our development of some of our product candidates.
• We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully
than we do.
• We rely, and expect to continue to rely, on contract manufacturing organizations, or CMOs, to manufacture our product candidates. If we are
unable to enter into such arrangements as expected or if such organizations do not meet our supply requirements, development and/or
commercialization of our product candidates may be delayed.
• We rely, and expect to continue to rely, on third parties to conduct our clinical trials, and those third parties may not perform satisfactorily,
including failing to meet deadlines for the completion of such trials, which may harm our business.
• We have entered into, and may in the future enter into, collaborations with third parties for the discovery, development or commercialization of
product candidates, including our collaborations with Acceleron and MyoKardia. If our collaborations are not successful, we may not be able
to capitalize on the market potential of these product candidates and our business could be adversely affected.
•
•
If we are unable to obtain, maintain, enforce and protect patent protection for our technology and product candidates or if the scope of the
patent protection obtained is not sufficiently broad, our competitors could develop and commercialize technology and products similar or
identical to ours, and our ability to successfully develop and commercialize our technology and product candidates may be adversely affected.
If we fail to comply with our obligations in our intellectual property licenses and funding arrangements with third parties, or otherwise
experience disruptions to our business relationships with our licensors, we could lose intellectual property rights that are important to our
business.
iii
Item 1. Business.
Overview
PART I
We are a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases in areas of high
unmet medical need. Our most advanced clinical product candidate, losmamipod, is in development to treat the root cause of facioscapulohumeral muscular
dystrophy, or FSHD. Our other clinical product candidate is FTX-6058, which is being developed for the treatment of certain hemoglobinopathies,
including sickle cell disease, or SCD, and ß-thalassemia. We expect to initiate REACH, a randomized, double-blind, placebo-controlled, multi-national
Phase 3 clinical trial of losmapimod, our product candidate for FSHD, in the second quarter of 2022. We initiated a Phase 1b clinical trial of FTX-6058 in
people with SCD in the fourth quarter of 2021, and we expect to report initial data from that Phase 1b trial in the second quarter of 2022. Additionally, we
submitted an investigational new drug application, or IND, in the fourth quarter of 2021 for FTX-6058 in other select hemoglobinopathies, including ß-
thalassemia, and expect to initiate a Phase 1b study in the second quarter of 2022.
We have developed a proprietary product engine, FulcrumSeek, that we employ to systematically identify and validate cellular drug targets that can
potentially modulate gene expression to treat known root causes of genetically defined diseases. Our product engine integrates patient-derived tissue and
disease-relevant cell models that we interrogate using our pharmacologically diverse and highly annotated small-molecule compound library and
customized CRISPR and RNAi libraries. These screens generate tens of millions of data points and high-content imaging. We then apply computational
biology and analytics to identify targets with specificity and selectivity accompanied by a comprehensive data set that significantly accelerates
development. This approach led to the identification of both losmamipod for FSHD and FTX-6058 for hemoglobinopathies, as well as a robust discovery
pipeline. We expect to nominate our next development candidate this year to support our fourth IND by the end of the first quarter of 2023.
Our most advanced product candidate, losmapimod, is a small molecule that we are developing for the treatment of FSHD, a rare, progressive and
disabling disorder characterized by muscle degeneration and fat infiltration. Disease progression results in the accumulation of disability with many
patients ultimately becoming dependent on wheelchairs and losing independence as their ability to perform activities of daily living decreases.
Losmapimod selectively targets p38α/ß mitogen activated protein kinase, or p38α/ß. We utilized our product engine to discover that inhibition of p38α/ß
reduced expression of the DUX4 gene in muscle cells derived from patients with FSHD. The aberrant expression of the DUX4 gene is the known root cause
of FSHD. There are no approved therapies for FSHD, one of the most common forms of muscular dystrophy, with an estimated patient population of
16,000 to 38,000 in the United States and 300,000 to 780,000 globally. Losmapimod has received orphan drug designation from both the FDA and the
European Medicines Agency, or EMA, for the treatment of FSHD, and in May 2021, received fast track designation from the FDA.
Following our discovery of the role of p38α/ß inhibitors in the reduction of DUX4 expression in preclinical models of FSHD, we performed an
extensive review of known compounds. As a result of our evaluation, we identified losmapimod as the preferred developmental candidate based on the
substantial and attractive preclinical and clinical data. We in-licensed losmapimod from affiliates of GlaxoSmithKline plc, or GSK, in February 2019. GSK
had previously administered losmapimod to nearly 3,500 subjects across multiple clinical trials, including one Phase 3 clinical trial, and losmapimod was
generally well-tolerated across these studies. GSK did not conduct a clinical trial of losmapimod in patients with FSHD or any other muscle disorder. We
conducted extensive preclinical testing of losmapimod in patient-derived, tissue-relevant cell models and observed that losmapimod selectively reduced
DUX4-driven gene expression and restored a healthy gene expression signature with minimal impact on healthy human muscle cells or other cell types.
We conducted a randomized, double-blind, placebo-controlled, multicenter, international Phase 2b clinical trial, referred to as ReDUX4, to evaluate
losmapimod in 80 patients with FSHD. In this Phase 2b clinical trial, the primary endpoint was change in DUX4-driven gene expression, an experimental
molecular biomarker. Secondary endpoints included evaluation of safety and tolerability, pharmacokinetics, or PK, in blood, as well as measures of muscle
health, structure and function, including muscle fat infiltration, or MFI, reachable workspace, or RWS, and patient-reported outcomes. Concurrently, we
initiated a single-center open label Phase 2 clinical trial to investigate the safety and tolerability of chronic treatment with losmapimod in patients with
FSHD. In the ongoing extension of the open label trial, we are also evaluating measures of muscle function, muscle strength, and patient reported quality of
life.
We presented the full data from the ReDUX4 trial in June 2021. While the primary endpoint was not met, results demonstrated clinically relevant
benefits versus placebo on multiple measures of muscle health and function as well as
1
patient reported outcomes at 48 weeks. Losmapimod-treated participants showed decreased progression of MFI as measured in intermediate muscles,
which are muscles already affected by disease and most likely to show signs of disease progression. Normal appearing muscles appeared to be preserved in
the losmapimod group versus placebo. Treatment with losmapimod was shown to slow the rate of decline and improve accessible surface area in RWS,
which is a measure of function that assesses upper extremity range of motion and has been shown to be an important measure of independence.
Additionally, patients reported feeling better when treated with losmapimod compared to placebo through the Patient Global Impression of Change, or
PGIC, assessment. PGIC is a measure of self-reported change in how a patient feels and functions. Losmapimod was generally well-tolerated, with no
drug-related serious adverse events reported.
Based on the ReDUX4 data , we engaged with external experts,U.S. and EU regulatory agencies, including FDA, and gained alignment on key
aspects of the design of a Phase 3 trial. We expect to initiate our Phase 3 trial, REACH, in the second quarter of 2022. REACH will be a randomized,
double-blind, placebo-controlled, multi-national trial to evaluate the efficacy and safety of losmapimod for the treatment of FSHD. The trial is expected to
enroll approximately 230 adults with FSHD. Patients will be randomized 1:1 to receive either losmapimod, administered orally as a 15 mg tablet twice a
day, or placebo, and evaluated over a 48-week treatment period. The primary endpoint of the study is the absolute change from baseline in RWS. Secondary
endpoints include MFI, PGIC, and Quality of Life in Neurological Disorders of the upper extremity, or Neuro QoL UE. The trial will also include patient-
centered assessments of healthcare utilization.
Our other product candidate, FTX-6058, is an investigational oral fetal hemoglobin, or HbF, inducer that is in development for SCD and select other
hemoglobinopathies, including ß-thalassemia. FTX-6058 is designed to bind to embryonic ectoderm development, or EED, and inhibit the transcriptional
silencing activity of the polycomb repressive complex 2, or PRC2. By doing so, preclinical studies have shown that FTX-6058 downregulates key HbF
repressors, including BCL11A and MYB, and upregulates HbF.
SCD is a genetic blood disorder caused by a mutation in the ß-subunit gene, or HBB gene. This mutation results in the formation of abnormal
hemoglobin, or HbS, which causes red blood cells, or RBCs, to change from a round shape into a sickle shape that significantly impairs their function. ß-
thalassemia is a rare blood disorder caused by various genetic mutations in the HBB gene that can significantly impair the production of hemoglobin and
RBCs. We designed FTX-6058 to compensate for the root cause of these hemoglobinopathies by inducing the expression of the two γ-globin genes,
HBG1/2, whose expression is normally silenced shortly after birth. The HBG1/2 genes encode for γ-globin, a component of HbF, which is known to repair
the abnormal RBC shape in SCD and to compensate for the presence of HbS in SCD and ß-thalassemia. We have observed in vitro and in vivo activation of
the HBG1/2 genes in preclinical studies with FTX-6058. We have also observed that FTX-6058 demonstrated robust levels of HbF elevation with no
adverse effects on important cellular health markers. We conducted additional pre-clinical profiling in CD34+ derived cells and observed that treatment
with FTX-6058 increased HbF levels to approximately 30% of total hemoglobin, as measured by mass spectrometry, high performance liquid
chromatography, and fast protein liquid chromatography techniques. The elevation of HbF was significantly greater than we observed with hydroxyurea in
the cell models.
In the fourth quarter of 2020, we initiated a Phase 1 clinical trial of FTX-6058 in healthy adult volunteers. The Phase 1 randomized, double-blind,
placebo-controlled trial was designed to evaluate the safety, tolerability, and PK of ascending doses of FTX-6058. In the single-ascending dose, or SAD,
cohorts, healthy volunteers received one dose of either placebo or 2, 4, 10, 20, 30, 40 or 60mg of FTX-6058. In the multiple-ascending dose, or MAD,
cohorts, healthy volunteers received a once-daily dose of placebo or 2, 6, 10, 20 or 30mg of FTX-6058 for 14 consecutive days. Each MAD cohort had six
subjects on drug and two on placebo. Food effect was also studied in a separate 20mg dose cohort. Exploratory measures were included in the MAD
cohorts to assess target engagement, changes in HBG mRNA and HbF-containing reticulocytes, or F-reticulocytes. A 6mg dose cohort in people with SCD
was later added to this trial to further inform PK and pharmacodynamic, or PD, modeling for future dose selections.
We reported data from the 2, 4, 10, 20, 30 and 40mg SAD cohorts and the 2, 6 and 10 mg MAD cohorts in healthy volunteers in August 2021, and
we reported data from the 60 mg SAD cohort and the 20 and 30 mg MAD cohorts in healthy volunteers, as well as data from the 20 mg cohort assessing
food effect in December 2021.
FTX-6058 was generally well-tolerated with no serious adverse events reported and no discontinuations due to treatment-emergent adverse events,
or TEAEs, across all SAD and MAD cohorts. Data continued to show dose-proportional PK, with a mean half-life of approximately 6-7 hours in the MAD
cohorts, supporting once-daily dosing, and no food effect was observed with FTX-6058. Data from the MAD cohorts continued to show robust target
engagement, as evidenced by an approximately 75-95% reduction from baseline in H3K27me3 after 14 days of treatment.
2
Data from the MAD cohorts also showed time- and dose-dependent HBG mRNA induction, as shown in the chart below, demonstrating proof-of-
biology. Persistent HBG mRNA induction was observed for 7-10 days after treatment. In preclinical studies of FTX-6058, increases in HBG mRNA have
consistently translated to the same fold increases in HbF protein. Notably, human genetics show that 2-3-fold increases in HbF above typical baseline levels
in SCD are associated with significantly improved outcomes, and even functional cures, in people with SCD. FTX-6058 has now demonstrated dose-
proportional greater than mean 2-fold induction in HBG mRNA, the key precursor to HbF protein, starting with the 6mg dose.
HBG mRNA Mean Fold Induction for FTX-6058 versus Placebo
6mg*
2mg*
10mg*
20 mg
30mg
Day 7
Day 14
Safety Follow-up (Day
21-24)
Mean Fold
Induction
1.28
1.20
1.21
P-value
0.3494
0.5122
0.3736
Mean Fold
Induction
1.94
2.45
2.75
P-value
0.0135
0.0025
<0.0001
Mean Fold
Induction
2.08
3.54
3.22
P-value
0.0063
<0.0001
<0.0001
Mean Fold
Induction
2.06
5.63
6.45
P-value
0.0072
<0.0001
<0.0001
Mean Fold
Induction
2.29
6.15
6.13
P-value
0.0025
<0.0001
<0.0001
As shown in the chart below, HbF containing F-cells, or F-reticulocytes, also increased starting at day 14 and continued to increase at the safety
follow-up visit, which was seven to 10 days after conclusion of dosing. Notably, increases in F-reticulocytes of any magnitude are a first indicator that
HBG mRNA is translating to HbF protein production but fold changes in F-reticulocytes are not correlated with fold changes in HbF.
F-Reticulocyte Mean Fold Increase for FTX-6058 versus Placebo
Day 7
Day 14
Safety Follow-up (Day 21-24)
2mg*
Mean Fold
Increase
0.53
0.88
0.63
6mg*
10mg*
20 mg
30mg
P-value
0.1070
0.6881
0.2167
Mean Fold
Increase
1.02
1.25
1.65
P-value
0.9524
0.4895
0.0943
Mean Fold
Increase
0.83
2.23
3.93
P-value
0.6214
0.0180
<0.0001
Mean Fold
Increase
0.71
1.00
1.79
P-value
0.3831
0.9880
0.0591
Mean Fold
Increase
1.50
1.71
2.38
P-value
0.2928
0.1049
0.0059
* Fold changes from these cohorts were updated to reflect the fold-increase over pooled placebo data across all cohorts from 2-30mg versus
previously reported fold changes over pooled placebo data across 2-10mg cohorts.
We initiated a Phase 1b clinical trial of FTX-6058 in people with SCD in the fourth quarter of 2021, with the aim of establishing early proof of
concept in SCD. The open label trial is designed to assess safety, tolerability, PK and PD effects, including HbF protein induction of up to three doses,
starting with 6mg once daily dose, to inform dose selection for future development. Each dose cohort will have up to 10 patients who will be treated for up
to three months. We expect to report initial data, including HbF protein levels, from the trial in the second quarter of 2022.
According to the National Institutes of Health, or NIH, there are approximately 7,000 rare, genetically defined human diseases, many of which have
inadequate or no approved treatments. Our current drug target identification and development efforts are focused on rare muscular, hematologic and
neurologic, disorders. We also anticipate utilizing FulcrumSeek to discover drug targets for genetically defined diseases in other therapeutic areas and for
other disorders. In addition to drug targets that we prioritize for internal development, we may identify other drug targets that we would consider for
development through partnerships. For example, we are utilizing FulcrumSeek to discover drug targets within a targeted indication within the pulmonary
disease space under our collaboration and license agreement with Acceleron, a wholly owned subsidiary of Merck, and for the potential treatment of certain
genetically defined cardiomyopathies under our collaboration and license agreement with MyoKardia, a wholly-owned subsidiary of Bristol-Myers Squibb
Company.
3
Our Pipeline
Using FulcrumSeek, we have generated a pipeline of disease-modifying therapies that address the known root cause of rare genetic diseases. The
following chart summarizes key information about our pipeline.
Our Strategy
We are leveraging the broad applicability of our proprietary product engine to discover and develop small molecule therapies that modulate gene
expression to address the known root cause of genetically defined rare diseases in areas of high unmet medical need. We believe that our initial product
candidates for the treatment of FSHD, SCD and ß-thalassemia may have the potential to treat patients with these debilitating and, in some cases, life-
threatening illnesses. The key components of our strategy include:
•
•
•
•
Rapidly develop losmapimod for the treatment of FSHD. We aim to rapidly develop losmapimod for the treatment of FSHD through clinical
development and regulatory approval. In the second quarter of 2022, we plan to initiate a randomized, double-blind, placebo-controlled, 48-
week Phase 3 trial to evaluate the efficacy and safety of losmapimod for the treatment of FSHD.
Rapidly develop FTX-6058 for the treatment of select hemoglobinopathies. We have initiated a Phase 1b clinical trial of FTX-6058 in people
with SCD and expect to report initial data from the trial in the second quarter of 2022. We submitted an IND to the FDA in the fourth quarter
of 2021 for FTX-6058 in other select hemoglobinopathies, including ß-thalassemia, and expect to initiate a Phase 1b study in the second
quarter of 2022.
Continue to apply FulcrumSeek to grow our portfolio of product candidates for the treatment of genetically defined diseases. We have
developed a rigorous assessment and selection process to determine which of the approximately 7,000 rare, genetically defined diseases we
intend to evaluate in drug target identification activities. We are applying FulcrumSeek to discover drug targets to modulate gene expression
and develop product candidates for the potential treatment of the root cause of disease.
Further expand our product engine capabilities. We have significantly enhanced the scale and power of FulcrumSeek to increase the pace of
discovery and we intend to further expand our capabilities to enhance the therapeutic reach and productivity of our drug discovery process. We
expect to name our next development candidate in 2022 to support our fourth IND by the end of the first quarter of 2023.
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• Maximize the commercial potential of our product candidates. We have retained all rights to our lead product candidates focused on rare
genetically defined diseases, and plan to commercialize any approved product for such rare genetically defined diseases using a targeted sales
infrastructure. We may in the future pursue commercialization partnerships for certain product candidates and/or markets outside the United
States.
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Selectively enter into strategic partnerships to maximize the value of our product engine and pipeline. Given the breadth of opportunities for
our proprietary product engine to discover drug targets and develop product candidates for genetically defined diseases, we may enter into
strategic partnerships for certain drug targets, product candidates or disease areas, such as our collaboration and license agreements with
Acceleron, a wholly-owned subsidiary of Merck, and MyoKardia, a wholly-owned subsidiary of Bristol Myers Squibb. Partnerships may
provide an attractive avenue for expanding the impact of our proprietary product engine
Gene Regulation
The human genome provides the blueprint, or genetic code, for life. The sequencing of the human genome has enabled significant insights into
understanding the genetic underpinnings of many diseases. Genes are the fundamental units of biology, but the gene itself is rather static. The identity and
function of each cell is determined by a specific set of factors that activate or repress mechanisms that regulate genes in the desired manner. There are many
mechanisms that control the human genome by up or down regulating gene expression, and these regulatory mechanisms are controlled by various
pathways and signals. Defects in a gene or any of these regulatory mechanisms can result in misexpression, aberrant expression or silencing of a gene that
may lead to or is closely associated with disease.
The graphic below illustrates the key steps in the gene expression process in cells and how they are under the control of a variety of regulatory
signals and pathways.
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Our Opportunity
We have the ability to develop, scale and characterize complex cellular models of human disorders of gene misexpression and mis-regulation. Our
current drug target identification and development efforts are focused on rare muscular, hematologic and neurologic disorders. We also anticipate utilizing
FulcrumSeek to discover drug targets for genetically defined diseases in other therapeutic areas. Our target identification and validation process provides a
systematic way to approach the identification of unique drug targets that, when activated or inhibited, may increase or decrease gene expression in
genetically defined diseases with the aim of restoring a healthy or functional phenotype. Our product engine is designed to be agnostic to cell type, pathway
and therapeutic modality. While our drug target selection process is guided by our strategy to advance small molecule therapeutics that treat the root cause
of disease into clinical development, we also may identify drug targets that might be addressable by other treatment modalities, such as antisense
oligonucleotides, or ASOs, small interfering RNAs, or siRNAs, or antibodies.
We are continuing to expand our proprietary library of highly annotated small molecules to facilitate the process by which we assess diseases and
generate drug target hypotheses through our computational biology expertise. We screen our proprietary small molecule library and customized CRISPR or
RNAi libraries in patient-derived tissue and disease-relevant cell models, such as skeletal muscle cells, cardiac muscle cells, brain cells and blood cells.
FulcrumSeek is designed to provide a unique understanding into gene regulatory and signaling pathways that may be relevant for the activation or
repression of a particular gene associated with the disease of interest. To achieve this, we profile many features that are impacted when a cell of interest is
treated with a perturbagen, such as a small molecule probe, CRISPR guide, siRNA, or microRNAs. These features include a comprehensive assessment of
transcripts that are modulated (quantified by RNA sequencing, or RNAseq) and cellular processes that are measured by imaging techniques. We expect that
the data from these screens will allow us to develop a broader understanding of biology that may be relevant in disease. With the completion of each
additional screening, FulcrumSeek increases in size, and our insights and knowledge are further expanded. Moreover, with the initiation of our
collaborations with Acceleron and MyoKardia, we are further demonstrating the scope of our disease modeling and target identification capabilities with
the expansion into pulmonary and cardiovascular disease.
According to the NIH there are approximately 7,000 rare, genetically defined human diseases, many of which have inadequate or no approved
treatments. We believe that our approach to selecting and modeling certain of these human diseases with patient-derived tissue-relevant cells, followed by
screening with our proprietary small molecule library and customized CRISPR or RNAi libraries, could be broadly applied to the identification of drug
targets that have the potential to balance the expression of many genes known to drive or ameliorate disease.
Our Approach
The ability to intervene in gene regulatory pathways that control gene expression provides the basis of FulcrumSeek. Our approach is to broadly
search for mechanisms that can change gene expression in the desired manner. These drug targets may be intracellular targets or extracellular targets that
affect a signaling pathway. Key considerations we use to determine which genetically defined diseases are suitable to evaluate in drug target identification
activities include:
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Unmet medical need and market opportunity: we consider the severity of disease, the number of patients who could be treated and the
competitive landscape.
Clear mechanistic link between a root cause genetic defect and disease: we evaluate whether there is genetic validation of the gene’s role in
disease and the effect of gene modulation on disease.
Drug discovery execution: we consider whether relevant patient-derived, tissue-specific cell models and assays are available or whether we can
develop such models using our expertise.
Clinical feasibility: we evaluate potential biomarker and clinical endpoints, whether there is a meaningful treatment window and whether there
is an accessible patient population to undertake clinical trials in a reasonable time frame.
FulcrumSeek is designed to enable us to address diseases in which genes are mis-expressed, silenced or result in mutated gene products, such as
RNA or protein, due to an underlying genetic defect. There are varied approaches to treating disease by balancing gene expression including reducing the
expression of a gene that causes disease (e.g., DUX4 in FSHD), increasing the expression of an under-expressed gene or expressing a compensatory gene
(e.g., HBG1/2 in SCD and ß-thalassemia). Our preclinical modeling of the relevant tissue is critical for success, and we believe this is best achieved using
human cell systems derived from patients with the disease. We primarily seek to identify drug targets that may balance gene expression in these human cell
systems and that are amenable to drugging using a small molecule. In addition to drug targets that we prioritize for internal development, we may identify
other drug targets that we would consider for development through partnerships.
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Our Lead Product Candidates
We have used our proprietary product engine and screening efforts to identify drug targets for our lead product candidates. The following chart
summarizes key information about our lead product candidates.
Our Product Candidate for FSHD - Losmapimod
Overview of Facioscapulohumeral Muscular Dystrophy
Facioscapulohumeral muscular dystrophy is a rare, progressive and disabling disease for which there are no approved treatments. FSHD is one of
the most common forms of muscular dystrophy and affects both sexes equally, with onset typically in teens and young adults. FSHD is characterized by
progressive skeletal muscle loss that initially causes weakness in muscles in the face, shoulders, arms and trunk and progresses to weakness in muscles in
lower extremities and the pelvic girdle. Skeletal muscle weakness results in significant physical limitations, including progressive loss of independence,
including impacts to facial muscles that can cause problems with communication, difficulty using arms for activities of daily living and difficulty getting
out of bed, with many patients ultimately becoming dependent upon the use of a wheelchair for daily mobility activities. The majority of patients with
FSHD also report experiencing chronic pain, anxiety and depression. The diagnosis and treatment of patients with FSHD is typically performed by
neurologists.
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The FSH Society estimated that the prevalence of FSHD in the United States is approximately 1 in 20,000 people. A recent study conducted in the
Netherlands reported a more frequent prevalence of 1 in 8,333. Based on these estimates and a U.S. population of 320 million, we estimate that the patient
population is between 16,000 to 38,000 in the United States. We believe that there may be additional patients who are not formally diagnosed due to a
perceived difficulty of obtaining a diagnosis and the fact that there are no approved treatments. Approximately two-thirds of cases are familial-inherited in
an autosomal dominant fashion and one-third of cases are sporadic. FSHD affects all ethnic groups with similar incidence and prevalence.
FSHD Biology
FSHD is caused by aberrant expression of DUX4 in skeletal muscle resulting in the inappropriate presence of DUX4 protein, a transcription factor
causing the expression of other genes. Normally DUX4-driven gene expression is limited to early embryonic development, after which time the DUX4
gene is silenced. In patients with FSHD, aberrant production of DUX4 protein in skeletal muscle regulates other genes encoding proteins, some of which
are toxic to the muscle. The result of aberrant DUX4 expression in FSHD is death of muscle and its replacement by fat, resulting in skeletal muscle
weakness and progressive disability. We believe that reducing expression of the DUX4 gene and its downstream transcriptional program could provide a
disease-modifying therapeutic approach for the treatment of FSHD at its root cause. Published preclinical and human data, in addition to in vitro
experiments that we have conducted, suggest that any reduction in DUX4 expression may be beneficial for patients. In preclinical studies, we have
demonstrated that there is a direct relationship between muscle cell death (apoptosis) and the level of DUX4 expression, and a reduction in DUX4 leads to a
concomitant decrease in apoptosis. As illustrated in the graphic below, in animal models where expression of DUX4 in skeletal muscle is induced, a
corresponding loss of function is observed with increasing levels of DUX4 expression. In these animal models where low levels of DUX4 are expressed, the
animals performed similarly to healthy animals in a mobility assessment, suggesting that complete DUX4 reduction is not required for a functional benefit.
Data from human muscle biopsies likewise indicated that increased DUX4 activity is related to worsening muscle pathology.
In all patients with FSHD, the DUX4 gene is unsilenced, or de-repressed, as a result of one of two different types of genetic alterations, leading to
FSHD1 or FSHD2. Approximately 95% of patients have FSHD1 and approximately 5% of patients have FSHD2. FSHD1 is caused by the contraction of an
array of DNA, known as a D4Z4 repeat, from greater than ten repeat units to nine or fewer units. This contraction causes de-repression of DUX4. Patients
with FSHD2 do not have meaningful D4Z4 repeat contraction, but have mutations in a regulatory gene, known as the SMCHD1 gene, that normally
contributes to the repression of the DUX4 gene via DNA methylation.
FulcrumSeek Identified the Drug Target for FSHD
We utilized patient-derived FSHD1 muscle cells, known as myotubes, and screened them with our small molecule probe library to identify drug
targets that reduced DUX4 expression. We identified several potential drug targets, however the modulation of the majority of the targets adversely affected
the health or differentiation of muscle cells. One drug target that we identified from our screening efforts for which we did not observe adverse cell health
issues was p38α/ß, which had been studied extensively in other diseases, but had not been reported to be linked to DUX4 expression or FSHD until we
conducted our screening efforts. We evaluated multiple small molecule p38α/ß inhibitors and observed a consistent reduction of both DUX4 expression and
DUX4-driven gene transcripts with each p38α/ß inhibitor. We conducted further validation experiments to confirm that inhibition of p38α using genetic
approaches such as siRNA and CRISPR single-guide RNAs, also led to a reduction in DUX4 expression. Additionally, researchers from Saint Louis
University independently published
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the results of a study which concluded that inhibitors of p38α/ß, including losmapimod, suppressed DUX4 expression in cellular and animal FSHD models.
Losmapimod Overview
After identifying p38α/ß as a potential drug target, we evaluated multiple small molecule inhibitors of p38α/ß. Each of these inhibitors had
previously been evaluated in clinical trials for the treatment of various diseases but never in muscle disorders. As a result of our evaluation and relative to
other p38α/ß inhibitors, we identified losmapimod as the preferred development candidate based on substantial and attractive preclinical and clinical data
regarding safety, PK and target inhibition, and its advanced stage of development. Losmapimod was originally evaluated by GSK in nearly 3,500 subjects
in clinical trials across multiple indications and in multiple countries. GSK did not evaluate losmapimod in FSHD or in any other muscle disorder.
Although GSK did not pursue regulatory approval in the indications evaluated, losmapimod demonstrated an attractive PK, PD, safety and tolerability
profile, including in chronic dosing. Additionally, we observed in preclinical studies using losmapimod that inhibition of the p38α/ß pathway reduced
DUX4 expression and downstream gene expression. After identifying losmapimod, we in-licensed the molecule from GSK because we believed that its
safety and pharmacology history would significantly expedite our development plan and enhance our future regulatory submissions.
In June 2021, we reported full data from the randomized, double-blind placebo-controlled multicenter international Phase 2b clinical trial, or
ReDUX4. Although the primary endpoint was not met, we demonstrated slowing of disease progression and improved function in FSHD patients treated
with losmapimod compared to placebo. In the second quarter of 2022, we expect to initiate a randomized, double-blind, placebo-controlled, 48-week Phase
3 trial to evaluate the efficacy of losmapimod for the treatment of FSHD.
In January 2020, the FDA granted orphan drug designation to losmapimod for the treatment of FSHD. In March 2020, the EMA granted orphan
drug designation to losmapimod for the treatment of FSHD. In May 2021, the FDA granted fast track designation to losmapimod for the treatment of
FSHD.
Clinical Trial: Phase 2b (ReDUX4)
In June 2021, at the FSHD International Research Congress, we presented full data from our randomized, double-blind, placebo-controlled
multicenter international Phase 2b clinical trial, the ReDUX4 trial, in 80 patients with FSHD1 and clinical severity scores of two to four on the Ricci scale.
In this trial, we evaluated treatment with 15 mg of losmapimod or placebo tablets twice per day over a 24 or 48-week period. Enrollment was completed in
February 2020. Patients were randomized 1:1 between the treatment and placebo arms. The FDA accepted the IND for losmapimod in June 2019, and we
also submitted CTAs at various dates during 2019 to conduct the trial at sites in Europe and Canada, all of which were accepted. We presented data from a
pre-specified interim analysis in August 2020. We completed the ReDUX4 trial in January 2021 and presented full data from the trial at the FSHD
International Research Congress on June 24, 2021.
The primary endpoint was the change in DUX4-driven gene expression in affected skeletal muscle at 16 or 36 weeks, which was included as an
experimental biomarker. The trial was also designed to capture a wide range of data relating to FSHD progression in addition to safety, target engagement
and PK data. The secondary endpoints were evaluation of safety and tolerability in FSHD patients, PK in blood, losmapimod concentration in skeletal
muscle biopsies, target engagement in blood and in muscle biopsies, and efficacy based on the whole-body skeletal muscle MRI biomarker. The whole-
body MRI scans evaluated changes in MFI , muscle fat fraction and lean muscle volume. The muscles evaluated in the trial were classified as normal
appearing (not affected by disease), intermediate (clearly affected by disease but not so severely fat replaced to have lost all function) or end stage (severely
fat replaced and have lost most if not all function). The exploratory endpoints included RWS, timed up and go, or TUG test, an optimized timed up and go
test for FSHD, or FSHD TUG, muscle strength measured by hand-held dynamometry, other muscle function measures and patient reported outcomes.
The original design of ReDUX4 included a muscle biopsy at week 16 during the 24-week treatment period followed by an open label extension.
Sixteen of the 80 subjects in trial completed the 24-week treatment period and rolled over to the open label extension portion of the trial. As a result of the
ongoing COVID-19 pandemic, we extended the ReDUX4 treatment period from 24 to 48 weeks through a protocol amendment to ensure the safety of the
subjects and to allow for the opportunity for a biopsy at week 16 as originally intended or at week 36. Approximately 64 subjects who did not complete the
original 24-week treatment period continued in the 48-week treatment period in the randomized portion of the trial. The extension from 24 to 48 weeks also
allowed for a longer assessment in a placebo-controlled design of the skeletal muscle MRI secondary endpoint and the various exploratory clinical
endpoints, such as RWS, optimized FSHD TUG test, muscle function measures and patient reported outcomes.
In August 2020, we announced results from a pre-specified interim analysis of the primary endpoint of the ReDUX4 trial, which is the reduction
from baseline of DUX4-driven gene expression in affected skeletal muscle after subjects have
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been treated with losmapimod or placebo. Secondary and exploratory endpoints were not assessed as part of this analysis. Results from the interim analysis
in the first 29 randomized subjects indicate that DUX4-driven gene expression did not show a separation from placebo at 16 weeks. However, in a pre-
specified sensitivity analysis, those with the highest pre-treatment DUX4-driven gene expression in their muscle biopsy sample showed a large reduction in
DUX4-driven gene expression following treatment with losmapimod compared to placebo. The highest expressing muscle biopsies represent the top
quartile of biopsies assessed based on baseline DUX4-driven gene expression.
The interim results included an analysis of the first 29 subjects who completed their 16-week biopsy. PK, demographics and the primary endpoint
were assessed. The interim analysis was not powered for statistical significance and did not include individual patient level data. Subjects were randomized
to receive an oral dose of losmapimod 15mg (n=15) or placebo (n=14) twice per day. While results showed a significant reduction in DUX4-driven gene
expression in the muscle biopsies of subjects whose baseline biopsy showed the highest levels of DUX4 gene expression (38-fold decrease with
losmapimod, n=3, and 5.4 fold-decrease with placebo, n=5), the population level data analysis of the reduction in DUX4-driven gene expression from all 29
subjects did not show a separation of losmapimod from placebo (3.7 fold increase with losmapimod, n=15, and 2.8 fold increase with placebo, n=14).
Results suggested that muscle biopsies within the higher range of DUX4-driven gene expression at baseline may be needed to observe a reduction.
In June 2021, we reported full results from ReDUX4. The trial did not meet the primary endpoint, change from baseline in DUX4-driven gene
expression in affected skeletal muscle at Week 16 or Week 36. Secondary and exploratory endpoints showed clinically relevant and nominally statistically
significant benefits in the losmapimod treated group versus placebo on multiple measures of structural and functional FSHD progression and patient
reported outcomes at 48 weeks. As the primary endpoint was not met, all comparative analyses are reported with nominal statistical p-values.
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Losmapimod-treated participants showed decreased progression in the treatment efficacy composite measure of MFI as measured in
intermediate muscles, those most likely to change (p=0.01). Normal appearing muscles appeared to be preserved in the losmapimod group
versus placebo based on a post hoc analysis. MFI is a measure of diffuse fatty infiltration in lean muscle tissue that is correlated with disease
severity in FSHD.
Treatment with losmapimod was shown to slow the rate of decline and improve accessible surface area in RWS measures (p<0.05). RWS is a
measure of function that assesses upper extremity range of motion. Prior studies have shown that RWS correlates with changes in the ability
of patients to independently perform activities of daily living. Based on published results, RWS is an important measure of independence.
The disease tends to progress from the upper body down, and loss of shoulder movement leads to loss of mobility. Participants in the
losmapimod group showed improvements of up to 1.5 points from baseline in the accessible surface area when using a 500g weight on their
wrist compared to placebo. Participants in the placebo group were able to access 2 to 4 points less total surface area (with and without 500g
weights) measured by RWS after 48 weeks. The net difference between the groups at 48 weeks was 3.5 to 5 points, which in some patients is
the difference between functional independence and dependence.
Participants reported feeling better when treated with losmapimod compared to placebo through the PGIC assessment (p=0.02). PGIC, a
measure of self-reported change in how a patient feels and functions, showed that participants were able to recognize improvements after 48
weeks of treatment. More participants in the losmapimod group reported improvement at 48 weeks compared to placebo. Four times more
losmapimod participants reported improvement over time as compared to participants treated with placebo. Importantly, fewer losmapimod
participants reported worsening as compared to placebo, and no losmapimod participants reported being “much worse” as compared to more
than 13% of placebo participants, who reported that their disease had become “much worse.”
Additional secondary and exploratory endpoints measuring disease progression and function demonstrated differences between losmapimod and
placebo at week 48. In a post hoc analysis, dynamometry, which measures muscle strength, demonstrated that participants in the losmapimod group showed
non-statistically significant trends of slower progression, as well as meaningful improvements (12-27%) in the strength of bilateral shoulder abductors and
ankle dorsiflexors, two muscle groups particularly affected in FSHD, compared to placebo. Functional scales including RWS and TUG showed
improvements in limb function consistent with dynamometry results. Two recently designed scales (FSHD TUG, and FSHD Health Index), did not
demonstrate changes from baseline in either group or differences between losmapimod and placebo groups, suggesting that these tests are not sensitive to
change over the 48-week time period. Motor function measure also showed no changes in either group or differences between the groups over 48 weeks.
There was no difference in muscle fat fraction or lean muscle volume between losmapimod and placebo groups at 48 weeks in intermediate muscles.
Safety and tolerability data were consistent with previously reported results with no drug-related SAEs reported. Losmapimod was generally well-
tolerated and the majority of TEAEs were deemed unlikely related or not related to study drug by the investigator. There were three SAEs (post-op wound
infection, alcohol poisoning and a suicide attempt) reported in two participants in the losmapimod group, each assessed as unrelated to losmapimod. There
were no deaths or
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discontinuations due to adverse events. Losmapimod has now been evaluated in over 3,600 subjects in clinical trials across multiple indications, including
FSHD.
REACH, a Phase 3 Registrational Trial
We plan to initiate REACH, a Phase 3 trial of losmapimod in FSHD, in the second quarter of 2022. Based on data from the ReDUX4 Phase 2b
study, we engaged with U.S. and EU regulatory agencies, including the FDA, and gained alignment on key aspects of the design of a Phase 3 trial intended
to support a full registration approval. REACH will be a randomized, double-blind, placebo-controlled, multi-national trial to evaluate the efficacy and
safety of losmapimod for the treatment of FSHD. The trial is expected to enroll approximately 230 adults with FSHD. Patients will be randomized 1:1 to
receive either losmapimod, administered orally as a 15 mg tablet twice a day, or placebo, and evaluated over a 48-week treatment period. The primary
endpoint of the study is the absolute change from baseline in RWS. Secondary endpoints include MFI, PGIC, and Neuro QoL UE. The trial will also
include patient-centered assessments of healthcare utilization.
Clinical Trial: ReDUX4 Open Label Extension
In February 2020 we initiated an open label extension of the ReDUX4 trial to enable patients who have completed the 24-week or 48-week
treatment period with losmapimod or placebo in ReDUX4 to receive long term treatment with losmapimod. This open label extension includes clinical
assessments of safety and efficacy every three months, whole-body musculoskeletal MRI every six months, and a muscle needle biopsy once after six
months of treatment. We anticipate that this trial will continue until such time as the drug is approved and available in the commercial setting or the clinical
development of losmapimod in FSHD is terminated.
Clinical Trial: Phase 2 Open Label Study Trial
In parallel with the ReDUX4 Phase 2b clinical trial, we also initiated in August 2019 an open label, single center Phase 2 clinical trial of
losmapimod in up to 16 patients with FSHD and clinical severity scores of two to four on the Ricci scale. In the first part of the trial, patients receive tablets
containing 15 mg of losmapimod twice per day for up to 52 weeks. The treatment period is preceded by eight weeks of pre-treatment assessments to
establish a baseline for musculoskeletal MRI biomarkers and clinical outcome assessments. We also performed an outpatient mobility assessment using
wearable sensors. We are conducting the trial at a single center in the Netherlands. After the 52-week treatment period, participants had the option to elect
to continue in an extension of the study, which is ongoing.
The primary objective is to investigate the safety and tolerability of losmapimod for chronic dosing in FSHD patients. The primary endpoints are to
assess safety and tolerability over the 52-week period. The secondary endpoints are the change from baseline in pHSP27 and the ratio of pHSP27 to total
HSP27 in blood and muscle for assessment of the inhibition of p38α/ß during the dosing period. This trial is also designed to provide initial data regarding
changes in DUX4-driven gene expression, MRI biomarkers, objective clinical outcome assessments and patient-reported outcomes that may occur at
various times following initiation of treatment with losmapimod relative to the pre-treatment period. We intend to use this data to further guide our clinical
development strategy for losmapimod in FSHD.
In the 52-week treatment period, we measured DUX4-driven gene expression before and during treatment using muscle needle biopsies in affected
muscles. All patients had a pre-treatment biopsy and we will obtain a second muscle needle biopsy from each patient after four or eight weeks of treatment.
The original trial design included an additional biopsy during chronic treatment at week 48, but we have removed this assessment from the trial protocol
because the open label extension of ReDUX4 includes a biopsy during chronic treatment.
We measure potential losmapimod treatment effects on shoulder and upper arm function and mobility/ambulation, as well as on muscle strength and
function and quality of life and activities of daily living, similar to the assessments in the Phase 2b clinical trial. The clinical outcome assessments are
RWS, FSHD-TUG, muscle strength, motor function ability and generic and FSHD-specific patient reports of quality of life and activities of daily living.
Other exploratory assessments
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include the six minute walk test, spirometry, and muscle ultrasound. There is also an assessment of day-to-day mobility using wearable sensors.
ReSOLVE Natural History Study
The Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD, or ReSOLVE study, is an ongoing natural history study funded by the
NIH to help identify the patient population, efficacy biomarker and clinical outcome assessments for future FSHD drug trials. The study is being
coordinated by the University of Rochester and University of Kansas Medical Center and enrolled the first subject in April 2018. The study will follow up
to 160 subjects for 24 months across a network of eight U.S. clinical centers and will evaluate multiple biomarkers and clinical outcome assessments that
may be suitable for clinical trials and will evaluate patient selection criteria based on genetic, demographic or clinical characteristics. Three sites in the
European Union have joined the ReSOLVE protocol and will follow 60 subjects for 24 months. We believe that the results of this natural history study will
inform the design and implementation of clinical trials and will inform discussions with regulatory agencies. We also believe that this study may provide
valuable insights into the timeline for disease progression and functional changes in FSHD in the absence of treatment.
In connection with the ReSOLVE study, we have funded the addition of a clinical outcome assessment, which we refer to as RWS. RWS is a
measure of function that assesses upper extremity range of motion. Specifically, it evaluates total shoulder and proximal arm mobility by utilizing 3D
motion sensor technology. Preserving function, as assessed by RWS, is critical for maintaining abilities for self-care and other activities of daily living that
directly influence quality of life. Based on published results, RWS is an important measure of independence. The RWS assessments are analyzed by a
central reader. We have provided standardized hardware, software, and testing conditions to evaluate RWS at eight sites that are part of the ReSOLVE study
in the United States and at three European sites. Furthermore, the RWS assessment has been registered as a medical device in the United States, Canada and
Europe.
A recent third-party study assessed changes in RWS for 18 subjects with FSHD for up to five years. As illustrated in the figure below, the study
concluded that the RWS measure is able to detect slow declines in upper extremity function in subjects with FSHD as early as 1 year. The study also found
that the most notable declines in RWS were in above-the-shoulder level quadrants with no significant changes in lower quadrants and that RWS declined
more significantly if the subjects wore 500-gram weights on their wrists.
The figure above illustrates RWS in four quadrants. The optimized RWS includes an additional domain for the lower back, as illustrated in the figure
below.
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Clinical Trial: Phase 1
We conducted a randomized Phase 1 clinical trial of losmapimod in healthy adult volunteers and patients with FSHD in Europe under a CTA that we
filed in December 2018. The primary objective of the trial was to investigate the safety and tolerability of losmapimod in healthy volunteers and in FSHD
patients. The secondary objective was to evaluate repeated dose PK, and target engagement in FSHD patients in blood and muscle. This trial completed
dosing in September 2019 and we presented unblinded data in March 2020.
In the first cohort, 10 healthy volunteers were randomized to a single oral dose of 7.5 mg of losmapimod (n=8) followed by a single oral dose of 15
mg after a wash out period or to single oral dose placebo (n=2) in both dosing periods. In the second cohort, 15 FSHD patients were randomized and
treated with placebo (n=3) or 7.5 mg of losmapimod (n=6) or 15 mg of losmapimod (n=6) taken orally twice daily for 14 days. The third cohort was open
label with five FSHD patients treated with 15 mg of losmapimod twice daily for 14 days. Biopsies of normal appearing (second cohort) and actively
involved (STIR+) muscle (third cohort) were performed at baseline and during treatment.
Losmapimod was well tolerated with no serious adverse events reported. Similar tolerability, safety and PK were observed in healthy volunteers and
patients with FSHD. Treatment with losmapimod demonstrated dose-dependent PK and target engagement in blood. FSHD patients treated with
losmapimod also achieved dose-dependent concentrations in skeletal muscle, with a muscle to plasma exposure ratio of approximately 1:1. Evidence of
dose-dependent target engagement was also observed in skeletal muscle. The losmapimod 15 mg dose taken orally twice daily demonstrated sustained drug
concentrations that in preclinical models with human FSHD myotubes resulted in a robust reduction of DUX4-driven gene expression. These data support
the selection of the 15 mg dose of losmapimod taken orally twice daily in our ongoing Phase 2b placebo-controlled clinical trial and Phase 2 open label
clinical trial of losmapimod.
We manufactured the losmapimod capsules for this trial prior to our license agreement with GSK. For our ongoing Phase 2 clinical trials, we are
using losmapimod tablets that were manufactured by GSK. We confirmed that the PK of the losmapimod capsules were consistent with published data on
the PK of the losmapimod tablets manufactured by GSK. We also confirmed that the p38α/ß target engagement in blood from our losmapimod capsules is
consistent with the previous data on target engagement of the losmapimod tablets manufactured by GSK.
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Prior Clinical Development of Losmapimod by GSK
GSK conducted multiple Phase 1 and Phase 2 clinical trials and one Phase 3 clinical trial of losmapimod, including in patients with chronic
obstructive pulmonary disease, or COPD, acute coronary syndrome and other cardiovascular diseases, neuropathic pain, major depression disorder, focal
segmental glomerulosclerosis, and rheumatoid arthritis. Nearly 3,500 subjects in 24 trials were given losmapimod with single doses as high as 60 mg and
repeated oral doses as high as 15 mg twice per day for up to 52 weeks. We are using a dose of 15 mg twice per day in our clinical trials of losmapimod in
FSHD. GSK did not conduct a clinical trial of losmapimod in patients with FSHD or any other muscle disorder.
In clinical trials of losmapimod conducted by GSK, no significant differences were observed in the frequency of adverse events, or AEs, in subjects
given losmapimod and subjects given placebo. GSK generally observed a similar frequency of serious adverse events, or SAEs, and deaths between
patients given losmapimod and patients given placebo. These trials included extensive evaluation of the cardiovascular risk profile of losmapimod,
including completion of an evaluation of the potential to prolong corrected QT. GSK reported that there was no clinically relevant difference with regard to
the occurrence of electrocardiogram abnormalities post-baseline or vital signs with losmapimod as compared to placebo. GSK did not identify a safety
signal attributed to losmapimod in any of these trials. There were no SAEs reported in 14 of these 24 clinical trials of losmapimod.
The largest placebo-controlled clinical trial of losmapimod conducted by GSK was a Phase 3 clinical trial for the treatment of acute coronary
syndrome following a heart attack, in which over 1,700 patients were given 7.5 mg of losmapimod or placebo twice per day for 12 weeks and were
followed for an additional 12 weeks. In this trial, GSK observed a similar proportion of AEs and SAEs in the placebo group as compared to the
losmapimod group.
There were also ten SAEs of fatality in the placebo group and 13 SAEs of fatality in the losmapimod group. In the placebo group, the SAEs of
fatality were infections and infestations (two), general disorders and administrative site conditions (two), respiratory, thoracic and mediastinal disorders
(three), cardiac disorder (one), gastrointestinal disorder (one) and neoplasm (one). In the losmapimod group, the SAEs of fatatity were infections and
infestations (four), general disorders and administrative site conditions (three), respiratory, thoracic and mediastinal disorders (two), cardiac disorder (one),
injury poisoning and procedural complications (one), gastrointestinal disorder (one) and neoplasm (one).
Among the total of 14 Phase 1 and Phase2 placebo-controlled clinical trials of losmapimod (N=1327 on losmapimod; N=735 on placebo), the
distribution of SAEs was similar among losmapimod-treated and placebo-treated subjects. The most common SAEs were cardiac disorders (2% placebo;
3% losmapimod) and respiratory, thoracic and mediastinal disorders (1% placebo; 2% losmapimod). SAEs were reported in 11 of these 14 trials; 3 trials
reported no SAEs.
In addition to the 24 trials conducted by GSK, another sponsor conducted a placebo-controlled Phase 2 clinical trial of losmapimod in which 73
subjects with COPD with cardiovascular manifestations were given 7.5 mg of losmapimod or placebo for 16 weeks. There were 36 subjects in the
losmapimod group and 37 in the placebo group. In this trial, there were a total of six (17%) SAEs in the losmapimod group, consisting of exacerbations of
COPD and pneumonia, and there was one (3%) SAE in the placebo group.
In prior studies, GSK observed that the p38α/ß target inhibition in humans was approximately 10%, 30% and 50% at trough and 40%, 60% and 70%
at peak following twice per day doses of 2.5 mg, 7.5 mg and 15 mg, respectively. In addition, based on in vitro data from our studies in FSHD myotubes
with losmapimod, we believe that the muscle exposures that we have achieved in rodents, which are similar to concentrations in human blood from the 15
mg twice per day dose, will result in robust p38α/ß target engagement and will reduce DUX4-driven gene expression in FSHD skeletal muscle by more
than 50%. We believe that this data supports our determination that 15 mg of losmapimod twice per day is an appropriate dose for the treatment of patients
with FSHD.
Our Product Candidate for Hemoglobinopathies - FTX-6058
Hemoglobinopathies are a category of genetic disorders affecting hemoglobin, a critical component of RBCs. The function of hemoglobin is to
delivery oxygen to tissues: hemoglobin picks up oxygen as RBCs circulate through the lungs and then drops off oxygen to the tissues so that they may
function normally. Hemoglobinopathies result in either abnormal (mutant) hemoglobin or low levels of hemoglobin, and both of these conditions are
associated with significant morbidity and mortality risks. We are developing FTX-6058, which is designed elevate the level of HbF for the treatment of
patients with SCD and select other hemoglobinopathies, including ß-thalassemia.
Overview of Sickle Cell Disease
Sickle cell disease is a genetic disorder of RBCs. The root cause of SCD is a mutant hemoglobin that polymerizes in low oxygen conditions. This
polymerization creates the abnormal, elongated, or sickle, shape of the RBC and results in, ultimately, hemolysis and vascular injury that causes major
morbidities and significantly limits lifespan in people with SCD.
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SCD patients typically suffer from serious clinical consequences, which may include vaso-occlusive crises, anemia, pain, infections, stroke, heart disease,
pulmonary hypertension, kidney failure, liver disease and reduced life expectancy. According to a study published by the American Medical Association,
approximately 32.5% of adult patients with SCD were hospitalized three or more times per year due to pain crises. SCD is reported to shorten patient life
expectancy by approximately 20 to 30 years. Patients with SCD are primarily treated by hematologists.
In the United States, where newborn screening for SCD is mandatory, the estimated prevalence is approximately 100,000 individuals. In Europe, the
estimated prevalence is approximately 134,000 individuals according to the EMA. According to the World Health Organization, the global incidence is
estimated to be approximately 300,000 births annually. SCD is most prevalent in Africa and the Middle East.
Approved drug treatments for SCD focus primarily on the management and reduction of pain episodes, vaso-occlusive crises, and inhibition of
hemoglobin S polymerization. The four drug treatments approved in the United States are hydroxyurea, voxelotor, crizanlizumab, and L-glutamine.
Hydroxyurea is approved for the treatment of anemia related to SCD to reduce the frequency of painful crises and the need for blood transfusions.
Hydroxyurea has a black box warning for myelosuppression and malignancy. In general, it is limited by its adverse side effects, inconsistent patient
responses and concerns regarding the cytotoxic effect of the drug. L-glutamine is approved to reduce severe complications associated with the disorder.
Voxelotor, marketed by Global Blood Therapeutics, is approved under accelerated approval as a hemoglobin polymerization inhibitor. This approach
maintains or increases the total amount of HbS, the mutant hemoglobin in SCD, by holding on to oxygen longer. Crizanlizumab, a P-selectin inhibitor
marketed by Novartis AG, or Novartis, is approved for the reduction in the frequency of vaso-occlusive crises.
Blood transfusions can be utilized to decrease the sickling of RBCs. While blood transfusions can be critical to manage SCD, there are a number of
limitations associated with this therapeutic approach, including limited patient access and serious complications such as iron overload. The only potentially
curative treatment currently approved for severe SCD is bone marrow transplantation. However, this treatment option is not commonly used due to the
difficulties of finding a suitable matching donor and the risks associated with the treatment, which include an approximately 5% mortality rate. Bone
marrow transplantation is more commonly offered to pediatric patients with available sibling-matched donors.
While multiple experimental approaches to treat SCD are being explored in clinical trials, the majority are focused on symptomatic relief or as last-
line gene therapy approaches. Symptomatic approaches under investigation aim to affect issues associated with cell adhesion, sickling, thrombosis and iron
homeostasis. We anticipate that a novel oral HbF inducer that affects the root cause of SCD by inhibiting the pathological polymerization caused by the
mutant hemoglobin may become the standard of care for SCD. Novartis and Global Blood Therapeutics, Inc. have received approval for therapies aiming
to provide relief for specific elements of SCD (low hemoglobin and VOCs respectively). Several gene therapy approaches to treat SCD are focused on
elevating HbF, however no gene therapy approaches have been approved for SCD and the efficacy, safety and durability of gene therapy approaches have
yet to be established. Gene therapies need to be administered in an in-patient procedure through a bone marrow transplant, which is also referred to as a
stem cell transplant or hematopoietic stem cell transplant. As part of the transplant process, the patient receives myeloablative chemotherapy which kills
cells in the bone marrow in order to support the gene therapy. Despite ongoing efforts to develop gene therapies for SCD, we believe there is still a high
unmet need that could be better addressed by a small molecule, oral therapy to treat the disease by increasing HbF.
SCD Biology
SCD is caused by a mutation in the HBB gene. This gene encodes a protein that is a key component of hemoglobin, a protein complex whose
function is to transport oxygen in the body. Hemoglobin in adults is a complex of four proteins, two hemoglobin ß-subunits and two hemoglobin α-
subunits. In patients with SCD, hemoglobin is composed of two mutant ß-subunits and two α-subunits and the result is the formation of HbS. The result of
the mutation is less efficient oxygen transport and the formation of RBCs that have a sickle shape. These sickle shaped cells are much less flexible than
healthy cells and can block blood vessels (vaso-occlusion) or rupture cells (lysis), leading to pain, anemia, irreversible organ damage or even death.
During fetal development, the major form of hemoglobin is HbF. Similar to hemoglobin in adults, HbF is also a complex of four proteins, two α-
subunits and two γ-subunits. Shortly after birth, the genes encoding the γ-subunits, the HBG1 and HBG2 genes, are silenced and the HBB gene is activated.
As described above, SCD is caused by a mutation in the HBB gene that gives rise to mutated ß-subunits.
A small subset of individuals with the sickle cell mutation continue to produce high levels of HbF due to inheritance of additional genetic mutations,
which is called Hereditary Persistence of HbF, or HPFH. Patients with elevated HbF exhibit
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minimal clinical manifestations of SCD. HbF levels as low as 3% over baseline in patients without HPFH, due to either therapeutic intervention or the
inheritance of other genetic traits, can result in reduced clinical manifestations of the disease.
Our Approach to Address the Root Cause of SCD
Our strategy to address the root cause of SCD was to identify a drug mechanism that induces expression of HbF. We believe that FTX-6058 may
address the root cause of SCD through this mechanism of action.
Overview of ß-Thalassemia
ß-thalassemia is a rare blood disorder associated with the absence or reduced production of ß-globin, which is one of the two proteins that comprise
adult hemoglobin. This results in an abnormally low level of hemoglobin as well as an excess of α-globin chains that cause destruction of RBCs. The
severity of the phenotype is related to the degree of imbalance between α- and non-α-globin chain synthesis. The absence of ß-globin due to HBB gene
deletions is referred to as ß0 thalassemia. Other HBB gene alterations allow some ß-globin to be produced but in reduced amounts. A reduced amount of ß-
globin is called ß+thalassemia. Many patients with ß-thalassemia require chronic blood transfusions due to severe anemia that results from low hemoglobin
levels, which are referred to as transfusion-dependent patients. It is estimated that 40,000 babies are born worldwide with ß-thalassemia per year of whom
25,000 require blood transfusions. Patients with ß-thalassemia are primarily treated by hematologists.
ß-thalassemia has been clinically characterized into three forms, depending on disease severity: major, intermedia and minor. The most severe form,
ß-thalassemia major (also known as Cooley’s anemia), is generally diagnosed shortly after birth and patients have life-threatening anemia. Pediatric
patients do not grow and gain weight at the typical rates, and often have liver, heart and bone problems. Many ß-thalassemia major patients require frequent
blood transfusions to prevent severe anemia, a treatment that itself can cause long-term problems due to a build-up of iron in the body. ß-thalassemia
intermedia is a less severe form of the disease that results in mild to moderate anemia. These patients sometimes require blood transfusions depending on
the severity of the symptoms. Patients with ß-thalassemia minor suffer from very mild anemia and generally do not require treatment. Having either ß0 or
ß+ thalassemia does not necessarily predict clinical disease severity as people with both types have been diagnosed with thalassemia major and thalassemia
intermedia. Any increase in HbF has the potential to ameliorate the disease.
The current standard of care for many patients with ß-thalassemia is frequent blood transfusions to manage anemia. The only potentially curative
therapy for ß-thalassemia is allogeneic hematopoietic stem cell transplant, which is associated with risks of complications, including mortality, and is
limited to patients with a suitable donor. The European Commission granted conditional marketing authorization for ZYNTEGLO, a gene therapy
developed by bluebird bio, Inc., or bluebird, for the treatment of adult and adolescent patients with transfusion-dependent ß-thalassemia and with certain
genotypes, in Europe in June 2019. bluebird has initiated a rolling biologics license application, or BLA, submission for betibeglogene autotemcel in the
United States. The FDA accepted the BLA for betibeglogene autotemcel for priority review in November 2021, with a PDUFA goal date of May 20, 2022.
Acceleron in collaboration with Celgene Corp., or Celgene, received FDA
16
and EMA approval for luspatercept, an erythroid maturation agent for the treatment of adult patients with anemia associated with ß-thalassemia and who
require frequent transfusions. There are also multiple other experimental approaches to treat ß-thalassemia being explored in clinical trials, including
approaches that use small molecule, gene therapy and gene editing approaches. Despite ongoing efforts to develop new therapies for ß-thalassemia, we
believe there is still a high unmet need that could be addressed by a small molecule, oral therapy to treatment the disease by increasing HbF.
Biology of ß-Thalassemia
ß-thalassemia is caused by genetic mutations in the HBB gene. The mutations interfere with the production of ß-globin. Some mutations result in no
ß-globin being produced, while other mutations result in a decreased amount of ß-globin being produced.
Our Approach to Address the Root Cause of ß-Thalassemia
We believe that some types of ß-thalassemia may be treated by a therapy that upregulates HbF. Babies born with ß-thalassemia major generally do
not have any symptoms shortly after birth because they have HbF in their blood. As the HbF levels decrease after birth and the ß-globin fails to increase,
anemia appears and the babies with ß-thalassemia begin to exhibit symptoms of the disease. Patients with ß-thalassemia intermedia that have higher levels
of HbFhave fewer symptoms than patients with low levels of HbF. We believe that FTX-6058 may be suitable for clinical development for the treatment of
patients who are not ß0 but who are transfusion dependent.
FulcrumSeek Identified the Drug Target for SCD and ß-Thalassemia
Applying FulcrumSeek, we conducted target identification and validation activities using human umbilical cord blood-derived erythroid progenitor
2, or HUDEP2, cells as a model to study HbF reactivation. HUDEP2 cells are immature RBCs. By screening our small molecule probe library and a
CRISPR library, we identified several potential drug targets that activated the HBG1/2 genes and resulted in HbF elevation. Each screening approach
identified the same protein complex which we believe plays an important role in the expression of genes responsible for the production of HbF. We
conducted additional validation experiments in which we observed that inhibition of several components of this complex resulted in the desired elevation of
HbF. We also observed that inhibition of these components did not adversely affect important cell health markers.
We selected a member of this protein complex for drug discovery activities following an assessment of its tractability as a drug target, which we
refer to as the HbF drug target. The normal physiological role of the HbF drug target is to facilitate a post-translational protein modification, and the goal of
our medicinal chemistry program was to optimize inhibitors of the HbF drug target. We developed in vitro and in vivo target engagement assays, as well as
enabled X-ray crystallography, to discover and develop FTX-6058, a novel small molecule inhibitor of the HbF drug target.
FTX-6058
FTX-6058 is an oral HbF inducer that is in development for SCD and select other hemoglobinopathies, including ß-thalassemia. FTX-6058 is
designed to bind to EED and inhibit the transcriptional silencing activity of the PRC2. By doing so, preclinical studies have shown that FTX-6058
downregulates key HbF repressors, including BCL11A and MYB, and upregulates HbF. We initiated our Phase 1b clinical trial of FTX-6058 in people with
SCD in the fourth quarter of 2021. Additionally, we submitted an IND in the fourth quarter of 2021 for FTX-6058 in other select hemoglobinopathies,
including ß-thalassemia, and expect to initiate a Phase 1b study in the second quarter of 2022. In February 2022, the FDA granted orphan drug designation
to FTX-6058 for the treatment of SCD.
Clinical Trial: Phase 1 FTX-6058
In the fourth quarter of 2020, we initiated a Phase 1 clinical trial of FTX-6058 in healthy adult volunteers. The Phase 1 randomized, double-blind,
placebo-controlled trial was designed to evaluate the safety, tolerability, and PK of ascending doses of FTX-6058. In the SAD cohorts, healthy volunteers
received one dose of either placebo or 2, 4, 10, 20, 30, 40 or 60mg of FTX-6058. In the MAD cohorts, healthy volunteers received a once-daily dose of
placebo or 2, 6, 10, 20 or 30mg of FTX-6058 for 14 consecutive days. Each MAD cohort had six subjects on drug and two on placebo. Food effect was also
studied in a separate 20mg dose cohort. Exploratory measures were included in the MAD cohorts to assess target engagement, changes in HBG mRNA and
HbF-containing reticulocytes (F-reticulocytes). A 6mg dose cohort in people with SCD was later added to this trial to further inform PK and PD modeling
for future dose selection. All other cohorts in the trial have been completed.
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We reported data from the 2, 4, 10, 20, 30 and 40mg SAD cohorts and the 2, 6 and 10 mg MAD cohorts in healthy volunteers in August 2021, and
we reported data from the 60 mg SAD cohort and the 20 and 30 mg MAD cohorts in healthy volunteers, as well as data from the 20 mg cohort assessing
food effect in December 2021.
FTX-6058 was generally well-tolerated with no SAEs reported and no discontinuations due to TEAEs across all SAD and MAD cohorts. Data
continued to show dose-proportional PK, with a mean half-life of approximately 6-7 hours in the MAD cohorts, supporting once-daily dosing, and no food
effect was observed with FTX-6058. Data from the MAD cohorts continued to show robust target engagement, as evidenced by an approximately 75-95%
reduction from baseline in H3K27me3 after 14 days of treatment. Based on our preclinical studies, this level of target engagement is predicted to result in
robust induction of HBG1/2 and subsequently increase HbF production.
Data from the MAD cohorts also showed time- and dose-dependent HBG mRNA induction, as shown in the chart below, demonstrating proof-of-
biology. Persistent HBG mRNA induction was observed for 7-10 days after treatment. In preclinical studies of FTX-6058, increases in HBG mRNA have
consistently translated to the same fold increases in HbF protein. Notably, human genetics show that 2-3-fold increases in HbF are associated with
significantly improved outcomes, and even functional cures, in people with SCD. FTX-6058 has now demonstrated greater than a mean 2-fold induction
starting with the 6mg dose.
HBG mRNA Mean Fold Induction for FTX-6058 versus Placebo
2mg*
6mg*
10mg*
20 mg
30mg
Mean Fold
Induction
1.28
1.20
1.21
P-value
0.3494
0.5122
0.3736
Mean Fold
Induction
1.94
2.45
2.75
P-value
0.0135
0.0025
<0.0001
Mean Fold
Induction
2.08
3.54
3.22
P-value
0.0063
<0.0001
<0.0001
Mean Fold
Induction
2.06
5.63
6.45
P-value
0.0072
<0.0001
<0.0001
Mean Fold
Induction
2.29
6.15
6.13
P-value
0.0025
<0.0001
<0.0001
Day 7
Day 14
Safety Follow-up (Day
21-24)
As shown in the chart below, F-reticulocytes also increased as of the safety follow up visit, which was seven to 10 days after conclusion of dosing.
Notably, increases in F-reticulocytes of any magnitude are a first indicator that HBG mRNA is translating to HbF protein production but fold changes in F-
reticulocytes are not correlated with fold changes in HbF.
F-Reticulocyte Mean Fold Increase for FTX-6058 versus Placebo
Day 7
Day 14
Safety Follow-up (Day 21-24)
2mg*
Mean Fold
Increase
0.53
0.88
0.63
6mg*
10mg*
20 mg
30mg
P-value
0.1070
0.6881
0.2167
Mean Fold
Increase
1.02
1.25
1.65
P-value
0.9524
0.4895
0.0943
Mean Fold
Increase
0.83
2.23
3.93
P-value
0.6214
0.0180
<0.0001
Mean Fold
Increase
0.71
1.00
1.79
P-value
0.3831
0.9880
0.0591
Mean Fold
Increase
1.50
1.71
2.38
P-value
0.2928
0.1049
0.0059
* Fold changes from these cohorts were updated to reflect the fold-increase over pooled placebo data across all cohorts from 2-30mg versus previously
reported fold changes over pooled placebo data across 2-10mg cohorts.
In fourth quarter of 2021, we initiated a Phase 1b clinical trial in SCD patients and we expect to report initial data from that trial in the second
quarter of 2022. This trial could provide an opportunity to demonstrate HbF protein induction in people living with SCD and will be used to help inform a
potential Phase 2/3 trial, which we anticipate initiating in 2023. We also submitted an IND in the fourth quarter of 2021 to support the initiation of clinical
development in non-SCD hemoglobinopathies, including ß-thalassemia. We anticipate initiating a Phase 1b trial in non-SCD hemoglobinopathies in the
second quarter of 2022.
Preclinical Studies
We have observed in vitro and in vivo activation of the HBG1/2 genes in preclinical studies with FTX-6058. We observed that FTX-6058 elevated
levels of HbF with minimal adverse effects on important cellular health markers. As
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depicted in the graphic below, we also observed in vitro upregulation of HbF in primary human CD34+ cells differentiated into RBCs from five different
healthy human donors and one SCD donor after seven days of drug treatment. FTX-6058 showed a significant elevation of HbF over baseline in each of
these six donor cell lines. We have conducted additional preclinical profiling in CD34+ derived cells and observed that treatment with FTX-6058 increased
HbF levels to approximately 30% of total hemoglobin, as measured by mass spectrometry, high performance liquid chromatography, and fast protein liquid
chromatography techniques. Notably, based on a review of data from other mechanisms, HbF fold induction in CD34+ cells has translated reliably into the
clinic.
Effect of FTX-6058 treatment
in differentiated primary human CD34+ cells
Additionally, we compared the effect of FTX-6058 in CD34+ derived cells relative to that of hydroxyurea. We observed that hydroxyurea had a
minimal impact on HbF elevation, whereas we observed that FTX-6058 significantly elevated HbF. In cells treated with the combination of FTX-6058 and
hydroxyurea, we observed an increased effect relative to either compound alone.
Additionally, we studied FTX-6058 in a mouse model of SCD, known as the Townes mouse model. In this model, mouse globin genes have been
replaced with human globin genes, thereby allowing investigations of mechanisms that may regulate human hemoglobin gene expression. The Townes
mouse model has been widely used to study potential treatments for SCD. As shown in the figures below, we observed that FTX-6058 resulted in a
significant increase in HbFexpressing cells, or F-cells, and HbF protein levels after 13 days of dosing at 5 mg/kg once per day whereas hydroxyurea
resulted in modest increases in F-cells and HbF.
Percentage of F-cells in Townes mice
treated with FTX-6058
HbF protein levels in Townes mice
treated with FTX-6058
In the graphic on the left, we quantified the percentage of F-cells as a percentage of total cells (%F-cells) for the three treatment conditions from
mouse blood, shown as a percentage of vehicle-alone-treated SCD mice. In the graphic on the right, we determined the level of human HbF protein for the
three treatment conditions, quantifying HbF protein as a
19
percentage of total hemoglobin. Each value represents the mean value from eight mice per treatment after 13 days of treatment. In these studies, we used a
conventional method of assessing statistical significance known as a one-way analysis of variance, or ANOVA. The p-value for FTX-6058 was less than
0.001 for both studies and the p-value for hydroxyurea in the study depicted on the right was less than 0.01.
Overview of Our Product Engine
FulcrumSeek is a high-throughput discovery platform that we designed to identify and validate drug targets that balance the expression of the genes
known to drive or ameliorate root cause biology. We obtain patient-derived, tissue-relevant cell lines or other relevant human cell lines. We then
differentiate these cell lines into those most relevant for the disease pathology, including skeletal muscle myotubes, cardiomyocytes, neurons, RBCs, or
other cell lines of interest, which we then scale up, characterize and prepare for screening. We also generate methods to quantify the desired modulation of
expression of the gene of interest in these cell lines. We apply our highly annotated proprietary small-molecule compound library and customized CRISPR
or RNAi libraries to the cells to assess for the desired modulation. We have continued to build our capabilities to maximally profile changes in transcription
that occur when relevant cells are treated with small molecules or genetic reagents. In addition to profiling a specific gene of interest, we can evaluate
multiple genes of potential interest through multiplexed transcriptome profiling to assess effects on root cause biology. We have made significant
enhancements to FulcrumSeek so thousands of transcripts can be measured, and additional features of cellular health and function can be assessed using
high-throughput imaging techniques. We confirm drug target hits with multiple modalities and undertake further validation in several patient-derived,
tissue-relevant cell lines. Additional studies in these cell models are conducted to understand how the modulation of the gene of interest affects cellular
function. We employ computational biology, such as machine learning algorithms, to guide drug target selection and generate hypotheses on other drug
targets that might be related along a gene regulatory pathway.
To further optimize and increase productivity of FulcrumSeek, we have continued to invest in customized lab automation and applied technologies.
We believe that these investments have increased assay throughput and robustness and have expanded the breadth of biological parameters we can
effectively measure in our assay systems. The first-generation of our product engine was focused on single gene readouts, simple immunocytochemistry,
and one-dimensional data analysis focused on an individual gene of interest. With continued investment in the product engine, we have enabled our next-
generation product engine which utilizes RNAseq, high-content imaging, and machine learning. We believe that this next-generation product engine
enables drug target screening at scale in physiologically relevant assay systems.
We designed our discovery and development model to recapitulate this systematic approach of applying FulcrumSeek to each new disease that we
evaluate with the goal of providing disease-modifying therapies to patients. The following graphic presents an overview of our drug target identification
process.
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Importantly, we designed FulcrumSeek to iteratively and systematically explore disease or indication areas of interest by incorporating both
preclinical and clinical data related to potential drug targets. In the case of heterogeneous diseases, this iterative and systematic approach enables us to
explore diseases with less-defined root cause genes, and instead screen for targets that modulate root cause biology. This approach not only enables us to
validate the translatability of our preclinical models to the clinic, but also enables us to generate unique clinical biology insights utilizing public and
proprietary clinical datasets. As a result, we believe that we have greatly expands the number of diseases that we can potentially interrogate with
FulcrumSeek.
Disease-Relevant Cell Models
Accurate modeling of human disease is critical for drug discovery endeavors, and we have the ability to model disease and identify drug targets that
modulate gene expression in patient-derived, differentiated cells and other disease-relevant cell models. These cells provide the appropriate context in
which to understand signaling pathways that affect human gene expression and function, and they have the potential to increase the translatability from
preclinical studies to clinical trials. Prior to initiating screening activities, we characterize and expand the cells. We also create a cell line where the genetic
defect associated with the disease has been corrected, or use a cell line from a healthy individual, in order to compare the gene regulation between diseased
and normal cells. If the degree of gene activation or repression required to have a functional benefit is not known, we will undertake physiological
characterization of these cell lines in order to define what threshold of gene regulation is functionally relevant.
Drug Target Identification
We employ three approaches to identify drug targets that can potentially modulate gene expression to treat genetically defined diseases at the root
cause—two lab-based library screening approaches as well as computational biology using our FulcrumSeek database and other databases. We then
evaluate possible drug targets identified from these efforts with the goal to advance programs into lead optimization.
Highly Annotated Small Molecule Compound Library
Our small molecule probe library is annotated, which means it consists of known, well-characterized molecules that interact with biochemical
mechanisms and that have cellular activity. The purpose of our small molecule probe library is to identify and interrogate mechanisms that regulate the
expression of genes of interest. We designed our library with the intent to optimize biological diversity, in contrast with other small molecule screening
approaches that optimize chemical diversity. Our library currently includes more than 6,000 small molecules relating to approximately 2,500 biochemical
targets covering a wide breadth of pharmacology, including chromatin modifiers, transcription regulation and RNA processing, kinases and metabolic
enzymes. Our library will continue to expand as we identify and acquire new mechanistic probes.
Genetic Screening
We may also use a customized CRISPR or RNAi library screening, which is an approach to interrogate the genome by selectively knocking out,
reducing or increasing gene expression, for target identification. We have chosen to use CRISPR and RNAi libraries as complementary or additional
screening tools for drug target identification alongside our small molecule screening approach. If small molecules that interact with these targets are
identified from the literature, they are then obtained for further pharmacological validation. If no known chemical matter is available, we may establish a
screen to identify chemical matter that interacts with the drug target. This chemical matter would serve as a starting point for medicinal chemistry work.
Alternatively, we may seek partnerships for development using other modalities.
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Computational Biology & Analytics
We have a proprietary database containing profiles of the effect of perturbagens, or disruptions to cellular processes, on disease-relevant, human
derived cell systems. The features captured in this database consist of measures of gene regulation on thousands of genes, and other important assessments
of cellular function and health. Our database and analysis can provide information as to which genes are modulated by our perturbagens and which genes
may be difficult to modulate. This information is then integrated into our decision-making process for disease selection. Using FulcrumSeek, our approach
is to leverage our network biology capabilities and expertise to determine how pathways interact with each other in a cell, to develop a network map of
regulatory interactions that control gene expression and cellular function and propose targets that potentially could be pursued to modulate the root cause
gene or root cause biology of diseases of interest. In each case, we explore these hypotheses through biological experimentation designed to validate
predicted drug targets and biomarkers. We use confirmatory studies to aid in the refinement of our computational models in an iterative manner.
Drug Target Validation
Our initial focus on drug target validation is to establish a robust link between the drug target that we identified through our screening approaches
and modulation of the expression of the root cause gene of interest. Our validation work seeks to evaluate identified drug targets in a manner that allows us
to prioritize targets where we may be able to deliver safe and effective therapies to patients. We conduct our validation tests using a diverse set of
pharmacological tools and multiple genetic reagents to profile their effect on orthogonal read-outs of gene expression (RNA and protein) and the
subsequent effects on physiological function.
The important elements of our systematic approach to drug target validation include:
•
•
•
•
•
•
Evaluation of different treatment modalities to interact with the drug target: we evaluate whether small molecules and genomic modulation
approaches similarly affect expression of the gene of interest.
Efficacy: we attempt to establish a link between the identified drug target and the level of the expression of the gene of interest.
Safety: we evaluate whether modulation of the target and the resulting changes in gene expression cause undesired effects, including an
assessment of cell health markers to ensure there is minimal cellular toxicity.
Profiling cell lines from multiple patients: we analyze the modulation of the drug target to determine whether the original cell line used to
screen targets is representative of disease in other patients.
Verification: we conduct studies designed to ensure that the modulation of the drug target and the resulting change in gene expression leads to a
desired functional effect.
Prioritization: we prioritize drug targets based on our assessment of our ability to deliver a candidate for clinical development based on that
target.
Development Candidate Discovery and Characterization
Following target identification and target validation, we initiate medicinal chemistry and drug discovery activities to advance a development
candidate that is suitable for testing in clinical trials. This work optimizes characteristics that are important for an orally available small molecule, including
potency, selectivity, PK and safety parameters. There is an opportunity to bypass or considerably accelerate discovery and characterization activities if we
identify and validate an attractive drug target that has been pursued previously by others in different indications. For example, available chemical matter
and support from the scientific literature regarding p38α/ß enabled us to rapidly identify our product candidate for the treatment of FSHD.
A key element of our preclinical compound profiling approach is to investigate a development candidate across many patient-derived tissue-relevant
cells. We choose these cells based on our assessment of the patient heterogeneity that may be encountered in clinical trials. The purpose of this analysis is
to enable us to understand if the activity of the molecule differs among cells with different genetic subtypes, or if a patient stratification strategy is
appropriate for clinical trials.
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Many genetically defined diseases are not well modeled with animal models because such models do not have appropriate predictive validity. In
these cases, we seek to develop an engraftment model where patient-derived human cells are engrafted into the relevant tissue of a host, immunodeficient
mouse to produce a chimeric mouse. We may use these chimeric mice to assess gene regulation in the engrafted human cells, and for the efficient
development of PK/PD, relationships that will be the basis of therapeutic index calculations and human dose projections.
Advantages of a Small Molecule Approach
We believe that our approach to the treatment of genetically defined diseases using orally available, small molecule therapeutics may offer
significant advantages over other treatment modalities due to:
•
•
•
•
Biodistribution: small molecules can achieve broad distribution in the body. The ability to access tissues broadly is particularly relevant in
neuromuscular disorders where multiple muscles are affected by disease, or in CNS disorders where brain permeability may be limited with
other treatment modalities.
Tolerability: small molecules have a limited risk of immunogenicity and lack procedural risk relative to administering other treatment
modalities, such as ASOs and gene therapies.
Manufacturing and quality: the production and quality control of drug supplies for clinical development are well understood. Specialized
facilities are generally not required, and many vendors offer services for manufacturing. We believe small molecule manufacturing may
provide cost advantages relative to other modalities.
Patient access: small molecule, oral medicines can be administered by the patient and do not require complicated in-patient procedures that are
sometimes only available in a limited number of treatment centers.
Discovery Screening Programs
We have leveraged FulcrumSeek to discover targets that we are pursuing with small molecules for FSHD, SCD and ß-thalassemia. We are
leveraging the broad applicability of FulcrumSeek to discover drug targets for other rare, genetically defined diseases across muscular, hematologic and
neurologic disorders.
Our target identification strategy and approach continue to evolve. In addition to conducting screens to identify targets that modulate the expression
of a single root cause gene, we are able to simultaneously interrogate multiple (approximately 10) root cause genes and to monitor effects on cell health all
in a single screen (i.e., multiplexed screening). We believe that this new approach provides significant efficiencies in productivity and allows us to test
multiple hypotheses in parallel. Importantly, the expansion of FulcrumSeek with the use of high content molecular profiling, including RNAseq and
cellular imaging, allows us to simultaneously measure the expression of 8,000-10,000 genes and integrate key measures related to cell health and biology,
which enables us to scale our screening capacity and productivity. With the use of our small molecule probe library and our functional genomics
capabilities, we aim to conduct target identification at a significantly increased scale and with cost-effectiveness. Moreover, we are using our product
engine in hypothesis testing mode and in hypothesis generation mode, which we expect to increase the probability of identifying attractive targets to
advance in our portfolio or in collaboration with partners.
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License Agreements and Collaborations
Right of Reference and License Agreement with GlaxoSmithKline
In February 2019, we entered into a right of reference and license agreement with affiliates of GSK, as amended in September 2020, pursuant to
which GSK granted us a right of reference to certain INDs filed with the FDA and controlled by GSK or its affiliates relating to losmapimod and an
exclusive worldwide license under certain patent rights related to losmapimod. The agreement also provides us with an exclusive worldwide license to
certain of GSK’s preclinical and clinical data with respect to losmapimod. As partial consideration for the right of reference and licenses granted under the
agreement, we issued 12,500,000 shares of our Series B preferred stock to GSK at the time we entered into the reference and license agreement. The
agreement obligates us to use commercially reasonable efforts to develop and commercialize a licensed product for the treatment of FSHD.
The agreement grants us an exclusive, sublicensable license under the licensed patent rights and data rights to research, develop and commercialize
losmapimod or any product containing losmapimod as an API, which we refer to as a licensed product, to treat disease in humans. GSK retained the right,
without the right to grant sublicenses, to conduct nonclinical research under the licensed patents and data rights and, with our consent, GSK may engage in
certain developmental activities relating to the use of a licensed product in connection with a specified prophylactic use. GSK also agreed to and has since
transferred to us its existing manufactured supply of losmapimod.
Under the agreement, we will be obligated to make milestone payments to GSK aggregating up to $37.5 million upon the achievement of specified
development and regulatory milestones with respect to the first licensed product to first achieve such milestones, including a $2.5 million milestone
payment we made to GSK during the year ended December 31, 2019 upon the initiation of the first Phase 2 clinical trial for a licensed product, and up to
$60.0 million upon the first achievement of one-time aggregate annual worldwide net sales milestones for a licensed product. We will also be obligated to
pay royalties ranging from a mid single-digit percentage to a low double-digit, but less than teens, percentage to GSK based on our, and any of our
affiliates’ and sublicensees’, annual net sales of licensed products. The royalties are payable on a licensed product-by-licensed product and country-by-
country basis, and may be reduced in specified circumstances.
Our obligation to make royalty payments extends with respect to a licensed product in a country until the earlier of the approval of a generic version
of such licensed product by the applicable regulatory agency in such country or the tenth anniversary of the first commercial sale of such licensed product
in such country, which we refer to as the royalty term. Following the expiration of any exclusive marketing rights or data exclusivity rights granted by a
regulatory authority, other than patent rights, for any licensed product on a country-by-country basis, the applicable royalty rate will be reduced in such
country. Additionally, if we or our affiliates or sublicensees determine that it is necessary to obtain a license from a third party under any patent rights to
exploit a licensed product in a country, then we may deduct a certain percentage of the license fees under such third party license payable by us to the third
party from the royalty payment that would otherwise be due to GSK in such country.
If, prior to our completion of a Phase 2 clinical trial for a licensed product, we wish to sublicense any of the licensed patent or data rights granted to
us under the agreement to any third party outside of the United States, we must notify GSK of the terms on which we propose to grant such sublicense.
GSK has the right to enter into negotiations with us for such sublicense, and if GSK so elects, then we must negotiate in good faith with GSK for a
prescribed period. If we and GSK do not agree to a sublicense of the relevant rights, we may sublicense the relevant rights to the third party on terms no
less favorable than any terms offered to us by GSK.
Unless earlier terminated in accordance with its terms, the agreement continues on a country-by-country and licensed product-by-licensed product
basis until the expiration of the royalty term in each country, at which time the agreement expires with respect to such licensed product in such country and
we shall have a fully-paid up, royalty-free and perpetual license to the licensed patent rights and data rights with respect to such licensed product in such
country. Either party has the right to terminate the agreement if the other party has materially breached in the performance of its obligations under the
agreement and such breach has not been cured within the applicable cure period.
Collaboration and License Agreement with Acceleron, a wholly-owned subsidiary of Merck
In December 2019, we entered into a collaboration and license agreement with Acceleron to identify biological targets to modulate specific
pathways associated with a targeted indication within the pulmonary disease space. Under the terms of the collaboration and license agreement, we granted
Acceleron an exclusive worldwide license under certain intellectual property rights to make, have made, use, sell, have sold, import, export, distribute and
have distributed, market, have marketed, promote, have promoted, or otherwise exploit molecules and products directed against or expressing certain
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biological targets identified by us for the treatment, prophylaxis, or diagnosis of a targeted indication within the pulmonary disease space, or the Indication.
Pursuant to a mutually agreed research plan, we will perform assay screening and related research activities to identify and validate potential
biological targets for further research, in order to support the development, manufacture and commercialization of product candidates by Acceleron. Upon
completion of the research activities, we will deliver a data package to Acceleron with respect to the biological targets identified by us in the conduct of the
research activities for the treatment, prophylaxis, or diagnosis of the Indication. Within a designated period after receipt of the data package, Acceleron will
have the right to designate a specified number of the biological targets identified by us as relevant for the treatment, prophylaxis, or diagnosis of the
Indication, for Acceleron’s research, development, manufacture and commercialization of products or molecules directed to such targets, or the Targets. If
Acceleron does not designate any Targets during the designated period, then the agreement will automatically terminate. If Acceleron designates one or
more Targets, then Acceleron will be obligated to use commercially reasonable efforts to seek regulatory approval for one product directed to a Target in
certain specified countries. Upon receipt of regulatory approval for any product directed to a Target in any of such certain specified countries, Acceleron
must use commercially reasonable efforts to commercialize such product in each of such certain specified countries.
While we are performing the research activities pursuant to the research plan and for a specified period thereafter, we may not research, develop,
manufacture, commercialize, use, or otherwise exploit any compound or product for the treatment, prophylaxis, or diagnosis of the Indication other than for
Acceleron. While we are performing the research activities pursuant to the research plan and for a specified period thereafter, other than for Acceleron, we
may not research, develop, manufacture, commercialize, use, or otherwise exploit any compound or product for the treatment, prophylaxis, or diagnosis of
the Indication that is directed against certain specified biological targets identified by us in the performance of the research activities.
Acceleron may also request that we perform medicinal chemistry services related to the generation and optimization of molecules directed against or
expressing biological targets for the treatment, prophylaxis, or diagnosis of the Indication beyond the scope of the research plan. If we agree to provide
such medicinal chemistry services, we and Acceleron will negotiate to determine the scope, timeline and budget for such medicinal chemistry services.
Under the agreement, Acceleron made a $10.0 million upfront payment to us. We will be entitled to research milestone payments of up to $18.5
million in the aggregate upon first achievement of specified research milestones. Additionally, we will be entitled to development milestone payments of up
to $135.0 million in the aggregate upon the first achievement of specified clinical and regulatory milestones by a product directed to a Target, and up to
$67.5 million in the aggregate upon the second achievement of specified clinical and regulatory milestones by a product directed to a Target. We will also
be entitled to sales-based milestone payments of up to $145.0 million in the aggregate upon the achievement of one-time aggregate annual worldwide net
sales milestones for the first product directed to a Target to achieve such milestones, and up to $72.5 million in the aggregate upon the achievement of one-
time aggregate annual worldwide net sales milestones for the second product directed to a Target to achieve such milestones. To date, we have achieved
$2.0 million of specified research milestones. Acceleron will also pay us tiered royalties ranging from a mid single-digit percentage to a low double-digit
percentage based on Acceleron’s, and any of its affiliates’ and sublicensees’, annual worldwide net sales of products directed to any Target. The royalties
are payable on a product-by-product basis during a specified royalty term, and may be reduced in specified circumstances.
The agreement continues on a country-by-country and Target-by-Target basis until the expiration of the last to expire royalty term for a product
directed to such Target, at which time the agreement expires with respect to such Target in such country, unless the agreement is terminated earlier in
accordance with its terms. Either party has the right to terminate the agreement if the other party has materially breached in the performance of its
obligations under the agreement and such breach has not been cured within the applicable cure period. Acceleron also has the right to terminate the
agreement for convenience in its entirety or on a Target-by-Target and molecule-by-molecule basis with respect to any molecule directed against a Target,
upon prior written notice to us.
Collaboration and License Agreement with MyoKardia, a wholly-owned subsidiary of Bristol-Myers Squibb Company
In July 2020, we entered into a collaboration and license agreement with MyoKardia to identify biological targets that are capable of modulating
genes of interest with relevance to certain genetically defined cardiomyopathies. Under the terms of the agreement, we granted MyoKardia an exclusive
worldwide license under certain intellectual property rights to research, develop, make, have made, use, have used, sell, have sold, offer for sale, have
offered for sale, import, have imported, export, have exported, distribute, have distributed, market, have marketed, promote, have promoted, or otherwise
exploit products directed against certain biological targets identified by us that are capable of modulating certain genes of interest with relevance to certain
genetically defined cardiomyopathies.
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Pursuant to a mutually agreed research plan, we will perform assay screening and related research activities to identify and validate up to a specified
number of potential cardiomyopathy gene targets, or the Identified Targets, for further research, development, manufacture and commercialization by
MyoKardia. We and MyoKardia will work together to determine how best to advance at each stage of the research activities under the research plan and to
identify which of the Identified Targets, if any, meet the criteria set forth in the research plan, or the Cardiomyopathy Target Candidates. Upon completion
of the research plan, the parties will work together to prepare a final data package and MyoKardia may designate certain Cardiomyopathy Target
Candidates for MyoKardia’s further exploitation under the agreement, or the Cardiomyopathy Targets. If MyoKardia does not designate any
Cardiomyopathy Targets during the designated period, then the agreement will automatically terminate. If MyoKardia designates one or more
Cardiomyopathy Targets, then MyoKardia will be obligated to use commercially reasonable efforts to seek regulatory approval for and to commercialize
one product directed against an Identified Target in certain specified countries.
During the period in which we are performing the research activities pursuant to the research plan, or the Research Term and for a specified period
beyond the Research Term if MyoKardia designates a Cardiomyopathy Target, we may only use the data generated from such research activities for
MyoKardia in accordance with the agreement. During the Research Term and for a specified period thereafter, we may not research, develop, manufacture,
commercialize, use, or otherwise exploit any compound or product (a) that is a compound or product under the agreement that is directed against the
Cardiomyopathy Target Candidates for the treatment, prophylaxis, or diagnosis of any indication or (b) for the treatment of any genetically defined
cardiomyopathies shown to be related to certain specified genes of interest that are modulated by the Cardiomyopathy Targets.
Under the agreement, MyoKardia made a $10.0 million upfront payment and a $2.5 million payment as prepaid research funding to us in July 2020.
MyoKardia will also reimburse us for the costs of the research activities not covered by the prepaid research funding, up to a maximum amount of total
research funding (including the prepaid research funding). Upon the achievement of specified preclinical, development and sales-based milestones, we will
be entitled to preclinical milestone payments, development milestone payments and sales-based milestone payments of up to $298.5 million in the
aggregate per target for certain Identified Targets, and of up to $150.0 million in the aggregate per target for certain other Identified Targets. To date, we
have achieved a $2.5 million specified preclinical milestone. MyoKardia will also pay us tiered royalties ranging from a mid single-digit percentage to a
low double-digit percentage based on MyoKardia’s, and any of its affiliates’ and sublicensees’, annual worldwide net sales of products under the agreement
directed against any Identified Target. The royalties are payable on a product-by-product basis during a specified royalty term, and may be reduced in
specified circumstances.
The agreement continues on a country-by-country and product-by-product basis until the expiration of the last to expire royalty term for a product,
at which time the agreement expires with respect to such product in such country, unless the agreement is terminated earlier in accordance with its terms.
Either party has the right to terminate the agreement if the other party has materially breached in the performance of its obligations and such breach has not
been cured within the applicable cure period. MyoKardia also has the right to terminate the agreement for convenience in its entirety or on a target-by-
target, product-by-product or molecule-by-molecule basis, upon prior written notice to us.
Intellectual Property
We strive to protect and enhance the proprietary technology, inventions and improvements that are commercially important to the development of
our business, including by seeking, maintaining and defending patent rights, whether developed internally or licensed from third parties. We also rely on
trade secrets, know-how, continuing technological innovation and in-licensing opportunities to develop, strengthen and maintain our proprietary position in
our field.
Our future commercial success depends, in part, on our ability to: obtain and maintain patent and other proprietary protection for commercially
important technology, inventions and know-how related to our business; defend and enforce in our intellectual property rights, in particular our patents
rights; preserve the confidentiality of our trade secrets; and operate without infringing, misappropriating or violating the valid and enforceable patents and
proprietary rights of third parties. Our ability to stop third parties from making, using, selling, offering to sell or importing our products may depend on the
extent to which we have rights under valid and enforceable patents or trade secrets that cover these activities.
The patent positions of biotechnology and pharmaceutical companies like ours are generally uncertain and can involve complex legal, scientific and
factual issues. 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. We also cannot ensure that patents will issue with respect to
any patent applications that we or our licensors may file in the future, nor can we ensure that any of our owned or licensed patents or future patents will be
commercially useful in protecting our product candidates and methods of manufacturing the same. In addition, the coverage claimed in a patent application
may be significantly reduced before a patent is issued, and its scope can be reinterpreted and
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even challenged after issuance. As a result, we cannot guarantee that any of our products will be protected or remain protectable by enforceable patents.
Moreover, any patents that we hold may be challenged, circumvented or invalidated by third parties. See “Risk Factors—Risks Related to Our Intellectual
Property” for a more comprehensive description of risks related to our intellectual property.
We generally file patent applications directed to our key programs in an effort to secure our intellectual property positions vis-a-vis these programs.
As of February 24, 2022, we owned or in-licensed nine U.S. patents, six U.S. pending non-provisional patent applications and related pending foreign
patent applications, and four U.S. provisional patent applications.
The intellectual property portfolio for our most advanced programs as of February 24, 2022, is summarized below. Prosecution is a lengthy process,
during which the scope of the claims initially submitted for examination by the U.S. Patent and Trademark Office may be significantly narrowed before
issuance, if issued at all. We expect this may be the case with respect to some of our pending patent applications referred to below.
Losmapimod
With respect to losmapimod, we own one U.S. patent covering the method of use of losmapimod for the treatment of patients with FSHD and one
U.S. patent covering the use of other clinical-stage p38 inhibitors for the treatment of patients with FSHD, each of which are expected to expire in 2038,
and related patents and pending patent applications in Canada and Mexico, Europe, Africa, Australia and New Zealand, South America, and Asia with
expiration dates in 2038. We also own two related pending U.S. non-provisional applications and one U.S. provisional application relating to method of
using losmapimod for FSHD and other disorders that, if resulting in issued patents, are expected to expire between 2038 and 2042. The patents to
losmapimod licensed from GSK as a composition of matter and pharmaceutical composition are expected to expire on February 10, 2023.
FTX-6058
Currently, our patent portfolio related to FTX-6058 includes one issued U.S. patent directed to composition of matter that is expected to expire in
2040, two U.S. non-provisional applications and related pending patent applications in Canada and Mexico, Europe, Africa, Australia and New Zealand,
South America, and Asia that, if issued, are expected to expire between 2039 and 2040. We also own three pending U.S. provisional applications directed
to FTX-6058 methods of use and formulations, that, if resulting in an issued patent, would be expected to expire in 2042.
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
file, 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 covering an FDA-approved drug may, in certain cases, be eligible for a patent term extension under the
Drug Price Competition and Patent Term Restoration Act of 1984 as compensation for the loss of patent term during the FDA regulatory review process.
The period of extension may be up to five years, 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 and only those claims covering the approved drug, a method for using it, or a method for
manufacturing it 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. It is possible that issued U.S. patents covering the use of losmapimod and products from our intellectual property may be entitled to patent
term extensions. If our use of drug candidates or the drug candidate itself receive FDA approval, we intend to apply for patent term extensions, if available,
to extend the term of patents that cover the approved use or drug candidate. We also intend to seek patent term extensions in any jurisdictions where
available, however, there is no guarantee that the applicable authorities, including the FDA, will agree with our assessment of whether such extensions
should be granted, and even if granted, the length of such extensions.
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In addition to patent protection, we rely upon unpatented trade secrets and confidential know-how and continuing technological innovation to
develop and maintain our competitive position. However, trade secrets and confidential know-how are difficult to protect. We seek to protect our
proprietary information, in part, using confidentiality agreements with any collaborators, scientific advisors, employees and consultants and invention
assignment agreements with our employees. We also have agreements requiring assignment of inventions with selected consultants, scientific advisors and
collaborators. These agreements may not provide meaningful protection. These agreements may also be breached, and we may not have an adequate
remedy for any such breach. In addition, our trade secrets and/or confidential know-how may become known or be independently developed by a third
party, or misused by any collaborator to whom we disclose such information. Despite any measures taken to protect our intellectual property, unauthorized
parties may attempt to copy aspects of our products or to obtain or use information that we regard as proprietary. Although we take steps to protect our
proprietary information, third parties may independently develop the same or similar proprietary information or may otherwise gain access to our
proprietary information. As a result, we may be unable to meaningfully protect our trade secrets and proprietary information. See “Risk Factors—Risks
Related to our Intellectual Property” for a more comprehensive description of risks related to our intellectual property.
Manufacturing
We do not have any manufacturing facilities. We have obtained sufficient losmapimod tablets, or drug product, from GSK to complete our ongoing
Phase 2 clinical trials in FSHD. We have engaged a contract manufacturing organization to prepare our own API and to manufacture losmapimod tablets,
and we believe that we have produced a sufficient quantity of losmapimod API and tablets to complete our planned Phase 3 clinical trial in FSHD.
We have obtained sufficient quantities of FTX-6058 from a contract manufacturing organization to complete our ongoing Phase 1 clinical trials.
We expect to continue to rely on third parties for the manufacture of FTX-6058 for any future clinical trials and for the manufacture of any future
product candidates for preclinical and clinical testing, as well as for commercial manufacture if our product candidates receive marketing approval. Our
lead product candidates are small molecules and can be manufactured in reliable and reproducible synthetic processes from readily available starting
materials. We expect to continue to develop product candidates that can be produced cost-effectively at contract manufacturing facilities.
Competition
The biotechnology and pharmaceutical industries are characterized by rapidly advancing technologies, intense competition and a strong emphasis on
proprietary products. While we believe that our technologies, knowledge, experience and scientific resources provide us with competitive advantages, we
face competition from many different sources, including major pharmaceutical, specialty pharmaceutical and biotechnology companies, academic
institutions and governmental agencies and public and private research institutions. Any product candidates that we successfully develop and
commercialize will compete with existing therapies and new therapies that may become available in the future.
Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial
resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and
marketing approved products than we do. Mergers and acquisitions in the pharmaceutical and biotechnology industry may result in even more resources
being concentrated among a smaller number of our competitors. Smaller or early stage companies may also prove to be significant competitors, particularly
through collaborative arrangements with large and established companies. These competitors also compete with us in recruiting and retaining qualified
scientific and management personnel and establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies
complementary to, or necessary for, our programs.
The key competitive factors affecting the success of all of our therapeutic product candidates, if approved, are likely to be their efficacy, safety,
convenience, price, the effectiveness of companion diagnostics in guiding the use of related therapeutics, the level of generic competition and the
availability of reimbursement from government and other third-party payors.
Our commercial opportunity could be reduced or eliminated if our 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. Our competitors also may obtain
FDA or other regulatory approval or emergency use authorizations 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. In addition, our ability to compete may be affected in many
cases by insurers or other third-party payors seeking to encourage the use of generic products. If our product
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candidates achieve marketing approval, we expect that they will be priced at a significant premium over competitive generic products.
If our lead product candidates are approved for the indications for which we are currently undertaking clinical trials, they will compete with the
therapies and currently marketed drugs discussed below.
FSHD
There are no approved therapies for the treatment of FSHD. Controlled trials of albuterol, corticosteroids and a myostatin inhibitor all failed to
demonstrate a clinical benefit to patients with FSHD. Low-intensity aerobic exercise tailored to the patient’s distribution of weakness may provide some
limited beneficial effect. Limited range of motion in the shoulder girdle can stem from periscapular muscle weakness, and in such cases surgical scapular
fixation can result in some functional improvement for certain patients. There is also no standard practice regarding the use of physical or occupational
therapy across countries and sites.
We are not aware of any product candidate currently in clinical development for FSHD with the same mechanism of action as losmapimod or that is
designed to treat the root cause of FSHD.
SCD
Approved drug treatments for SCD focus primarily on the management and reduction of pain episodes, vaso-occlusive crises, and inhibition of
hemoglobin S polymerization. The four drug treatments approved in the United States are hydroxyurea, voxelotor, crizanlizumab, and L-glutamine.
Hydroxyurea, marketed by Bristol-Myers Squibb Company, is approved for the treatment of anemia related to SCD, to reduce the frequency of painful
crises and the need for blood transfusions. Voxelotor, marketed by Global Blood Therapeutics, is approved under accelerated approval as a hemoglobin
polymerization inhibitor. Crizanlizumab, marketed by Novartis, is approved for the reduction in the frequency of vasoocclusive crises. L-glutamine,
marketed by Emmaus Life Sciences, Inc., is approved to reduce severe complications associated with the disorder.
Blood transfusions can be utilized to decrease the sickling of RBCs. While blood transfusions can be critically important to the management of
SCD, there are a number of limitations associated with this therapeutic approach, including limited patient access and serious complications such as iron
overload. The only potentially curative treatment currently approved for severe SCD is bone marrow transplantation. However, this treatment option is not
commonly used given the difficulties of finding a suitable matched donor and the risks associated with the treatment, which include an approximately 5%
mortality rate. Bone marrow transplantation is more commonly offered to pediatric patients with available sibling-matched donors.
FTX-6058 could face competition from a number of different therapeutic approaches in development for patients with SCD. Novo Nordisk A/S is
evaluating EPI01, a small molecule designed to increase production of HbF, which has completed a Phase 1 clinical trial. Imara, Inc. is evaluating IMR-
687, a PDE9 inhibitor, in Phase 2a and Phase 2b clinical trials in patients with sickle cell anemia. Agios Pharmaceuticals, Inc., is evaluating mitapivat, a
PKR activator, in a Phase 2/3 clinical trial in patients with SCD. Forma Therapeutics Holdings, Inc., is evaluating FT-4202, a PKR activator, in a Phase 2/3
clinical trial. Global Blood Therapeutics, Inc. is evaluating GBT-601, an HbS polymerization inhibitor, that is anticipated to initiate a Phase 2 study by mid-
2022 as well as inclacumab, a P-selectin inhibitor that is being evaluated in two Phase 3 trials. Takeda Pharmaceutical Company Limited, is evaluating
TAK-755, recombinant ADAMTS13 protein, in a Phase 1 clinical trial in participants with baseline health SCD and SCD with acute vaso-occlusive crisis.
Pfizer, is evaluating PF-06755347, an E-selectin antagonist, in a Phase 1 clinical trial. CRISPR Therapeutics AG (in collaboration with Vertex
Pharmaceuticals Incorporated, or Vertex), is evaluating CTX001, a gene therapy, in a Phase 1/2/3 clinical trial. CRISPR Therapeutics AG and Vertex plan
to file a BLA/MAA in Q4 2022. Aruvant Sciences, Inc. is evaluating ARU-1801, a gene therapy, in a Phase 1/2 clinical trial. CSL Behring, is evaluating
CSL200 CAL-H, a gene therapy, in a Phase 1 clinical trial. Sangamo Therapeutics Inc., or Sangamo is developing SAR445136, a gene editing cell therapy
that modifies cells to produce functional RBCs using HbF, in a Phase 1/2 clinical trial. bluebird is evaluating lovo-cel, a gene therapy, in a Phase 3 clinical
trial. There are also several other gene editing approaches being evaluated by Intellia Therapeutics, Inc. (in collaboration with Novartis), Editas Medicine,
Inc., and Beam Therapeutics.
ß-thalassemia
The current standard of care for many patients with ß-thalassemia is frequent blood transfusions to manage anemia. The only potentially curative
therapy for ß-thalassemia is allogeneic hematopoietic stem cell transplant, which is associated with risks of complications, including mortality, and is
limited to patients with a suitable donor. The European Commission
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granted conditional marketing authorization for ZYNTEGLO, a gene therapy developed by bluebird, for the treatment of adult and adolescent patients with
transfusion-dependent ß-thalassemia and with certain genotypes, in Europe in June 2019. However, in August 2021, bluebird announced plans to end
commercial operations in Europe and has decided to focus on the U.S. market. The FDA accepted the BLA for betibeglogene autotemcel for priority
review in November 2021, with a PDUFA goal date of May 20, 2022. Acceleron in collaboration with Celgene, received FDA and EMA approval for
luspatercept, an erythroid maturation agent for the treatment of adult patients with anemia associated with ß-thalassemia and who require frequent
transfusions. There are also multiple other experimental approaches to treat ß-thalassemia being explored in clinical trials, including approaches that use
small molecule, gene therapy and gene editing approaches. Despite ongoing efforts to develop new therapies for ß-thalassemia, we believe there is still a
high unmet need that could be addressed by a small molecule, oral therapy to treatment the disease by increasing HbF.
FTX-6058 could face competition from a number of different therapeutic approaches in development for patients with transfusion-dependent ß-
thalassemia.
Bellicum Pharmaceuticals, Inc. is conducting a Phase 1/2 clinical trial to evaluate a modified donor T cell therapy to be used in conjunction with
hematopoietic stem cell transplant Imara, Inc. is evaluating IMR-687, a PDE9 inhibitor, in a Phase 2b clinical trial in patients with ß-thalassemia. Agios
Pharmaceuticals, Inc., intends to evaluate mitapivat, a PKR activator, in two Phase 3 clinical trials planned for 2021 in patients with non-transfusion
dependent and transfusion-dependent ß-thalassemia. Forma Therapeutics Holdings, Inc., intends to evaluate FT-4202, a PKR activator, in a Phase 2 clinical
trial in non-transfusion and transfusion-dependent ß-thalassemia. Ionis Pharmaceuticals, Inc., is evaluating IONIS TMPRSS6-LRx, an ASO therapy
targeting TMPRSS6, in a Phase 2 clinical trial of non-transfusion dependent β-thalassemia intermedia. Silence Therapeutics is investigating SLN124, an
siRNA therapy targeting TMPRSS6, in a Phase 1 healthy volunteer study. Orchard Therapeutics plc is conducting Phase 2 clinical trials of OTL-300, an
autologous ex vivo gene therapy for the treatment of transfusion-dependent ß-thalassemia. Sangamo, is conducting a Phase 1/2 clinical trial of ST-400,
which uses a genome-edited cell therapy approach designed to produce functional RBCs using HbF. CRISPR Therapeutics AG, in collaboration with
Vertex, is conducting a Phase 1/2 clinical trial of CTX001, which uses a gene editing approach to upregulate the expression of HbF, in patients with
transfusion-dependent ß-thalassemia. CRISPR Therapeutics AG and Vertex plan to file a BLA/MAA in Q4 2022.
Government Regulation and Product Approvals
Government authorities in the United States at the federal, state and local level, and in other countries and jurisdictions, including the European
Union, extensively regulate, among other things, the research, development, testing, manufacture, pricing, reimbursement, quality control, approval,
packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, post-approval monitoring and reporting, and import and export
of biopharmaceutical products. The processes for obtaining marketing approvals in the United States and in foreign countries and jurisdictions, along with
compliance with applicable statutes and regulations and other regulatory authorities, require the expenditure of substantial time and financial resources.
Approval and Regulation of Drugs in the United States
In the United States, drug products are regulated under the Federal Food, Drug and Cosmetic Act, or FDCA, and applicable implementing
regulations and guidance. The failure of an applicant to comply with the applicable regulatory requirements at any time during the product development
process, including non-clinical testing, clinical testing, the approval process or post-approval process, may result in delays to the conduct of a study,
regulatory review and approval and/or administrative or judicial sanctions.
An applicant seeking approval to market and distribute a new drug in the United States generally must satisfactorily complete each of the following
steps before the product candidate will be approved by the FDA:
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preclinical testing including laboratory tests, animal studies and formulation studies, which must be performed in accordance with the FDA’s
good laboratory practice, or GLP, regulations and standards;
submission to the FDA of an IND for human clinical testing, which must become effective before human clinical trials may begin;
approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;
performance of adequate and well-controlled human clinical trials to establish the safety, potency and purity of the product candidate for each
proposed indication, in accordance with current good clinical practices, or GCP;
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preparation and submission to the FDA of a new drug application, or NDA, for a drug product which includes not only the results of the
clinical trials, but also, detailed information on the chemistry, manufacture and quality controls for the product candidate and proposed
labelling for one or more proposed indication(s);
review of the product candidate by an FDA advisory committee, where appropriate or if applicable;
satisfactory completion of an FDA inspection of the manufacturing facility or facilities, including those of third parties, at which the product
candidate or components thereof are manufactured to assess compliance with current good manufacturing practices, or cGMP, requirements
and to assure that the facilities, methods and controls are adequate to preserve the product’s identity, strength, quality and purity;
satisfactory completion of any FDA audits of the non-clinical and clinical trial sites to assure compliance with GCP and the integrity of clinical
data in support of the NDA;
payment of user fees and securing FDA approval of the NDA to allow marketing of the new drug product; and
compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy,
or REMS, and the potential requirement to conduct any post-approval studies required by the FDA.
Preclinical Studies
Before an applicant begins testing a product candidate with potential therapeutic value in humans, the product candidate enters the preclinical testing
stage, including in vitro and animal studies to assess the safety and activity of the drug for initial testing in humans and to establish a rationale for
therapeutic use. Preclinical tests include laboratory evaluations of product chemistry, formulation and stability, as well as other studies to evaluate, among
other things, the toxicity of the product candidate. The conduct of the preclinical tests and formulation of the compounds for testing must comply with
federal regulations and requirements, including GLP regulations and standards. The results of the preclinical tests, together with manufacturing
information, analytical data, any available clinical data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an
IND. Some long-term preclinical testing, such as animal tests of reproductive adverse events and carcinogenicity and long-term toxicity studies may
continue after the IND is submitted.
The IND and IRB Processes
Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in
accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their voluntary informed consent
in writing before their participation in any clinical trial. Clinical trials are conducted under written study protocols detailing, among other things, the
inclusion and exclusion criteria, the objectives of the study, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated. A
protocol for each clinical trial and any subsequent protocol amendments must be submitted to the FDA as part of the IND.
An IND is an exemption from the FDCA 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 NDA. 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. 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, among other things, 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 these cases, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.
Following commencement of a clinical trial under an IND, the FDA may also place a clinical hold or partial clinical hold on that trial. Clinical holds
are imposed by the FDA whenever there is concern for patient safety and may be a result of new data, findings, or developments in clinical, nonclinical,
and/or chemistry, manufacturing, and controls areas. 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. For
example, a specific protocol or part of a protocol may not be allowed to proceed, while other protocols may be allowed. 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, a clinical trial may only
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resume after the FDA has so notified the sponsor. The FDA will base that determination on information provided by the sponsor correcting the deficiencies
previously cited or otherwise satisfying the FDA that the clinical trial can proceed.
A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an
IND, all FDA IND requirements must be met unless waived. When a foreign clinical study is not conducted under an IND, the sponsor must ensure that the
study complies with certain regulatory requirements, including GCP requirements, of the FDA in order to use the study as support for an IND or
application for marketing approval. The GCP requirements encompass both ethical and data integrity standards for clinical studies. The FDA’s regulations
are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical studies, as well as the quality and integrity of the resulting
data. They further help ensure that non-IND foreign studies are conducted in a manner comparable to that required for IND studies.
In addition to the foregoing IND requirements, 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 reapprove 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, the protocol, or other requirements or if the product candidate has been
associated with unexpected serious harm to patients.
Additionally, 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. 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.
Suspension or termination of development during any phase of clinical trials can occur for many reasons, including if the FDA, an IRB, a data safety
monitoring board, or we determine that the participants or patients are being exposed to an unacceptable health risk. Other reasons for suspension or
termination may be made by us based on factors such as evolving business objectives and/or the competitive environment.
Information about clinical trials must be submitted within specific timeframes to the NIH for public dissemination on its ClinicalTrials.gov website.
Similar requirements for posting clinical trial information are present in the European Union (EudraCT) website: https://eudract.ema.europa.eu/ and other
countries, as well.
Expanded Access to an Investigational Drug for Treatment Use
Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of registrational clinical trials to
treat patients with serious or immediately life-threatening diseases or conditions when there are no comparable or satisfactory alternative treatment options.
The rules and regulations related to expanded access are intended to improve access to investigational drugs for patients who may benefit from
investigational therapies that do not conflict with registrational trials. FDA regulations allow access to investigational drugs under an IND by the company
or the treating physician for treatment purposes on a case-by-case basis for: individual patients (single-patient IND applications for treatment in emergency
settings and non-emergency settings); intermediate-size patient populations; and larger populations for use of the drug under a treatment protocol or
Treatment IND Application.
When considering an IND application for expanded access to an investigational product, the FDA will determine suitability when all of the
following criteria apply: patient(s) have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory alternative
therapy to diagnose, monitor, or treat the disease or condition; the potential patient benefit justifies the potential risks of the treatment and the potential
risks are not unreasonable in the context or condition to be treated; and the expanded use of the investigational drug for the requested treatment will not
interfere with the initiation, conduct, or completion of clinical investigations that could support marketing approval of the product or otherwise compromise
the potential development of the product.
There is no obligation for a sponsor to make its drug products available for expanded access; however, sponsor must make its expanded access
policy publicly available upon the earlier of initiation of a Phase 2 or Phase 3 clinical trial; or 15 days after the drug or biologic receives designation as a
breakthrough therapy, fast track product, or regenerative medicine advanced therapy.
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Human Clinical Trials in Support of an NDA
Clinical trials involve the administration of the investigational product candidate to human subjects under the supervision of a qualified investigator
in accordance with GCP requirements, which include, among other things, the requirement that all research subjects provide their informed consent in
writing before their participation in any clinical trial. Clinical trials are conducted under written clinical trial protocols detailing, among other things, the
objectives of the study, inclusion and exclusion criteria, the parameters to be used in monitoring safety and the effectiveness criteria to be evaluated.
Human clinical trials are typically conducted in three sequential phases, but the phases may overlap or be combined. Additional studies may also be
required after approval.
Phase 1 clinical trials are initially conducted in a limited population to test the product candidate for safety, including adverse effects, dose
tolerance, absorption, metabolism, distribution, excretion and pharmacodynamics in healthy humans or in patients. During Phase 1 clinical trials,
information about the investigational drug product’s PK and pharmacological effects may be obtained to permit the design of scientifically valid Phase 2
clinical trials.
Phase 2 clinical trials are generally conducted in a limited patient population to identify possible adverse effects and safety risks, evaluate the
efficacy of the product candidate for specific targeted indications and determine dose tolerance and optimal dosage. Multiple Phase 2 clinical trials may be
conducted by the sponsor to obtain information prior to beginning larger and more costly Phase 3 clinical trials. Phase 2 clinical trials are well controlled,
closely monitored and conducted in a limited patient population.
Phase 3 clinical trials proceed if the Phase 2 clinical trials demonstrate that a dose range of the product candidate is potentially effective and has an
acceptable safety profile. Phase 3 clinical trials are undertaken within an expanded patient population to further evaluate dosage, provide substantial
evidence of clinical efficacy and further test for safety in an expanded and diverse patient population at multiple, geographically dispersed clinical trial
sites. A well-controlled, statistically robust Phase 3 clinical trial that is designed to deliver the data that regulatory authorities will use to decide whether or
not to approve, and, if approved, how to appropriately label a drug, is referred to as “pivotal.”
In some cases, the FDA may approve an NDA for a product candidate but require the sponsor to conduct additional clinical trials to further assess
the product candidate’s safety and effectiveness after approval. Such post-approval trials are typically referred to as Phase 4 clinical trials. These studies are
used to gain additional experience from the treatment of a larger number of patients in the intended treatment group.
IND annual reports detailing, among other things, the results of the clinical trials must be submitted to the FDA and IND safety reports must be
submitted to the FDA for any of the following: serious and unexpected suspected adverse reactions; findings from other studies or animal or in vitro testing
that suggest a significant risk in humans exposed to the product; and any clinically important increase in the case of a serious suspected adverse reaction
over that listed in the protocol or investigator brochure. Phase 1, Phase 2 and Phase 3 clinical trials may not be completed successfully within any specified
period, or at all. The FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted.
Concurrent with clinical trials, companies often complete additional animal studies. They must also develop additional information about the
chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with
cGMP requirements. The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things,
must develop methods for testing the identity, strength, quality, purity, and potency of the final drug. Additionally, appropriate packaging must be selected
and tested and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.
Pediatric Studies
Under the Pediatric Research Equity Act of 2003, or PREA, an NDA or supplement thereto must contain data that are adequate to assess the safety
and effectiveness of the 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. Sponsors must also submit pediatric study plans that contain an outline of the proposed
pediatric study or studies the applicant plans to conduct, including study objectives and design, any deferral or waiver requests and other information
required by regulation. The applicant, the FDA, and the FDA’s internal review committee must then review the information submitted, consult with each
other and agree upon a final plan. The FDA or the applicant may request an amendment to the plan at any time.
The FDA may, on its own initiative or at the request of the applicant, grant deferrals for submission of some or all pediatric data until after approval
of the product for use in adults, or grant full or partial waivers from the pediatric data
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requirements. The FDA maintains a list of diseases that are exempt from the requirements of PREA, due to low prevalence of disease in the pediatric
population, and product candidates that have received orphan drug designation are generally exempt from PREA requirements, although orphan-designated
drugs intended for treatment of certain molecularly targeted cancer indications are not eligible for the exemption.
Review and Approval of an NDA
In order to obtain approval to market a drug product in the United States, a marketing application must be submitted to the FDA that provides
sufficient data establishing the safety and effectiveness of the proposed drug product for its intended indication. The application includes all relevant data
available from pertinent preclinical and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed
information relating to the product’s chemistry, manufacturing, controls and proposed labeling, among other things. Data can come from company-
sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies
initiated by independent investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety,
purity and potency of the drug product to the satisfaction of the FDA.
The NDA is a vehicle through which applicants formally propose that the FDA approve a new drug product for marketing and sale in the United
States for one or more indications. Every new non-biologic drug product candidate must be the subject of an approved NDA before it may be
commercialized in the United States. BLAs are submitted for approval of biologic products. Under federal law, the submission of most NDAs is subject to
an application user fee, which for federal fiscal year 2022 is $3,117,218 for an application requiring clinical data. The sponsor of an approved NDA is also
subject to an annual program fee, which for fiscal year 2022 is $369,413. Certain exceptions and waivers are available for some of these fees, such as an
exception from the application fee for products with orphan designation, an exception from the program fee when the program does not engage in
manufacturing the drug during a particular fiscal year and a waiver for certain small businesses.
The FDA conducts a preliminary review of the application, generally within 60 calendar days of its receipt, and strives to inform the sponsor within
74 days whether the application is sufficiently complete to permit substantive review. The FDA may request additional information rather than accept the
application for filing. In this event, the application must be resubmitted with the additional information. The resubmitted application is also subject to
review before the FDA accepts it for filing. Under certain circumstances, the FDA may determine the application is not sufficiently complete to permit a
substantive review and will issue a refuse to file letter. Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA
has agreed to specified performance goals in the review process of NDAs. Under that agreement, 90% of applications seeking approval of New Molecular
Entities, or NMEs, are meant to be reviewed within ten months from the date on which the FDA accepts the application for filing, and 90% of applications
for NMEs that have been designated for Priority Review are meant to be reviewed within six months of the filing date. The review process and the
Prescription Drug User Fee Act, or PDUFA, goal date may be extended by the FDA to consider new information or clarification provided by the applicant,
to address a deficiency identified by the FDA in the original submission, or for other reasons.
Before approving an application, the FDA typically will inspect the facility or facilities where the product is being or will be manufactured. These
pre-approval inspections may cover all facilities associated with an NDA submission, including component manufacturing, finished product manufacturing
and control testing laboratories. The FDA will not approve an application 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. Additionally, before
approving an NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP.
The FDA may refer an application for a novel product to an advisory committee or explain why such referral was not made. Typically, an advisory
committee is a panel of independent experts, including clinicians and other scientific experts, that review, evaluate and provide 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 the
FDA considers such recommendations carefully when making decisions.
Fast Track, Breakthrough Therapy, Priority Review
The FDA has certain programs designed to expedite the development and review of product candidates intended to address an unmet medical need
in the treatment of a serious or life-threatening disease or condition. These programs include Fast Track designation, Breakthrough Therapy designation,
Priority Review designation and Regenerative Medicine Advanced Therapy designation. Sponsors must request these designations at appropriate points in
the development process.
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The FDA may designate a product for Fast Track review if it is intended, whether alone or in combination with one or more other products, for the
treatment of a serious or life-threatening disease or condition and it demonstrates the potential to address unmet medical needs for such a disease or
condition. For Fast Track products, sponsors may have greater interaction with the FDA, and the FDA may initiate review of sections of a Fast Track
product’s application before the application is complete, in a process called rolling review. The sponsor must also provide, and the FDA must approve, a
schedule for the submission of the remaining information, and the sponsor must pay applicable user fees. However, the FDA’s PDUFA goal for reviewing a
Fast Track application does not begin until the last section of the application is submitted. In addition, the Fast Track designation may be withdrawn if the
FDA believes that the designation is no longer supported by data emerging in the clinical trial process or for the other reasons.
A product may be designated as a Breakthrough Therapy if it is intended, either alone or in combination with one or more other products, to treat a
serious or life-threatening disease or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over
existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. A product
that receives Breakthrough Therapy Designation is eligible for all of the features of Fast Track Designation, and additionally is eligible for intensive
guidance throughout the development process and a commitment to involve senior staff.
The FDA may designate a product for Priority Review if it treats a serious condition and, if approved, would provide a significant improvement in
safety or effectiveness. The FDA determines, on a case-by-case basis, whether the proposed product represents a significant improvement when compared
with other available therapies. Significant improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition,
elimination or substantial reduction of a treatment-limiting product reaction, documented enhancement of patient compliance that may lead to improvement
in serious outcomes, and evidence of safety and effectiveness in a new subpopulation. A Priority Review designation is intended to direct overall attention
and resources to the evaluation of such applications and to shorten the FDA’s goal for taking action on a marketing application from ten months to six
months.
Accelerated Approval Pathway
The FDA may grant accelerated approval to a product for a serious or life-threatening condition that provides meaningful therapeutic advantage to
patients over existing treatments based upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely, based on
epidemiologic, therapeutic, pathophysiologic, or other evidence, to predict clinical benefit. The FDA may also grant accelerated approval for such a
condition when the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or
mortality, or IMM, and that is reasonably likely to predict an effect on IMM or other clinical benefit, taking into account the severity, rarity or prevalence of
the condition and the availability or lack of alternative treatments. Products granted accelerated approval must meet the same statutory standards for safety
and effectiveness as those granted traditional approval.
For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign,
efficacy biomarker or other measure that is thought to predict clinical benefit but is not itself a measure of clinical benefit. Surrogate endpoints can often be
measured more easily or more rapidly than clinical endpoints.
The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required
to measure the intended clinical benefit of a product, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. The benefit of
accelerated approval derives from the potential to receive approval based on surrogate endpoints sooner than possible for trials with clinical or survival
endpoints, rather than deriving from any explicit shortening of the FDA approval timeline, as is the case with Priority Review.
The accelerated approval pathway is contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post-approval confirmatory
studies to verify and describe the product’s clinical benefit. As a result, a product candidate approved on this basis is subject to rigorous post-marketing
compliance requirements, including the completion of Phase 4 or post-approval clinical trials to confirm the effect on the clinical endpoint. Failure to
conduct required post-approval studies, or to confirm a clinical benefit during post-marketing studies, would allow the FDA to initiate expedited
proceedings to withdraw approval of the product. 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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The FDA’s Decision on an NDA
On the basis of the FDA’s evaluation of the application and accompanying information, including the results of the inspection of the manufacturing
facilities, the FDA may issue an approval letter or a complete response letter. An approval letter authorizes commercial marketing of the product with
specific prescribing information for specific indications. A complete response letter generally outlines the deficiencies in the submission and may require
substantial additional testing or information in order for the FDA to reconsider the application. If and when those deficiencies have been addressed to the
FDA’s satisfaction in a resubmission of the NDA, the FDA will issue an approval letter. The FDA has committed to reviewing such resubmissions in two or
six months depending on the type of information included. Even with submission of this additional information, the FDA ultimately may decide that the
application does not satisfy the regulatory criteria for approval.
If the FDA approves a new product, it may limit the approved indications for use of the product, require that contraindications, warnings or
precautions be included in the product labeling, or require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess the
drug’s safety after approval. The agency may also require testing and surveillance programs to monitor the product after commercialization, or impose
other conditions, including distribution restrictions or other risk management mechanisms, including Risk Evaluation and Mitigation Strategies (REMS), to
help ensure that the benefits of the product outweigh the potential risks. REMS programs can include medication guides, communication plans for health
care professionals, and elements to assure safe use, or ETASU. ETASU can include, but are not limited to, special training or certification for prescribing or
dispensing, dispensing only under certain circumstances, special monitoring and the use of patent registries. The FDA may prevent or limit further
marketing of a product based on the results of post-market studies or surveillance programs. The FDA may require a REMS before or after approval if it
becomes aware of a serious risk associated with use of the product. The requirement for a REMS can materially affect the potential market and profitability
of a product. After approval, many types of changes to the approved product, such as adding new indications, changing manufacturing processes and
adding labeling claims, are subject to further testing requirements and FDA review and approval.
Post-Approval Regulation
A sponsor that obtains regulatory approval for marketing of a new product or a new indication for an existing product, will be subject to numerous
post-approval regulatory requirements. The sponsor will be required to report, among other things, certain adverse reactions and manufacturing problems to
the FDA, provide updated safety and efficacy information, comply with requirements concerning advertising and promotional labeling requirements, and
submit NDA annual reports. Manufacturers and certain of their subcontractors 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 ongoing regulatory requirements,
including cGMP regulations, which impose certain procedural and documentation requirements upon manufacturers. Changes to the manufacturing process
are strictly regulated and often require prior FDA approval before being implemented. Accordingly, the sponsor and its third-party manufacturers must
continue to expend time, money and effort to maintain compliance with cGMP regulations and other regulatory requirements.
The FDA may withdraw approval if compliance with regulatory requirements is not maintained or if problems occur after the product reaches the
market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with
manufacturing processes, may result in revisions to the approved labeling to add new safety information, requirements for post-market studies or clinical
trials to assess safety risks; or imposition of distribution or other restrictions under a REMS program. Other potential consequences may include:
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restrictions on the marketing or manufacturing of the product, complete withdrawal of the product from the market or product recalls;
fines, warning letters or holds on post-approval clinical trials;
refusal of the FDA to approve pending applications or supplements to approved applications, or suspension or revocation of product license
approvals;
product seizure or detention, or refusal to permit the import or export of products; or
injunctions or the imposition of civil or criminal penalties.
The FDA strictly regulates the marketing, labeling, advertising and promotion of prescription drug products placed on the market. This regulation
includes, among other things, standards and regulations for direct-to-consumer advertising, communications regarding unapproved uses, industry-
sponsored scientific and educational activities, and promotional activities involving the Internet and social media. Promotional claims about a drug’s safety
or effectiveness are prohibited before the drug is approved. After approval, a drug product generally may not be promoted for uses that are not approved by
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the FDA, as reflected in the product’s prescribing information. In the United States, health care professionals are generally permitted to prescribe drugs for
such uses not described in the drug’s labeling, known as off-label uses, because the FDA does not regulate the practice of medicine. However, FDA
regulations impose rigorous restrictions on manufacturers’ communications, prohibiting the promotion of off-label uses. It may be permissible, under very
specific, narrow conditions, for a manufacturer to engage in nonpromotional, non-misleading communication regarding off-label information, such as
distributing scientific or medical journal information.
If a company is found to have promoted off-label uses, it may become subject to administrative and judicial enforcement by the FDA, the
Department of Justice, or the DOJ, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities.
This could subject a company to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements
that materially restrict the manner in which a company promotes or distributes drug products. The federal government has levied large civil and criminal
fines against companies for alleged improper promotion, and has also requested that companies enter into consent decrees or permanent injunctions under
which specified promotional conduct is changed or curtailed.
In addition, manufacturers and other parties involved in the drug supply chain for prescription drug products must comply with product tracking and
tracing requirements and for notify the FDA of counterfeit, diverted, stolen and intentionally adulterated products or products that are otherwise unfit for
distribution in the United States.
Section 505(b)(2) NDAs
NDAs for most new drug products are based on two full clinical studies which must contain substantial evidence of the safety and efficacy of the
proposed new product for the proposed use. These applications are submitted under Section 505(b)(1) of the FDCA. The FDA is, however, authorized to
approve an alternative type of NDA under Section 505(b)(2) of the FDCA. This type of application allows the applicant to rely, in part, on the FDA’s
previous findings of safety and efficacy or literature for a previously approved drug product, also known as a listed drug. Specifically, Section 505(b)(2)
applies to NDAs for which certain investigations made to show whether or not the drug is safe and effective “were not conducted by or for the applicant
and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”
NDAs filed under Section 505(b)(2) provide an alternate and potentially more expeditious pathway to FDA approval for new or improved
formulations or new uses of previously approved products. If the 505(b)(2) applicant can establish that reliance on the FDA’s previous approval is
scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical or clinical studies of the new product. The FDA may also
require companies to perform additional studies or measurements to support the change from the approved product. The FDA may then approve the new
drug candidate for all or some of the label indications for which the listed drug has been approved, subject to any regulatory exclusivities or patents for the
listed drug (as further described below), as well as for any new indication or use sought by the Section 505(b)(2) applicant.
Abbreviated New Drug Applications for Generic Drugs
In 1984, with passage of the Hatch-Waxman Amendments to the FDCA, Congress established an abbreviated regulatory scheme authorizing the
FDA to approve generic drugs that are shown to contain the same active ingredients as, and to be bioequivalent to, drugs previously approved by the FDA
pursuant to NDAs, known as the reference listed drugs, or RLDs. Abbreviated new drug applications, or ANDAs, generally do not include preclinical and
clinical data to demonstrate safety and effectiveness. Instead, the applicant must provide information and data showing that its proposed generic version is
identical to the RLD with respect to the active ingredients, route of administration, dosage form, strength and conditions of use of the drug. The FDA must
also determine whether the generic drug is bioequivalent to the RLD. Under the statute, a generic drug is bioequivalent to a RLD if “the rate and extent of
absorption of the drug do not show a significant difference from the rate and extent of absorption of the listed drug.” Upon approval of an ANDA, the FDA
indicates whether the generic product is “therapeutically equivalent” to the RLD in its publication “Approved Drug Products with Therapeutic Equivalence
Evaluations,” also referred to as the “Orange Book.” Depending on state laws, generic drugs that are found to be therapeutically equivalent may be
automatically substituted for prescriptions for the RLD by the dispensing pharmacist, without the intervention of the prescriber.
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Under the Hatch-Waxman Amendments, the FDA may not approve an ANDA until any applicable period of non-patent exclusivity for the RLD has
expired. The FDCA provides a period of five years of non-patent data exclusivity for a new drug containing a new chemical entity. For the purposes of this
provision, a new chemical entity, or NCE, is a drug that contains no active moiety that has previously been approved by the FDA in any other NDA. An
active moiety is the molecule or ion responsible for the physiological or pharmacological action of the drug substance. In cases where such NCE
exclusivity has been granted, an ANDA may not be filed with the FDA until the expiration of five years unless the submission is accompanied by a
Paragraph IV certification, in which case the applicant may submit its application four years following the original product approval.
Hatch-Waxman Patent Certification and the 30-Month Stay
Upon approval of an NDA or a supplement thereto, NDA sponsors are required to list with the FDA each patent with claims that cover the
applicant’s product or an approved method of using the product. Each of the patents listed by the NDA sponsor is published in the Orange Book. When an
ANDA applicant files its application with the FDA, the applicant is required to certify to the FDA concerning any patents listed for the reference product in
the Orange Book, except for patents covering methods of use for which the ANDA applicant is not seeking approval. To the extent that the Section 505(b)
(2) applicant is relying on studies conducted for an already approved product, the applicant is required to certify to the FDA concerning any relevant
patents listed for the approved product in the Orange Book in the same manner as an ANDA applicant.
Specifically, the applicant must certify with respect to each patent that:
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the required patent information has not been filed;
the listed patent has expired;
the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration; or
the listed patent is invalid, unenforceable or will not be infringed by the new product.
A certification that the new product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is
called a Paragraph IV certification. If the applicant does not challenge the listed patents, the application will not be approved until all the listed patents
claiming the referenced product have expired (other than method of use patents involving indications for which the applicant is not seeking approval).
If the ANDA or Section 505(b)(2) NDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the
Paragraph IV certification to the NDA and patent holders once the application has been accepted for filing by the FDA. The NDA and patent holders may
then initiate a patent infringement lawsuit in response to the notice of the Paragraph IV notice. The filing of a patent infringement lawsuit within 45 days
after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA or 505(b)(2) application until the earlier of 30
months after the receipt of the Paragraph IV notice, the expiration of the patent, or a decision in the infringement case that is favorable to the ANDA
applicant.
As a result, approval of a Section 505(b)(2) NDA or ANDA may be delayed until all the listed patents claiming the referenced product have expired,
until any non-patent exclusivity, such as exclusivity for obtaining approval of a new chemical entity, listed in the Orange Book for the referenced product
has expired, or, in the case of a Paragraph IV certification and subsequent patent infringement suit, until the earlier of 30 months, settlement of the lawsuit
or a decision in the infringement case that is favorable to the applicant.
Pediatric Exclusivity
Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an
additional six months of marketing protection to the term of an existing regulatory exclusivity or certain patents. This six-month exclusivity may be granted
if an NDA sponsor submits pediatric data that fairly respond to a written request from the FDA for such data. The data do not need to show the product to
be effective in the pediatric population studied; rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is
granted.
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Orphan Drug Designation and Exclusivity
Under the Orphan Drug Act, the FDA may designate a drug product as an “orphan drug” if it is intended to treat a rare disease or condition,
generally meaning that it affects fewer than 200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that the
cost of developing and making a product available in the United States for treatment of the disease or condition will be recovered from sales of the product.
A company must seek orphan drug designation before submitting an NDA for the candidate product. If the request is granted, the FDA will disclose the
identity of the therapeutic agent and its potential use. Orphan drug designation does not shorten the PDUFA goal dates for the regulatory review and
approval process, although it does convey certain advantages such as tax benefits and exemption from the PDUFA application fee.
If a product with orphan designation receives the first FDA approval for the disease or condition for which it has such designation or for an
indication or use within the rare disease or condition for which it was designated, the product generally will receive orphan drug exclusivity. Orphan drug
exclusivity means that the FDA may not approve another sponsor’s marketing application for the same drug for the same condition for seven years, except
in certain limited circumstances. Orphan exclusivity does not block the approval of a different product for the same rare disease or condition, nor does it
block the approval of the same product for different conditions. If a drug designated as an orphan drug ultimately receives marketing approval for an
indication broader than what was designated in its orphan drug application, it may not be entitled to exclusivity.
Orphan drug exclusivity also may not bar approval of another product under certain specified circumstances, including if a subsequent product with
the same drug for the same condition is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a
major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.
Patent Term Restoration and Extension
A patent claiming a new drug product may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent
restoration of up to five years for patent term lost during the FDA regulatory review. The restoration period granted on a patent covering a product is
typically one-half the time between the effective date of an IND and the submission date of an application, plus the time between the submission date of an
application and the ultimate approval date. Patent term restoration cannot be used to extend the remaining term of a patent past a total of 14 years from the
product’s approval date. Only one patent applicable to an approved product is eligible for the extension, and only those claims covering the approved
product, a method for using it, or a method for manufacturing it may be extended. Additionally, the application for the extension must be submitted prior to
the expiration of the patent in question. A patent that covers multiple products for which approval is sought can only be extended in connection with one of
the approvals. The United States Patent and Trademark Office reviews and approves the application for any patent term extension or restoration in
consultation with the FDA.
Health Care Law and Regulation
Health care providers and third-party payors play a primary role in the recommendation and prescription of drug products that are granted marketing
approval. Arrangements with providers, consultants, third-party payors and customers are subject to broadly applicable fraud and abuse, anti-kickback,
false claims laws, patient privacy laws and regulations and other health care laws and regulations that may constrain business and/or financial
arrangements. Restrictions under applicable federal and state health care laws and regulations, include the following:
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the federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering,
paying, receiving or providing remuneration, directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual
for, or the purchase, order or recommendation of, any good or service, for which payment may be made, in whole or in part, under a federal
health care program such as Medicare and Medicaid;
the federal civil and criminal false claims laws, including the civil False Claims Act, and civil monetary penalties laws, which prohibit
individuals or entities from, among other things, knowingly presenting, or causing to be presented, to the federal government, claims for
payment that are false, fictitious or fraudulent or knowingly making, using or causing to made or used a false record or statement to avoid,
decrease or conceal an obligation to pay money to the federal government;
the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal laws that
prohibit, among other things, knowingly and willfully executing, or attempting to
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execute, a scheme to defraud any health care benefit program or making false statements relating to health care matters;
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HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their respective implementing
regulations, including the Final Omnibus Rule published in January 2013, which impose obligations, including mandatory contractual terms,
with respect to safeguarding the privacy, security and transmission of individually identifiable health information;
the federal false statements statute, which prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making any
materially false statement in connection with the delivery of or payment for health care benefits, items or services;
the Foreign Corrupt Practices Act, or FCPA, which prohibits companies and their intermediaries from making, or offering or promising to
make improper payments to non-U.S. officials for the purpose of obtaining or retaining business or otherwise seeking favorable treatment;
the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the Patient Protection and Affordable
Care Act, as amended by the Health Care Education Reconciliation Act, or the ACA, which requires certain manufacturers of drugs, devices,
biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within the United States
Department of Health and Human Services, information related to payments and other transfers of value made by that entity to physicians and
teaching hospitals, as well as ownership and investment interests held by physicians and their immediate family members (effective January 1,
2022, these reporting obligations extend to include transfers of value made to certain non-physician providers (physician assistants, nurse
practitioners, clinical nurse specialists, certified registered nurse anesthetists and anesthesiologist assistants, and certified-nurse midwives));
federal government price reporting laws, which require us to calculate and report complex pricing metrics in an accurate and timely manner to
government programs;
federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm
consumers; and
analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to health care items or
services that are reimbursed by non-government third-party payors, including private insurers.
Further, some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the
relevant compliance guidance promulgated by the federal government in addition to requiring manufacturers to report information related to payments to
physicians and other health care providers or marketing expenditures. Additionally, some state and local laws require the registration of pharmaceutical
sales representatives in the jurisdiction. State and foreign laws 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. For example, in California,
the California Consumer Protection Act, or 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. While clinical trial data and information
governed by HIPAA are currently exempt from the current version of the CCPA, other personal information may be applicable and possible changes to the
CCPA may broaden its scope. In addition, a new California ballot initiative, the California Privacy Rights Act, or CPRA, was passed in November 2020.
Effective starting on January 1, 2023, 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. Further data privacy and security laws and
regulations in foreign jurisdictions that may be more stringent than those in the United States. (such as the European Union, which adopted the EU General
Data Protection Regulation, or GDPR, which became effective in May 2018). Analogous state laws may additionally govern the privacy and security of
health information in certain circumstances, many of which differ from each other in significant ways and may not have the same effect.
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Pharmaceutical Insurance Coverage and Health Care Reform
In the United States and markets in other countries, patients who are prescribed treatments for their conditions and providers performing the
prescribed services generally rely on third-party payors to reimburse all or part of the associated health care costs. Significant uncertainty exists as to the
coverage and reimbursement status of products approved by the FDA and other government authorities. Thus, even if a product candidate is approved,
sales of the product will depend, in part, on the extent to which third-party payors, including government health programs in the United States such as
Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage and establish adequate reimbursement levels for,
the product. The process for determining whether a payor will provide coverage for a product may be separate from the process for setting the price or
reimbursement rate that the payor will pay for the product once coverage is approved. Third-party payors are increasingly challenging the prices charged,
examining the medical necessity and reviewing the cost-effectiveness of medical products and services and imposing controls to manage costs. Third-party
payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the approved products for a
particular indication.
In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive
pharmacoeconomic studies in order to demonstrate the medical necessity and cost-effectiveness of the product, in addition to the costs required to obtain
FDA or other comparable marketing approvals. Nonetheless, product candidates may not be considered medically necessary or cost effective. A decision
by a third-party payor not to cover a product could reduce physician utilization once the product is approved and have a material adverse effect on sales,
results of operations and financial condition. Additionally, a payor’s decision to provide coverage for a product does not imply that an adequate
reimbursement rate will be approved. Further, one payor’s determination to provide coverage for a product does not assure that other payors will also
provide coverage and reimbursement for the product, and the level of coverage and reimbursement can differ significantly from payor to payor.
The containment of health care costs also has become a priority of federal, state and foreign governments and the prices of products have been a
focus in this effort. Governments have shown significant interest in implementing cost-containment programs, including price controls, restrictions on
reimbursement and requirements for substitution of generic products. Adoption of price controls and cost-containment measures, and adoption of more
restrictive policies in jurisdictions with existing controls and measures, could further limit a company’s revenue generated from the sale of any approved
products. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement status is attained
for one or more products for which a company or its collaborators receive marketing approval, less favorable coverage policies and reimbursement rates
may be implemented in the future.
There have been a number of federal and state proposals during the last few years regarding the pricing of pharmaceutical and biopharmaceutical
products, limiting coverage and reimbursement for drugs and biologics and other medical products, government control and other changes to the health
care system in the United States.
In March 2010, the United States Congress enacted the ACA, which, among other things, includes changes to the coverage and payment for drug
products under government health care programs. Among the provisions of the ACA of importance to our potential product candidates are:
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an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents, apportioned
among these entities according to their market share in certain government healthcare programs;
expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to certain
individuals with income at or below 133% of the federal poverty level, thereby potentially increasing a manufacturer’s Medicaid rebate
liability;
expanded manufacturers’ rebate liability under the Medicaid Drug Rebate Program by increasing the minimum rebate for both branded and
generic drugs and revising the definition of “average manufacturer price” for calculating and reporting Medicaid drug rebates on outpatient
prescription drug prices;
addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that
are inhaled, infused, instilled, implanted or injected;
expanded the types of entities eligible for the 340B drug discount program;
established the Medicare Part D coverage gap discount program by requiring manufacturers to provide a 70% point-of-sale-discount off the
negotiated price of applicable brand drugs to eligible beneficiaries during their coverage gap period as a condition for the manufacturers’
outpatient drugs to be covered under Medicare Part D; and
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a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness research,
along with funding for such research.
Other legislative changes have been proposed and adopted in the United States since the ACA was enacted. In August 2011, the Budget Control Act
of 2011, among other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit Reduction, tasked with
recommending a targeted deficit reduction of at least $1.2 trillion for the years 2013 through 2021, was unable to reach required goals, thereby triggering
the legislation’s automatic reduction to several government programs. This includes aggregate reductions of Medicare payments to providers up to 2% per
fiscal year. These reductions went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect through
2030, with the exception of a temporary suspension from May 1, 2020 through March 31, 2022 due to the COVID-19 pandemic. Following the temporary
suspension, a 1% payment reduction will occur beginning April 1, 2022 through June 30, 2022, and the 2% payment reduction will resume on July 1, 2022.
In January 2013, President Obama signed into law the American Taxpayer Relief Act of 2012, which, among other things, further reduced Medicare
payments to several providers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five
years. These laws may result in additional reductions in Medicare and other healthcare funding and otherwise affect the prices we may obtain for any of our
product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.
Since enactment of the ACA, there have been and continue to be, numerous legal challenges and Congressional actions to repeal and replace
provisions of the law. For example, the 2020 federal spending package permanently eliminated, effective January 1, 2020, the ACA-mandated “Cadillac”
tax on high-cost employer-sponsored health coverage and medical device tax and, effective January 1, 2021, also eliminated the health insurer tax. Further,
the Bipartisan Budget Act of 2018, among other things, amended the ACA, effective January 1, 2019, to increase from 50 percent to 70 percent the point-
of-sale discount that is owed by pharmaceutical manufacturers who participate in Medicare Part D and to close the coverage gap in most Medicare drug
plans, commonly referred to as the “donut hole”. Congress may consider other legislation to replace elements of the ACA during the next Congressional
session.
On November 10, 2020, the Supreme Court heard oral arguments as to whether the individual mandate portion of the ACA is an essential and
inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Cuts and Jobs Act, the remaining provisions of the ACA
are invalid as well. On June 17, 2021, the U.S. Supreme Court dismissed the most recent judicial challenge to the ACA brought by several states without
specifically ruling on the constitutionality of the ACA. Prior to the Supreme Court’s decision, President Biden issued an executive order to initiate a special
enrollment period from February 15, 2021 through August 15, 2021 for purposes of obtaining health insurance coverage through the ACA marketplace.
The executive order also instructed certain governmental agencies to review and reconsider their existing policies and rules that limit access to healthcare,
including among others, reexamining Medicaid demonstration projects and waiver programs that include work requirements, and policies that create
unnecessary barriers to obtaining access to health insurance coverage through Medicaid or the ACA. It is unclear how other healthcare reform measures of
the Biden administration or other efforts, if any, to challenge, repeal or replace the ACA will impact our business.
The costs of prescription pharmaceuticals have also been the subject of considerable discussion in the United States. To date, there have been several
recent U.S. congressional inquiries, as well as proposed and enacted federal and state legislation designed to, among other things, bring more transparency
to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform
government program reimbursement methodologies for drug products. At a federal level, President Biden signed an Executive Order on July 9, 2021
affirming the administration’s policy to (i) support legislative reforms that would lower the prices of prescription drug and biologics, including by allowing
Medicare to negotiate drug prices, by imposing inflation caps, and, by supporting the development and market entry of lower-cost generic drugs and
biosimilars; and (ii) support the enactment of a public health insurance option. Among other things, the Executive Order also directs HHS to provide a
report on actions to combat excessive pricing of prescription drugs, enhance the domestic drug supply chain, reduce the price that the Federal government
pays for drugs, and address price gouging in the industry; and directs the FDA to work with states and Indian Tribes that propose to develop section 804
Importation Programs in accordance with the Medicare Prescription Drug, Improvement, and Modernization Act of 2003, and the FDA’s implementing
regulations. FDA released such implementing regulations on September 24, 2020, which went into effect on November 30, 2020, providing guidance for
states to build and submit importation plans for drugs from Canada. On September 25, 2020, CMS stated drugs imported by states under this rule will not
be eligible for federal rebates under Section 1927 of the Social Security Act and manufacturers would not report these drugs for “best price” or Average
Manufacturer Price purposes. Since these drugs are not considered covered outpatient drugs, CMS further stated it will not publish a National Average
Drug Acquisition Cost for these drugs. If implemented, importation of drugs from Canada may materially and adversely affect the price we receive for any
of our product candidates. Further, on November 20, 2020 CMS issued an Interim Final Rule implementing the Most Favored Nation, or MFN, Model
under which Medicare Part B reimbursement rates would have been be calculated for certain drugs and biologicals based on the lowest price drug
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manufacturers receive in Organization for Economic Cooperation and Development countries with a similar gross domestic product per capita. However,
on December 29, 2021 CMS rescinded the Most Favored Nations rule. Additionally, on November 30, 2020, HHS published a regulation removing safe
harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit
managers, unless the price reduction is required by law. The rule also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as
a safe harbor for certain fixed fee arrangements between pharmacy benefit managers and manufacturers. Pursuant to court order, the removal and addition
of the aforementioned safe harbors were delayed and recent legislation imposed a moratorium on implementation of the rule until January 1, 2026. On May
23, 2019, CMS published a final rule to allow Medicare Advantage Plans the option of using step therapy for Part B drugs beginning January 1, 2020.
Although a number of these and other proposed measures may require authorization through additional legislation to become effective, and the Biden
administration may reverse or otherwise change these measures, both the Biden administration and Congress have indicated that they will continue to seek
new legislative measures to control drug costs.
At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control
pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and
marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing. In
addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and
which suppliers will be included in their prescription drug and other health care programs. These measures could reduce the ultimate demand for our
products, once approved, or put pressure on our product pricing. We expect that additional state and federal healthcare reform measures will be adopted in
the future, any of which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in
reduced demand for our product candidates or additional pricing pressures.
Review and Approval of Medicinal Products in the European Union
In order to market any product outside of the United States, a company must also comply with numerous and varying regulatory requirements of
other countries and jurisdictions regarding quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization,
commercial sales and distribution of products. Whether or not it obtains FDA approval for a product, an applicant will need to obtain the necessary
approvals by the comparable non-U.S. regulatory authorities before it can commence clinical trials or marketing of the product in those countries or
jurisdictions. The approval process ultimately varies between countries and jurisdictions and can involve additional product testing and additional
administrative review periods. The time required to obtain approval in other countries and jurisdictions might differ from and be longer than that required
to obtain FDA approval. Regulatory approval in one country or jurisdiction does not ensure regulatory approval in another, but a failure or delay in
obtaining regulatory approval in one country or jurisdiction may negatively impact the regulatory process in others. Specifically, however, the process
governing approval of medicinal products in the European Union, or EU, generally follows the same lines as in the United States. It entails satisfactory
completion of preclinical studies and adequate and well-controlled clinical trials to establish the safety and efficacy of the product for each proposed
indication. It also requires the submission to the relevant competent authorities of a marketing authorization application, or MAA, and granting of a
marketing authorization by these authorities before the product can be marketed and sold in the EU.
Clinical Trial Approval
In April 2014, the EU adopted the new Clinical Trials Regulation, (EU) No 536/2014, which replaced the current Clinical Trials Directive
2001/20/EC on January 31, 2022. The Clinical Trials Regulation is directly applicable in all EU Member States meaning no national implementing
legislation in each EU Member State is required. It will overhaul the current system of approvals for clinical trials in the EU. The new Clinical Trials
Regulation aims to simplify and streamline the approval of clinical trials in the EU. Under the new coordinated procedure for the approval of clinical trials,
the sponsor of a clinical trial will be required to submit a single application for approval of a clinical trial to a reporting EU Member State through an EU
Portal. The submission procedure will be the same irrespective of whether the clinical trial is to be conducted in a single EU Member State or in more than
one EU Member State.
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PRIME Designation in the EU
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 marketing authorization application 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. Products from small- and medium-sized enterprises, or SMEs, 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 Committee for Human Medicinal Products,
or CHMP, or Committee for Advanced Therapies, are appointed early in the PRIME scheme facilitating increased understanding of the product at 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.
Marketing Authorization
To obtain a marketing authorization for a product under EU regulatory systems, an applicant must submit an MAA either under a centralized
procedure administered by the EMA, or one of the procedures administered by competent authorities in the EU Member States (decentralized procedure,
national procedure or mutual recognition procedure). A marketing authorization may be granted only to an applicant established in the EU. Regulation
(EC) No 1901/2006 provides that prior to obtaining a marketing authorization in the EU, applicants have to demonstrate compliance with all measures
included in an EMA-approved Pediatric investigation plan, or PIP, covering all subsets of the pediatric population, unless the EMA has granted (1) a
product-specific waiver, (2) a class waiver or (3) a deferral for one or more of the measures included in the PIP.
The centralized procedure provides for the grant of a single marketing authorization by the European Commission that is valid throughout the EU,
and in the additional Member States of the European Economic Area Iceland, Liechtenstein and Norway. Pursuant to Regulation (EC) No 726/2004, the
centralized procedure is compulsory for specific products, including for medicines produced by certain biotechnological processes, products designated as
orphan medicinal products, advanced therapy medicinal products (gene-therapy, somatic cell-therapy or tissue-engineered medicines), and products with a
new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, diabetes, auto-immune and other immune
dysfunctions, and viral diseases. The centralized procedure is optional for products containing a new active substance not yet authorized in the EU, or for
products that constitute a significant therapeutic, scientific or technical innovation or which are in the interest of public health in the EU. We anticipate that
the centralized procedure will be mandatory for the product candidates we are developing.
Under the centralized procedure, the CHMP is responsible for conducting the initial assessment of a product and for several post-authorization and
maintenance activities, such as the assessment of modifications or extensions to an existing marketing authorization. Under the centralized procedure in the
EU, the maximum timeframe for the evaluation of an MAA by the EMA is 210 days, excluding clock stops, when additional written or oral information is
to be provided by the applicant in response to questions asked by the CHMP. Clock stops may extend the timeframe of evaluation of an MAA considerably
beyond 210 days. Where the CHMP gives a positive opinion, it provides the opinion together with supporting documentation to the European Commission,
who makes the final decision to grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s recommendation. Accelerated
evaluation might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of major interest from the point of view of
public health and in particular from the viewpoint of therapeutic innovation. If the CHMP accepts such request, the time limit of 210 days will be reduced
to 150 days, excluding clock stops, but it is possible that the CHMP can revert to the standard time limit for the centralized procedure if it considers that it
is no longer appropriate to conduct an accelerated assessment.
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The European Commission may grant a so-called “marketing authorization under exceptional circumstances”. Such authorization is intended for
products for which the applicant can demonstrate that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use,
because the indications for which the product in question is intended are encountered so rarely that the applicant cannot reasonably be expected to provide
comprehensive evidence, or in the present state of scientific knowledge, comprehensive information cannot be provided, or it would be contrary to
generally accepted principles of medical ethics to collect such information. Consequently, marketing authorization under exceptional circumstances may be
granted subject to certain specific obligations, which may include the following:
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the applicant must complete an identified program of studies within a time period specified by the competent authority, the results of which
form the basis of a reassessment of the benefit/risk profile;
the medicinal product in question may be supplied on medical prescription only and may in certain cases be administered only under strict
medical supervision, possibly in a hospital and in the case of a radiopharmaceutical, by an authorized person; and
the package leaflet and any medical information must draw the attention of the medical practitioner to the fact that the particulars available
concerning the medicinal product in question are as yet inadequate in certain specified respects.
A marketing authorization under exceptional circumstances is subject to annual review to reassess the risk-benefit balance in an annual reassessment
procedure. Continuation of the authorization is linked to the annual reassessment and a negative assessment could potentially result in the marketing
authorization being suspended or revoked. The renewal of a marketing authorization of a medicinal product under exceptional circumstances, however,
follows the same rules as a “normal” marketing authorization. Thus, a marketing authorization under exceptional circumstances is granted for an initial five
years, after which the authorization will become valid indefinitely, unless the EMA decides that safety grounds merit one additional five-year renewal.
The European Commission may also grant a so-called “conditional marketing authorization” prior to obtaining the comprehensive clinical data
required for an application for a full marketing authorization. Such conditional marketing authorizations may be granted for product candidates intended for
treating, preventing or diagnosing seriously debilitating or life-threatening diseases (including medicines designated as orphan medicinal products), if (i)
the risk-benefit balance of the product candidate is positive, (ii) it is likely that the applicant will be in a position to provide the required comprehensive
clinical trial data post-authorization, (iii) the product fulfills an unmet medical need and (iv) 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 are still required. A conditional marketing
authorization may contain specific obligations to be fulfilled by the marketing authorization holder, including obligations with respect to the completion of
ongoing or new studies, and with respect to the collection of pharmacovigilance data. Conditional marketing authorizations are valid for one year, and may
be renewed annually, if the risk-benefit balance remains positive, and after an assessment of the need for additional or modified conditions and/or specific
obligations. The timelines for the centralized procedure described above also apply with respect to the review by the CHMP of applications for a
conditional marketing authorization. A conditional marketing authorization can be converted into a standard centralized marketing authorization (no longer
subject to specific obligations) once the marketing authorization holder fulfils the obligations imposed and the complete data confirm that the medicine’s
benefits continue to outweigh its risks.
The EU medicines rules expressly permit the EU Member States to adopt national legislation prohibiting or restricting the sale, supply or use of any
medicinal product containing, consisting of or derived from a specific type of human or animal cell, such as embryonic stem cells. While the products we
have in development do not make use of embryonic stem cells, it is possible that the national laws in certain EU Member States may prohibit or restrict us
from commercializing our products, even if they have been granted an EU marketing authorization.
Unlike the centralized authorization procedure, the decentralized marketing authorization procedure requires a separate application to, and leads to
separate approval by, the competent authorities of each EU Member State in which the product is to be marketed. This application is identical to the
application that would be submitted to the EMA for authorization through the centralized procedure. The reference EU Member State prepares a draft
assessment and drafts of the related materials within 120 days after receipt of a valid application. The resulting assessment report is submitted to the
concerned EU Member States who, within 90 days of receipt, must decide whether to approve the assessment report and related materials. If a concerned
EU Member State cannot approve the assessment report and related materials due to concerns relating to a potential serious risk to public health, disputed
elements may be referred to the European Commission, whose decision is binding on all EU Member States.
The mutual recognition procedure similarly is based on the acceptance by the competent authorities of the EU Member States of the marketing
authorization of a medicinal product by the competent authorities of other EU Member States. The
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holder of a national marketing authorization may submit an application to the competent authority of an EU Member State requesting that this authority
recognize the marketing authorization delivered by the competent authority of another EU Member State.
Data and Market Exclusivity
In the EU, innovative medicinal products approved on the basis of a complete independent data package qualify for eight years of data exclusivity
upon marketing authorization and an additional two years of market exclusivity pursuant to Directive 2001/83/EC. Regulation (EC) No 726/2004 repeats
this entitlement for medicinal products authorized in accordance the centralized authorization procedure. Data exclusivity prevents applicants for
authorization of generics or biosimilars of these innovative products 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 in the EU, during a period of eight years from the date
on which the reference product was first authorized in the EU. During an additional two-year period of market exclusivity, a generic or biosimilar MAA
can be submitted and authorized, and the innovator’s data may be referenced, but no generic or biosimilar medicinal product can be placed on the EU
market until the expiration of the market exclusivity. The overall ten-year period will be extended to a maximum of 11 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 their authorization, are held to bring a significant clinical benefit in comparison with existing therapies. There is no guarantee that a
product will be considered by the EMA to be an innovative medicinal product, and products may not qualify for data exclusivity. Even if a product is
considered to be an innovative medicinal product so that the innovator gains the prescribed period of data exclusivity, another company nevertheless could
also market another version of the product if such company obtained marketing authorization based on an MAA with a complete independent data package
of pharmaceutical tests, preclinical tests and clinical trials.
Periods of Authorization and Renewals
A marketing authorization has an initial validity for five years in principle. The marketing authorization may be renewed after five years on the basis
of a re-evaluation of the risk-benefit balance by the EMA or by the competent authority of the EU Member State for a nationally authorized product. Once
subsequently definitively renewed, the marketing authorization shall be valid for an unlimited period, unless the European Commission or the national
competent authority decides, on justified grounds relating to pharmacovigilance, to proceed with one additional five-year renewal period. Any
authorization which is not followed by the actual placing of the medicinal product on the EU market (in the case of the centralized procedure) or on the
market of the authorizing EU Member State for a nationally authorized product within three years after authorization ceases to be valid (the so-called
sunset clause).
Paediatric Studies and Exclusivity
Prior to obtaining a marketing authorization in the EU, applicants must demonstrate compliance with all measures included in an EMA-approved
PIP covering all subsets of the pediatric population, unless the EMA has granted a product-specific waiver, a class waiver, or a deferral for one or more of
the measures included in the PIP. The respective requirements for all marketing authorization procedures are laid down in Regulation (EC) No 1901/2006,
the so-called Pediatric Regulation. This requirement also applies when a company wants to add a new indication, pharmaceutical form or route of
administration for a medicine that is already authorized. The Paediatric Committee of the EMA, or PDCO, may grant deferrals for some medicines,
allowing a company to delay development of the medicine for children until there is enough information to demonstrate its effectiveness and safety in
adults. The PDCO may also grant waivers when development of a medicine for children is not needed or is not appropriate, such as for diseases that only
affect the elderly population. Before an MAA can be filed, or an existing marketing authorization can be amended, the EMA determines that companies
actually comply with the agreed studies and measures listed in each relevant PIP. If an applicant obtains a marketing authorization in all EU Member States,
or a marketing authorization granted in the centralized procedure by the European Commission, and the study results for the pediatric population are
included in the product information, even when negative, the medicine is then eligible for an additional six-month period of qualifying patent protection
through extension of the term of the 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 two 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.
Orphan Drug Designation and Exclusivity
Products receiving orphan designation in the EU can receive ten years of market exclusivity, during which time no “similar medicinal product” 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
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intended for the same therapeutic indication. An orphan 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.
Regulation (EC) No. 141/2000, as implemented by Regulation (EC) No. 847/2000 provides that a drug can be designated as an orphan drug by the
European Commission if its sponsor can establish: (1) that the product is intended for the diagnosis, prevention or treatment of a life-threatening or
chronically debilitating condition; (2) either (a) such condition affects no more than five (5) in ten thousand (10,000) persons in the EU when the
application is made, or (b) it is unlikely that the product, without the benefits derived from orphan status, would generate sufficient return in the EU to
justify the necessary investment in 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 method exists, the product will be of significant benefit to those affected by that condition. Orphan medicinal
products are eligible for financial incentives such as reduction of fees or fee waivers. The application for orphan drug designation must be submitted before
the application for marketing authorization. The applicant will receive a fee reduction for the MAA if the orphan drug designation has been granted, but not
if the designation is still pending at the time the marketing authorization is submitted. Orphan drug designation does not convey any advantage in, or
shorten the duration of, the regulatory review and approval process.
However, marketing authorization may be granted to a similar medicinal product with the same orphan indication during the ten-year period with
the consent of the marketing authorization holder for the original orphan medicinal product or if the manufacturer of the original orphan medicinal product
is unable to supply sufficient quantities. Marketing authorization may also be granted to a similar medicinal product with the same orphan indication if this
product is safer, more effective or otherwise clinically superior to the original orphan medicinal product. The period of market exclusivity may, in addition,
be reduced to six years if, at the end of the fifth year, it is established that the product no longer meets the criteria for orphan designation, for example, if
the product is sufficiently profitable not to justify maintenance of market exclusivity.
Regulatory Requirements After a Marketing Authorization has been Obtained
In case an authorization for a medicinal product in the EU is obtained, the holder of the marketing authorization is required to comply with a range
of requirements applicable to the manufacturing, marketing, promotion and sale of medicinal products. These include:
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Compliance with the EU’s stringent pharmacovigilance or safety reporting rules must be ensured. These rules can impose post-authorization
studies and additional monitoring obligations.
The manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in
strict compliance with the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC, Regulation
(EC) No 726/2004 and the European Commission Guidelines for Good Manufacturing Practice. These requirements include compliance with
EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients, including the manufacture of active
pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU.
The marketing and promotion of authorized drugs, including industry-sponsored continuing medical education and advertising directed toward
the prescribers of drugs and/or the general public, are strictly regulated in the EU. Direct-to-consumer advertising of prescription medicines is
prohibited across the EU.
The aforementioned EU rules are generally applicable in the European Economic Area, or EEA, which consists of the EU Member States, plus Norway,
Liechtenstein and Iceland.
General Data Protection Regulation
The collection, use, disclosure, transfer, or other processing of personal data regarding individuals in the EU, including personal health data, is
subject to the GDPR, which became effective on May 25, 2018. 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, 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, providing notification of data breaches, ensuring certain accountability measures are in place and taking certain measures
when engaging third-party processors. The GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the United
States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of
annual global revenues, 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
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violations of the GDPR. Compliance with the GDPR will be a rigorous and time-intensive process that may increase the cost of doing business or require
companies to change their business practices to ensure full compliance.
Brexit and the Regulatory Framework in the United Kingdom
On June 23, 2016, the electorate in the United Kingdom voted in favor of leaving the EU, commonly referred to as Brexit, and the United Kingdom
formally left the EU on January 31, 2020. There was a transition period during which EU pharmaceutical laws continued to apply to the United Kingdom,
which expired on December 31, 2020. However, the EU and the United Kingdom have concluded a trade and cooperation agreement, or TCA, which was
provisionally applicable since January 1, 2021 and has been formally applicable since May 1, 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 with
EU regulations, however it is possible that these regimes will diverge 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.
Furthermore, the Data Protection Act of 2018 in the United Kingdom “implements” and complements the EU’s GDPR, and is effective in the United
Kingdom. On June 28, 2021, unless the European Commission adopted an adequacy decision in respect of transfers of personal data to the United
Kingdom for a four-year period (until 27 June 2025). Similarly, the United Kingdom has determined that it considers all of the EU and EEA Member States
to be adequate for the purposes of data protection. This ensures data flows between the United Kingdom and the EU and EEA remain unaffected.
Pricing Decisions for Approved Products
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. Some countries may require the completion of additional studies that compare the cost-effectiveness of a
particular product candidate to currently available therapies or so-called health technology assessments, in order to obtain reimbursement or pricing
approval. For example, EU Member States have the option to restrict the range of products for which their national health insurance systems provide
reimbursement and to control the prices of medicinal products for human use. EU Member States may approve a specific price for a product or it may
instead adopt a system of direct or indirect controls on the profitability of the company placing the product on the market. Other EU Member States allow
companies to fix their own prices for products, but monitor and control prescription volumes and issue guidance to physicians to limit prescriptions.
Recently, many countries in the EU have increased the amount of discounts required on pharmaceuticals and these efforts could continue as countries
attempt to manage health care expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the EU. The downward
pressure on health care costs in general, particularly prescription products, has become intense.
As a result, increasingly high barriers are being erected to the entry of new products. Political, economic and regulatory developments may further
complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various EU
Member States, and parallel trade, i.e., arbitrage between low-priced and high-priced EU Member States, can further reduce prices. Special pricing and
reimbursement rules may apply to orphan drugs. Inclusion of orphan drugs in reimbursement systems tend to focus on the medical usefulness, need, quality
and economic benefits to patients and the healthcare system as for any drug. Acceptance of any medicinal product for reimbursement may come with cost,
use and often volume restrictions, which again can vary by country. In addition, results-based rules of reimbursement may apply. 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 products, if approved in those countries.
The delivery of healthcare in the EU, including the establishment and operation of health services and the pricing and reimbursement of medicines,
is almost exclusively a matter for national, rather than EU, law and policy. National governments and health service providers have different priorities and
approaches to the delivery of healthcare and the pricing and reimbursement of products in that context. In general, however, the healthcare budgetary
constraints in most EU Member States have resulted in restrictions on the pricing and reimbursement of medicines by relevant health service providers.
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Human Capital Management
Our Mission & Our Employees
We launched with a bold vision to change the course of genetically defined diseases by treating them at their root cause. Our approach to drug
discovery generates significant insights into disease biology and allows us to think creatively about the best way to modulate and balance gene expression.
Our patient-focused product engine, FulcrumSeek, is designed to systematically identify and validate cellular drug targets that can modulate gene
expression to treat the known root cause of genetically defined diseases. We take great pride in being purposeful patient partners who do this work, not just
for patients, but with patients.
We view our employees as one of our most valuable assets in serving our mission. We believe that our future success is dependent on attracting,
motivating and retaining talented employees. We value the health and wellness of our employees and their families. We aim to create an equitable,
inclusive and empowering work environment in which our employees can grow and advance their careers, with the overall goal of developing, expanding
and retaining our workforce to support our current pipeline and future business goals. Our success also depends on our ability to attract, engage and retain a
diverse group of employees.
Our Behaviors Support Our Mission
We believe success comes when we and our employees align with our mission to improve the lives of patients with genetically-defined rare
diseases in areas of high unmet medical need. We are the FULcrew united around these Pillars:
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We take great pride in being Purposeful Patient Partners
We have a culture of Trust and Transparency
We are Invested in our People
We have a Playful spirit and have fun together at work
We launched Fulcrum with a Bold Scientific Vision and remain committed to this journey
Our Management of Human Capital
To effectively leverage and manage our peoples, we ensure our hiring needs are directly aligned with our strategy, we invest in our people focused
on their development and journey while at Fulcrum and most importantly we identify our key talent to ensure we are focused on their retention. We track
and report internally on key talent metrics including a focus on overall headcount and by function, hiring metrics, career development (promotions, etc.),
turnover trends, and employee demographics (including race, gender, ethnicity). Our senior executives use these metrics to make thoughtful decisions
around our people including resource planning, recruitment and retention initiatives and design of compensation and benefits programs. We share these
metrics quarterly with the senior executives and board of directors to assist it in fulfilling its duties to (a) establish our enterprise compensation philosophy,
(b) administer our compensation plans, (c) evaluate the performance of our executive officers and key employees and (d) review and monitor management
development and succession plans.
As of February 24,2022, we had 104 full-time employees, including a total of 41 employees with M.D. or Ph.D. degrees. Of these full-time
employees, 67 employees are engaged in research and development. None of our employees are represented by labor unions or covered by collective
bargaining agreements. We consider our relationship with our employees to be good.
Our Commitment to Diversity, Equity & Inclusion
We strongly believe in a diverse workplace where all our employees can thrive in an inclusive environment free from discrimination, harassment,
bias and prejudice. We aim to treat all individuals with respect and dignity and to provide all our employees with equal opportunity and fair treatment based
on merit. By embracing diversity and inclusion, we create an organization committed to working together to develop innovative solutions in support of our
mission consistent with our values. We cultivate a culture and environment where different backgrounds and perspectives are not only respected and heard,
but embraced and celebrated. Not only is a diverse, equitable and inclusive mindset and culture critical to an engaged and committed workplace, but it is
also imperative to understanding and meeting the needs of the patients we seek to help with our medicines.
As we grow and mature, we look forward to establishing programs/metrics that support diversity, equity, inclusion, and belonging. We will focus
on continuing to bring more diversity talent to Fulcrum, creating an inclusive environment by creating awareness (speakers, etc.) and ensuring our
underrepresent employees are provided the right career opportunities.
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As of February 24, 2022, women accounted for approximate 49% of our full-time employees. As of February 24, 2022, our employee records
indicate that approximately 32% of our full-time U.S. employees identify as non-white.
Our Compensation & Benefits
Given the highly competitive nature of our industry and the importance of recruitment and retention to our success, we strive to furnish our
employees with what we believe is a very competitive and comprehensive total rewards package of compensation, benefits and services. This package
includes competitive compensation, including equity compensation, and comprehensive benefits program that provides resources to help employees
manage their health and well-being, finances, and life outside of work (promoting flexibility), including health insurance and dental care, vision insurance,
disability insurance, paid sick leave, a 401(k) plan, paid time off (inclusive of vacation, holidays, focus days) and employee assistance services.
Our Efforts to Address the COVID-19 Pandemic
Employee safety and wellbeing is of paramount importance to us in any year and was of particular focus in 2021 in light of the ongoing COVID-19
pandemic. In response to the pandemic, we have supported our employees to curb the COVID-19 pandemic through safety and communication efforts and
investments, which include:
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Creating a COVID-19 task force responsible for establishing COVID-19, safety protocols and regularly communicating updates to all
employees;
Decreasing density and increasing physical distancing in our facilities for employees working onsite using scheduling adjustments and
flexibility;
Adhering to robust cleaning protocols;
Providing on site testing ;
Requiring and providing masks to all onsite employees;
Proactively creating rigorous procedures to address actual and suspected COVID-19 cases and potential exposure; and
Being nimble reacting real time with a sense of urgency to anything that came our way to support our employees
Additionally, from time to time we have instituted additional programs during the pandemic to support our employees. We leveraged our weekly
company meeting to keep our employees connected on what was happening during the pandemic (managing expectations and listening to their needs) as
well as making employee connections (fun breakouts in the spirit of building relationships/connections). We also provided a subsidy for home office set-up,
flexibility to figure out work location/hours, and enhanced our employee assistance services (comprehensive mental health, work-life and management
services).
Corporate Information
Our principal executive office is located at 26 Landsdowne Street, Cambridge, MA 02139, and our telephone number is 617-651-8851. Our internet
website address is www.fulcrumtx.com. The information contained on, or that can be accessed through, our website is not a part of this Annual Report on
Form 10-K.
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Item 1A. Risk Factors.
Our future operating results could differ materially from the results described in this Annual Report on Form 10-K due to the risks and uncertainties
described below. You should consider carefully the following information about risks below in evaluating our business. If any of the following risks actually
occur, our business, financial conditions, results of operations and future growth prospects would likely be materially and adversely affected. In these
circumstances, the market price of our common stock would likely decline. In addition, we cannot assure investors that our assumptions and expectations
will prove to be correct. Important factors could cause our actual results to differ materially from those indicated or implied by forward-looking statements.
See “Cautionary Note Regarding Forward-Looking Statements” on page i of this Annual Report on Form 10-K for a discussion of some of the forward-
looking statements that are qualified by these risk factors. Factors that could cause or contribute to such differences include those factors discussed below.
Risks Related to our Financial Position and Need for Additional Capital
We have incurred significant losses since our inception. We expect to incur losses over the next several years and may never achieve or maintain
profitability.
Since inception, we have incurred significant operating losses. Our net loss was $80.8 million for the year ended December 31, 2021 and $70.8
million for the year ended December 31, 2020. As of December 31, 2021, we had an accumulated deficit of $302.5 million. To date, we have funded our
operations primarily from the sale of shares of our common stock in public offerings, a private placement, and in “at-the-market” offerings, or the ATM
Offering, through issuances of convertible preferred stock, and from upfront payments received under our collaboration and license agreements. We have
devoted substantially all of our financial resources and efforts to research and development, including clinical trials and preclinical studies. We are still in
the early stages of development of our product candidates, and we have not completed development of any product candidates. We expect to continue to
incur significant expenses and operating losses over the next several years. Our net losses may fluctuate significantly from quarter to quarter and year to
year. We anticipate that our expenses will increase substantially as we:
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continue our clinical development of losmapimod and FTX-6058;
continue our ongoing preclinical studies;
advance clinical-stage product candidates into later stage trials, such as a Phase 3 clinical trial of losmapimod for the treatment of FSHD;
pursue the discovery of drug targets for other genetically-defined rare diseases and the subsequent development of any resulting product
candidates;
seek regulatory approvals for any product candidates that successfully complete clinical trials;
scale up our manufacturing processes and capabilities, or arrange for a third party to do so on our behalf, to support our clinical trials of our
product candidates and commercialization of any of our product candidates for which we may obtain marketing approval;
establish a sales, marketing and distribution infrastructure to commercialize any products for which we may obtain regulatory approval;
acquire or in-license products, product candidates, technologies and/or data referencing rights;
make any milestone payments to affiliates of GSK, under our right of reference and license agreement with GSK upon the achievement of
specified clinical or regulatory milestones;
maintain, expand, enforce, defend and protect our intellectual property;
hire additional clinical, quality control and scientific personnel; and
add operational, financial and management information systems and personnel, including personnel to support our product development and
planned future commercialization efforts and our operations as a public company.
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To become and remain profitable, we must succeed in developing, and eventually commercializing, a product or products that generate significant
revenue. The ability to achieve this success will require us to be effective in a range of challenging activities, including completing preclinical testing and
clinical trials of our product candidates, discovering additional product candidates, obtaining regulatory approval for these product candidates and
manufacturing, marketing and selling any products for which we may obtain regulatory approval. We are only in the preliminary stages of most of these
activities. We may never succeed in these activities and, even if we do, may never generate revenues that are significant enough to achieve profitability.
Because of the numerous risks and uncertainties associated with pharmaceutical 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 profitability. Our expenses will increase if, among other things:
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we are required by the FDA, the EMA, or other regulatory authorities to perform trials or studies in addition to, or different than, those
expected;
there are any delays in completing our clinical trials or the development of any of our product candidates; or
there are any third-party challenges to our intellectual property or we need to defend against any intellectual property-related claim.
Even 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 depress the value of our company and could impair our ability to raise capital, expand our business, maintain our research and
development efforts, diversify our pipeline of product candidates or even continue our operations. A decline in the value of our company could also cause
our stockholders to lose all or part of their investment.
We will need substantial additional funding. If we are unable to raise capital when needed, we could be forced to delay, reduce or eliminate our product
development programs or commercialization efforts.
We expect to devote substantial financial resources to our ongoing and planned activities, particularly as we continue our ongoing and planned
clinical trials of losmapimod and FTX-6058, continue research and development and initiate additional clinical trials of, and seek regulatory approval for,
these and other product candidates. We expect our expenses to increase substantially in connection with our ongoing activities, particularly as we advance
our preclinical activities and clinical trials. In addition, if we obtain regulatory approval for any of our product candidates, we expect to incur significant
commercialization expenses related to product manufacturing, sales, marketing and distribution. Furthermore, we will incur additional costs associated with
operating as a public company. Accordingly, we will need to obtain substantial additional funding in connection with our continuing operations. If we are
unable to raise capital when needed or on acceptable terms, we could be forced to delay, reduce or eliminate our research and development programs or any
future commercialization efforts.
Our future capital requirements will depend on many factors, including:
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the progress, costs and results of our ongoing clinical trials of losmapimod and FTX-6058;
additional planned clinical trials, such as our planned Phase 1b clinical trial of FTX-6058 in select hemoglobinopathies, including ß-
thalassemia, and plans for a Phase 3 clinical trial of losmapimod for the treatment of FSHD;
the scope, progress, costs and results of discovery research, preclinical development, laboratory testing and clinical trials for our current
product candidates in additional indications or for any future product candidates that we may pursue;
the impact of the ongoing COVID-19 pandemic on our business and operations;
the number of and development requirements for other product candidates that we pursue;
the costs, timing and outcome of regulatory review of our product candidates;
our ability to enter into contract manufacturing arrangements for supply of active pharmaceutical ingredient, or API, and manufacture of our
product candidates and the terms of such arrangements;
the success of our collaborations with Acceleron and MyoKardia;
our ability to establish and maintain additional strategic collaborations, licensing or other arrangements and the financial terms of such
arrangements;
the payment or receipt of milestones, royalties and other collaboration-based revenues, if any;
the costs and timing of future commercialization activities, including product manufacturing, sales, marketing and distribution, for any of our
product candidates for which we may receive marketing approval;
the amount and timing of revenue, if any, received from commercial sales of our product candidates for which we receive marketing approval;
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the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property and
proprietary rights and defending any intellectual property-related claims; and
the extent to which we acquire or in-license other products, product candidates, technologies or data referencing rights.
As of December 31, 2021, we had cash, cash equivalents, and marketable securities of approximately $218.2 million. We believe that our cash, cash
equivalents, and marketable securities as of December 31, 2021 will enable us to fund our operating expenses and capital expenditure requirements into
2024. However, we have based this estimate on assumptions that may prove to be wrong, and our operating plan may change as a result of many factors
currently unknown to us. As a result, we could deplete our capital resources sooner than we currently expect.
Identifying potential product candidates and conducting preclinical testing and clinical trials is a time-consuming, expensive and uncertain process
that takes years to complete, and we may never generate the necessary data or results required to obtain regulatory approval and achieve product sales. In
addition, our product candidates, if approved, may not achieve commercial success. Commercial revenues, if any, will not be derived unless and until we
can achieve sales of products, which we do not anticipate 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. In addition, we may seek additional
capital due to favorable market conditions or strategic considerations, even if we believe we have sufficient funds for our current or future operating plans.
If adequate funds are not available to us on a timely basis, we may be required to delay, limit, reduce or terminate preclinical studies, clinical trials or other
development activities for one or more of our product candidates or discovery stage programs or delay, limit, reduce or terminate our establishment of sales
and marketing capabilities or other activities that may be necessary to commercialize our product candidates.
Raising additional capital may cause dilution to our stockholders, restrict our operations or require us to relinquish rights to our technologies or
product candidates.
Until such time, if ever, as we can generate substantial product revenues, we expect to finance our cash needs through a combination of equity
offerings, debt financings, collaborations, strategic alliances and marketing, distribution or licensing arrangements. We do not have any committed external
source of funds. To the extent that we raise additional capital through the sale of equity or convertible debt securities, our stockholders’ ownership interests
will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect our stockholders’ rights as common
stockholders. Debt financing and preferred equity financing, if available, may involve agreements that include covenants limiting or restricting our ability
to take specific actions, such as incurring additional debt, selling or licensing our assets, making capital expenditures or declaring dividends.
If we raise additional funds through collaborations, strategic alliances or marketing, distribution or licensing arrangements with third parties, we
may have to relinquish valuable rights to our technologies, future revenue streams, research programs or product candidates or grant licenses on terms that
may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to delay, limit,
reduce or terminate our product development or future commercialization efforts or grant rights to develop and market product candidates that we would
otherwise prefer to develop and market ourselves.
Our limited operating history may make it difficult for stockholders to evaluate the success of our business to date and to assess our future viability.
We commenced activities in 2015 and are an early-stage company. Our operations to date have been limited to organizing and staffing our company,
business planning, raising capital, establishing our intellectual property, building our discovery platform, identifying drug targets and potential product
candidates, in-licensing assets, producing drug substance and drug product material for use in clinical trials and conducting preclinical studies and
conducting clinical trials. We have not yet demonstrated our ability to successfully develop any product candidate, obtain regulatory approvals,
manufacture a commercial scale product or arrange for a third party to do so on our behalf, or conduct sales and marketing activities necessary for
successful product commercialization. Consequently, any predictions stockholders make about our future success or viability may not be as accurate as they
could be if we had a longer operating history or a history of successfully developing and commercializing products.
In addition, as our business grows, we may encounter unforeseen expenses, difficulties, complications, delays and other known and unknown
factors. We will need to transition at some point from a company with a research and development focus to a company capable of supporting commercial
activities. We may not be successful in such a transition.
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We expect our financial condition and operating results to fluctuate significantly from quarter-to-quarter and year-to-year due to a variety of factors,
many of which are beyond our control. Accordingly, stockholders should not rely upon the results of any quarterly or annual periods as indications of future
operating performance.
The ongoing COVID-19 pandemic has and may continue to affect our ability to initiate and complete current or future preclinical studies or clinical
trials, disrupt regulatory activities or have other adverse effects on our business and operations. In addition, this pandemic may continue to adversely
impact economies worldwide, which could result in adverse effects on our business and operations.
In light of the COVID-19 pandemic, we and our CMOs and contract research organizations, or CROs, may face disruptions that may affect our
ability to initiate and complete preclinical studies or clinical trials, including disruptions in procuring items that are essential for our research and
development activities, including, for example, raw materials and API used in the manufacturing of our product candidates, and laboratory supplies for our
current and future preclinical studies and clinical trials, in each case, for which there may be shortages because of ongoing efforts to address the pandemic.
We and our CMOs and CROs, may face disruptions related to our planned and ongoing clinical trials or future clinical trials arising from delays in IND-
enabling studies, manufacturing disruptions, and the ability to obtain necessary institutional review board or other necessary site approvals, as well as
enrollment and other delays at clinical trial sites. For example, in response to the COVID-19 pandemic, the clinical trial sites for our ReDUX4 clinical trial
temporarily postponed trial-related activities, impacting our clinical trial execution plans. We may also face difficulties recruiting or retaining patients for
our planned and ongoing clinical trials if patients are affected by the virus or are fearful of visiting or traveling to clinical trial sites because of the
pandemic. In addition, since the beginning of the COVID-19 pandemic, three vaccines for COVID-19 have received Emergency Use Authorization by the
FDA and one of those later received marketing approval. Additional vaccines may be authorized or approved in the future. The resultant demand for
vaccines and potential for manufacturing facilities and materials to be commandeered under the Defense Production Act of 1950, or equivalent foreign
legislation, may make it more difficult to obtain materials or manufacturing slots for the products needed for our clinical trials, which could lead to further
delays in these trials. The response to the ongoing COVID-19 pandemic may redirect resources with respect to regulatory and intellectual property matters
in a way that would adversely impact our ability to progress regulatory approvals and protect our intellectual property. In addition, we may face
impediments to regulatory meetings and approvals due to measures intended to limit in-person interactions.
Additionally, the impact of the ongoing COVID-19 pandemic in Massachusetts resulted in a temporary reduction in workforce presence at our
Cambridge research facility. While we increased workforce presence at our facilities starting in the second quarter of 2020, not all employees have returned
to our facility and we cannot be certain that we will not be required to close our facilities in the future as a result of the ongoing COVID-19 pandemic. A
closure of our facility may substantially impact our discovery and translational activities and may delay the experimentation needed to identify novel drug
targets, prosecute such targets, identify development candidates for such targets and identify biomarkers that inform the potential clinical development
paths for such targets. Moreover, discovery and implementation of clinical biomarker assays for ongoing clinical trials may be delayed. Furthermore, any
negative impact that the ongoing pandemic has on the ability of our CROs to deliver data sets and execute on experimentation could cause substantial
delays for our discovery activities and materially impact our ability to fuel our pipeline with new product candidates.
The ongoing COVID-19 pandemic has already caused significant disruptions in the financial markets, and may continue to cause such disruptions,
which could impact our ability to raise additional funds through public offerings and may also impact the volatility of our stock price and trading in our
stock. Moreover, it is possible the pandemic will continue to significantly impact economies worldwide, which could result in adverse effects on our
business and operations. We cannot be certain what the overall impact of the ongoing COVID-19 pandemic will be on our business. The extent of the
impact of COVID-19 on our business, financial condition, results of operations and prospects will depend on future developments that are highly uncertain,
including as a result of new information that may emerge concerning COVID-19 or any variant strains of the virus and actions to be taken to contain or
mitigate the impact of COVID-19, including the supply, distribution and effectiveness of vaccines.
Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.
The rules dealing with U.S. federal, state, and local income taxation are constantly under review by persons involved in the legislative process and
by the Internal Revenue Service and the U.S. Treasury Department. Changes to tax laws (which changes may have retroactive application), including with
respect to net operating losses and research and development tax credits, could adversely affect us or holders of our common stock. In recent years, many
such changes have been made and changes are likely to continue to occur in the future. Future changes in tax laws could have a material adverse effect on
our
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business, cash flow, financial condition or results of operations. We urge investors to consult with their legal and tax advisers regarding the implications of
potential changes in tax laws on an investment in our common stock.
Our ability to use our net operating losses and research and development tax credit carryforwards to offset future taxable income may be subject to
certain limitations.
As of December 31, 2021, we had federal and state net operating loss carryforwards of $245.8 million and $244.0 million, respectively, which begin
to expire in 2036. Approximately $214.8 million of the federal net operating losses can be carried forward indefinitely. As of December 31, 2021, we also
had federal orphan drug credits of $6.7 million, which begin to expire in 2040. As of December 31, 2021, we also had federal and state research and
development tax credit carryforwards of $6.1 million and $3.3 million, respectively, which begin to expire in 2035 and 2030, respectively. These net
operating loss and tax credit carryforwards could expire unused and be unavailable to offset future income tax liabilities.
In general, under Section 382 of the U.S. Internal Revenue Code of 1986, as amended, or the Code, and corresponding provisions of state law, a
corporation that undergoes an “ownership change,” which is generally defined as a greater than 50% change, by value, in its equity ownership by certain
stockholders over a three-year period, is subject to limitations on its ability to utilize its pre-change net operating losses and research and development tax
credit carryforwards to offset future taxable income. We have not conducted a study to assess whether any such ownership changes have occurred. We may
have experienced such ownership changes in the past and may experience such ownership changes in the future (which may be outside our control). As a
result, if, and to the extent that, we earn net taxable income, our ability to use our pre-change net operating losses and research and development tax credit
carryforwards to offset such taxable income may be subject to limitations. Our net operating losses or credits may also be impaired under state law.
We have a history of cumulative losses and anticipate that we will continue to incur significant losses in the foreseeable future; thus, we do not know
whether or when we will generate taxable income necessary to utilize our net operating losses or research and development tax credit carryforwards.
Risks Related to the Discovery and Development of our Product Candidates
We are early in our development efforts, and we only have two product candidates in clinical trials. If we are unable to commercialize our product
candidates or experience significant delays in doing so, our business will be materially harmed.
We are early in our development efforts, and we have advanced only two product candidates into clinical trials, losmapimod for the treatment of
FSHD, and FTX-6058 for the treatment of SCD and select hemoglobinopathies. We have invested substantially all of our efforts and financial resources in
our proprietary product engine to identify and validate cellular drug targets that can potentially modulate gene expression to address the root cause of
genetically-defined rare diseases. Our ability to generate product revenues, which we do not expect will occur for many years, if ever, will depend heavily
on the successful development, regulatory approval and eventual commercialization of our product candidates. The success of our product candidates will
depend on several factors, including the following:
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successfully completing preclinical studies and clinical trials;
allowance by the FDA or other regulatory agencies of the INDs, clinical trial applications, or CTAs, or other regulatory filings for losmapimod,
FTX-6058 and future product candidates;
expanding and maintaining a workforce of experienced scientists and others to continue to develop our product candidates;
applying for and receiving marketing approvals from applicable regulatory authorities;
obtaining and maintaining intellectual property protection and regulatory exclusivity for our product candidates;
making arrangements with third-party manufacturers for, or establishing, commercial manufacturing capabilities;
establishing sales, marketing and distribution capabilities and successfully launching commercial sales of the products, if and when approved,
whether alone or in collaboration with others;
acceptance of the products, if and when approved, by patients, the medical community and third-party payors;
effectively competing with other therapies;
obtaining and maintaining coverage, adequate pricing and adequate reimbursement from third-party payors, including government payors;
maintaining, enforcing, defending and protecting our rights in our intellectual property portfolio;
not infringing, misappropriating or otherwise violating others’ intellectual property or proprietary rights; and
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maintaining a continued acceptable safety profile of the products following receipt of any regulatory approvals.
If we do not achieve one or more of these factors in a timely manner or at all, we could experience significant delays or an inability to successfully
develop and commercialize our product candidates, which would materially harm our business.
We may not be successful in our efforts to use our product engine to build a pipeline of product candidates.
A key element of our strategy is to use our proprietary product engine to identify and validate cellular drug targets that can potentially modulate
gene expression to address the root cause of genetically-defined rare diseases, with an initial focus on identifying small molecules specific to the identified
cellular target. Even if we are successful in identifying drug targets and potential product candidates, such candidates that we identify may not be suitable
for clinical development, including as a result of being shown to have harmful side effects or other characteristics that indicate that they are unlikely to
receive marketing approval and achieve market acceptance. Identifying, developing, obtaining regulatory approval for and commercializing additional
product candidates will require substantial additional funding and is prone to the risks of failure inherent in product development. We cannot provide
stockholders any assurance that we will be able to successfully identify additional product candidates with our product engine, including as a result of our
collaborations with Acceleron and MyoKardia, advance any additional product candidates through the development process or successfully commercialize
any such additional product candidates. Regulatory authorities have substantial discretion in the approval process and may cause delays in the approval or
rejection of an application. As a result of these factors, it is difficult for us to predict the time and cost of product candidate development. There can be no
assurance that any development problems we experience in the future related to our proprietary product engine or any of our research or development
programs will not cause significant delays or unanticipated costs, or that such development problems can be solved. If we do not successfully identify,
develop, obtain regulatory approval for and commercialize product candidates based upon our technological approach, we will not be able to generate
product revenues.
Clinical drug development involves a lengthy and expensive process, with an uncertain outcome. The results of preclinical studies and early clinical
trials may not be predictive of future results. We may incur additional costs or experience delays in completing, or ultimately be unable to complete, the
development and commercialization of our product candidates.
We have two product candidates in clinical development. The risk of failure for each of our product candidates is high. It is impossible to predict
when or if any of our product candidates will prove effective or safe in humans or will receive regulatory approval. Before obtaining marketing approval
from regulatory authorities for the sale of any product candidate, we must complete preclinical development and then conduct extensive clinical trials to
demonstrate the safety and efficacy of our product candidates in humans. We have not yet completed a pivotal clinical trial of any product candidate.
Clinical trials may fail to demonstrate that our product candidates are safe for humans and effective for indicated uses. Even if the clinical trials are
successful, changes in marketing approval policies during the development period, changes in or the enactment or promulgation of additional statutes,
regulations or guidance or changes in regulatory review for each submitted product application may cause delays in the approval or rejection of an
application.
Before we can commence clinical trials for a product candidate, we must complete extensive preclinical testing and studies that support our planned
INDs and other regulatory filings in the United States and abroad. We cannot be certain of the timely completion or outcome of our preclinical testing and
studies and cannot predict if the FDA or other regulatory agencies will accept our proposed clinical programs or if the outcome of our preclinical testing
and studies will ultimately support the further development of our current or future product candidates. As a result, we cannot be sure that we will be able
to submit INDs or similar applications for our preclinical programs on the timelines we expect, if at all, and we cannot be sure that submission of INDs or
similar applications will result in the FDA or other regulatory authorities allowing clinical trials to begin. Furthermore, product candidates are subject to
continued preclinical safety studies, which may be conducted concurrent with our clinical testing. The outcomes of these safety studies may delay the
launch of or enrollment in future clinical trials and could impact our ability to continue to conduct our clinical trials.
Clinical testing is expensive, difficult to design and implement, can take many years to complete and is uncertain as to outcome. We cannot
guarantee that any clinical trials will be conducted as planned or completed on schedule, or at all. A failure of one or more clinical trials can occur at any
stage of testing, which may result from a multitude of factors, including, but not limited to, flaws in study design, dose selection issues, placebo effects,
patient enrollment criteria and failure to demonstrate favorable safety or efficacy traits. The outcome of preclinical testing and early clinical trials may not
be predictive of the success of later clinical trials, and preliminary or interim results of a clinical trial do not necessarily predict final results. For example,
our product candidates may fail to show the desired safety and efficacy in clinical development despite positive results in preclinical studies or having
successfully advanced through initial clinical trials. A lack of clinical benefit may be due to insufficient dosing or for other reasons. Many companies in the
pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials even after achieving promising results in
preclinical testing and earlier-stage clinical trials, and we cannot be certain that we will not face similar setbacks. Moreover, preclinical and clinical data are
often susceptible to varying interpretations and analyses, and many companies that have believed their
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product candidates performed satisfactorily in preclinical studies and clinical trials have nonetheless failed to obtain marketing approval of their products.
Furthermore, the failure of any of our product candidates to demonstrate safety and efficacy in any clinical trial could negatively impact the perception of
our other product candidates and/or cause the FDA or other regulatory authorities to require additional testing before approving any of our product
candidates.
As described in Item 1 “Business—Licenses and Collaborations--Right of Reference and License Agreement with GlaxoSmithKline” of this Annual
Report on Form 10-K, we have entered into a right of reference and license agreement, as amended, with affiliates of GSK. Although losmapimod was
originally evaluated by GSK in nearly 3,600 subjects, GSK did not evaluate losmapimod in FSHD or in any other muscular dystrophy, and most of the
subjects in these trials were given a dose that was lower than our planned dosage of 15 mg of losmapimod twice per day. Accordingly, the safety data
generated from GSK’s clinical trials of losmapimod may not be predictive or indicative of the results of our clinical trials. Similarly, while we believe the
safety data from GSK’s clinical trials may, in part, support the safety database for losmapimod, GSK evaluated a limited number of subjects at a dose of 15
mg twice daily.
We may experience numerous unforeseen events during, or as a result of, clinical trials that could delay or prevent our ability to receive marketing
approval or commercialize our product candidates, including:
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regulators or institutional review boards, or IRBs, may not authorize us or our investigators to commence a clinical trial or conduct a clinical
trial at a prospective trial site;
we may experience delays in reaching, or fail to reach, agreement on acceptable clinical trial contracts or clinical trial protocols with
prospective trial sites;
regulators may decide the design of our clinical trials is flawed, for example if our trial protocol does not evaluate treatment effects in trial
subjects for a sufficient length of time;
clinical trials of our product candidates may produce negative or inconclusive results, and we may decide, or regulators may require us, to
conduct additional clinical trials or abandon product development programs;
we may be unable to establish clinical endpoints that applicable regulatory authorities would consider clinically meaningful, or, if we seek
accelerated approval, biomarker efficacy endpoints that applicable regulatory authorities would consider likely to predict clinical benefit;
preclinical testing may produce results based on which we may decide, or regulators may require us, to conduct additional preclinical studies
before we proceed with certain clinical trials, limit the scope of our clinical trials, halt ongoing clinical trials or abandon product development
programs;
the number of patients required for clinical trials of our product candidates may be larger than we anticipate, enrollment in these clinical trials
may be slower than we anticipate or participants may drop out of these clinical trials at a higher rate than we anticipate;
our third-party contractors may fail to comply with regulatory requirements or meet their contractual obligations to us in a timely manner, or at
all;
we may decide, or regulators or IRBs may require us, to suspend or terminate clinical trials of our product candidates for various reasons,
including noncompliance with regulatory requirements or a finding that the participants are being exposed to unacceptable health risks;
regulators or IRBs may require us to perform additional or unanticipated clinical trials to obtain approval or we may be subject to additional
post-marketing testing requirements to maintain regulatory approval;
regulators may revise the requirements for approving our product candidates, or such requirements may not be as we anticipate;
the cost of clinical trials of our product candidates may be greater than we anticipate;
the supply or quality of our product candidates or other materials necessary to conduct clinical trials of our product candidates may be
insufficient or inadequate;
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our product candidates may have undesirable side effects or other unexpected characteristics, causing us or our investigators, regulators or
IRBs to suspend or terminate the trials;
unforeseen global instability, including political instability or instability from an outbreak of pandemic or contagious disease, such as the
ongoing COVID-19 pandemic, in or around the countries in which we conduct our clinical trials, could delay the commencement or rate of
completion of our clinical trials; and
regulators may withdraw their approval of a product or impose restrictions on its distribution, such as in the form of a risk evaluation and
mitigation strategy, or REMS.
For example, in response to the ongoing COVID-19 pandemic, the clinical trial sites for our ReDUX4 trial temporarily postponed trial-related
activities, impacting our clinical trial execution plans, and we cannot be certain that we will not face other postponements or similar difficulties in the
future.
If we are required to conduct additional clinical trials or other testing of our product candidates beyond those that we currently contemplate, if we
are unable to successfully complete clinical trials of our product candidates or other testing, if the results of these trials or tests are not positive or are only
modestly positive or if there are safety concerns, we may:
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be delayed in obtaining marketing approval for our product candidates;
not obtain marketing approval at all;
obtain approval for indications or patient populations that are not as broad as intended or desired;
obtain approval with labeling or a REMS that includes significant use or distribution restrictions or safety warnings;
be subject to additional post-marketing testing requirements; or
have the product removed from the market after obtaining marketing approval.
Our product development costs will also increase if we experience delays in testing or in obtaining marketing approvals. We do not know whether
any of our preclinical studies or clinical trials will begin as planned, will need to be restructured or will be completed on schedule, or at all. We may also
determine to change the design or protocol of one or more of our clinical trials, including to add additional patients or arms, which could result in increased
costs and expenses and/or delays. Significant preclinical study or clinical trial delays also could shorten any periods during which we may have the
exclusive right to commercialize our product candidates or allow our competitors to bring products to market before we do and impair our ability to
successfully commercialize our product candidates and may harm our business and results of operations.
Because we are developing some of our product candidates for the treatment of diseases in which there is limited clinical experience and, in some
cases, using new endpoints or methodologies, the FDA or other regulatory authorities may not consider the endpoints of our clinical trials to predict or
provide clinically meaningful results.
There are currently no therapies approved to treat FSHD, and there may be no therapies approved to treat the underlying causes of diseases that we
attempt to address or may address in the future. As a result, the design and conduct of a clinical trial or trials of the product candidates for the treatment of
these diseases may take longer, be more costly or be less effective as part of the novelty of development in these diseases. In some cases, we may use new
or novel endpoints or methodologies, such as RWS, which has not been proven for registration to our knowledge. The FDA or other regulatory authorities
have indicated support for RWS as a primary endpoint with additional supportive data but may not consider the endpoints of our clinical trial(s) to provide
clinically meaningful results, even where we believe such results are clinically meaningful. For example, we have met with regulators to discuss the design
of our future clinical trial and registration strategy for losmapimod for FSHD, including our proposed endpoints for REACH, but the regulators may require
additional data to support the RWS functional primary endpoint for full approval.
Even if the FDA does find our primary endpoint to be sufficiently validated and clinically meaningful, we may not achieve the pre-specified
endpoint to a magnitude, duration or degree of statistical significance in any pivotal or other clinical trials we may conduct for our product candidates.
Further, even if we do meet the primary endpoint, our trials may produce results that are unpredictable or inconsistent with the results of the other, more
traditional efficacy endpoints in the trials. The FDA also could ascribe substantial weight to other efficacy endpoints when interpreting the clinical trial
data, such that even if we achieve statistically significant results on our primary endpoint, the FDA may regard the failure to show a statistically significant
effect on our secondary efficacy endpoints as raising questions about the efficacy of the drug. The FDA also weighs the benefits of a product against its
risks and the FDA may view the efficacy results in the context of safety as not being supportive of approval. Other regulatory authorities in Europe and
other countries may make similar findings with respect to these endpoints.
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If we experience delays or difficulties in the enrollment of patients in clinical trials, our receipt of necessary regulatory approvals could be delayed or
prevented.
Identifying and qualifying patients to participate in clinical trials for our product candidates is critical to our success. Successful and timely
completion of clinical trials will require that we enroll a sufficient number of patients who remain in the trial until its conclusion. We may not be able to
initiate or continue clinical trials for our product candidates if we are unable to locate and enroll a sufficient number of eligible patients to participate in
these trials as required by the FDA or similar regulatory authorities outside of the United States. Because of our primary focus on genetically-defined rare
diseases, we may have difficulty enrolling a sufficient number of eligible patients.
Patient enrollment is affected by a variety of other factors, including:
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the prevalence and severity of the disease under investigation;
the eligibility criteria for the trial in question;
the perceived risks and benefits of the product candidate under trial;
the requirements of the trial protocols, including invasive procedures such as muscle biopsies;
the availability of existing treatments for the indications for which we are conducting clinical trials;
the ability to recruit clinical trial investigators with the appropriate competencies and experience;
the efforts to facilitate timely enrollment in clinical trials;
the patient referral practices of physicians;
the ability to monitor patients adequately during and after treatment;
the proximity and availability of clinical trial sites for prospective patients;
the conduct of clinical trials by competitors for product candidates that treat the same indications as our product candidates;
the ability to identify specific patient populations for biomarker-defined trial cohort(s); and
the cost to, or lack of adequate compensation for, prospective patients.
Our inability to locate and enroll a sufficient number of patients for our clinical trials would result in significant delays, could require us to abandon
one or more clinical trials altogether and could delay or prevent our receipt of necessary regulatory approvals.
Enrollment delays in our clinical trials may result in increased development costs for our product candidates, which would cause the value of our
company to decline and limit our ability to obtain additional financing.
If serious adverse events or unacceptable side effects are identified during the development of our product candidates, we may need to abandon or limit
our development of some of our product candidates.
If our product candidates are associated with serious adverse events or undesirable side effects in clinical trials or have characteristics that are
unexpected in clinical trials or preclinical testing, we may need to abandon their development or limit development to more narrow uses or subpopulations
in which the serious adverse events, undesirable side effects or other characteristics are less prevalent, less severe or more acceptable from a risk-benefit
perspective. In pharmaceutical development, many compounds that initially show promise in early-stage or clinical testing are later found to cause side
effects that delay or prevent further development of the compound.
Additionally, if results of our clinical trials reveal unacceptable side effects, we, the FDA or the IRBs at the institutions in which our studies are
conducted could suspend or terminate our clinical trials or the FDA or comparable foreign regulatory authorities could order us to cease clinical trials or
deny approval of our product candidates for any or all targeted indications. Treatment-related side effects could also affect patient recruitment or the ability
of enrolled patients to complete any of our clinical trials. If we elect or are forced to suspend or terminate any clinical trial of our product candidates, the
commercial prospects of such product candidate will be harmed, and our ability to generate product revenue from such product candidate will be delayed or
eliminated. Any of these occurrences could materially harm our business.
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If any of our product candidates receives marketing approval and we, or others, later discover that the drug is less effective than previously believed or
causes undesirable side effects that were not previously identified, our ability to market the drug could be compromised.
Clinical trials of our product candidates are conducted in carefully defined subsets of patients who have agreed to enter into clinical trials.
Consequently, it is possible that our clinical trials may indicate an apparent positive effect of a product candidate that is greater than the actual positive
effect, if any, or alternatively fail to identify undesirable side effects. If one or more of our product candidates receives regulatory approval, and we, or
others, later discover that they are less effective than previously believed, or cause undesirable side effects, a number of potentially significant negative
consequences could result, including:
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withdrawal or limitation by regulatory authorities of approvals of such product;
seizure of the product by regulatory authorities;
recall of the product;
restrictions on the marketing of the product or the manufacturing process for any component thereof;
requirement by regulatory authorities of additional warnings on the label, such as a “black box” warning or contraindication;
requirement that we implement a REMS or create a medication guide outlining the risks of such side effects for distribution to patients;
commitment to expensive post-marketing studies as a prerequisite of approval by regulatory authorities of such product;
the product may become less competitive;
initiation of regulatory investigations and government enforcement actions;
initiation of legal action against us to hold us liable for harm caused to patients; and
harm to our reputation and resulting harm to physician or patient acceptance of our products.
Any of these events could prevent us from achieving or maintaining market acceptance of a particular product candidate, if approved, and could
significantly harm our business, financial condition, and results of operations.
We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications
that may be more profitable or for which there is a greater likelihood of success.
Because we have limited financial and managerial resources, we are focusing our research and development efforts on rare neuromuscular,
muscular, hematologic and central nervous system disorders. As a result, we may forego or delay pursuit of opportunities with other product candidates or
for other indications that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable
commercial products or profitable market opportunities. Our spending on current and future research and development programs and product candidates for
specific indications may not yield any commercially viable products. If we do not accurately evaluate the commercial potential or target market for a
particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in
cases in which it would have been more advantageous for us to retain sole development and commercialization rights to such product candidate. Failure to
allocate resources or capitalize on strategies in a successful manner will have an adverse impact on our business.
We are conducting clinical trials of losmapimod in patients with FSHD in Europe and Canada and currently plan to conduct additional clinical trials
for our product candidates at sites outside the United States, and the FDA may not accept data from trials conducted in such locations.
We are currently conducting an open label extension of our Phase 2b clinical trial and of our Phase 2 open label clinical trial of losmapimod in
patients with FSHD in Europe and Canada. We may also conduct additional clinical trials outside the United States. Although the FDA may accept data
from clinical trials conducted outside the United States, acceptance of these data is subject to conditions imposed by the FDA. For example, the clinical
trial must be well designed and conducted and be 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, including GCP, and FDA’s ability to validate the data. If the FDA
does not accept the data from any trial that we
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conduct outside the United States, it would likely result in the need for additional trials, which would be costly and time-consuming and could delay or
permanently halt our development of the applicable product candidates.
Risks Related to the Commercialization of our Product Candidates
Even if any of our product candidates receives marketing approval, it may fail to achieve the degree of market acceptance by physicians, patients, third-
party payors and others in the medical community necessary for commercial success, and the market opportunity for any of our product candidates, if
approved, may be smaller than we estimate.
If any of our product candidates receives marketing approval, it may nonetheless fail to gain sufficient market acceptance by physicians, patients,
third-party payors and others in the medical community. Efforts to educate the medical community and third-party payors on the benefits of our product
candidates may require significant resources and may not be successful. If our product candidates do not achieve an adequate level of acceptance, we may
not generate significant product revenues and we may not become profitable. The degree of market acceptance of our product candidates, if approved for
commercial sale, will depend on a number of factors, including:
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the efficacy and potential advantages of our product candidates compared to the advantages and relative risks of alternative treatments;
the effectiveness of sales and marketing efforts;
the cost of treatment in relation to alternative treatments, including any similar generic treatments;
our ability to offer our products, if approved, for sale at competitive prices;
the clinical indications for which the product is approved;
the convenience and ease of administration compared to alternative treatments;
the willingness of the target patient population to try new therapies and of physicians to prescribe these therapies;
the strength of marketing and distribution support;
the timing of market introduction of competitive products;
the availability of third-party coverage and adequate reimbursement, and patients’ willingness to pay out of pocket for required co-payments or
in the absence of third-party coverage or adequate reimbursement;
the prevalence and severity of any side effects; and
any restrictions on the use of our products, if approved, together with other medications.
Our assessment of the potential market opportunity for our product candidates is based on industry and market data that we obtained from industry
publications and research, surveys and studies conducted by third parties, one of which we commissioned. Industry publications and third-party research,
surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the
accuracy or completeness of such information. While we believe these industry publications and third-party research, surveys and studies are reliable, we
have not independently verified such data. Our estimates of the potential market opportunities for our product candidates include several key assumptions
based on our industry knowledge, industry publications and third-party research, surveys and studies, which may be based on a small sample size and fail
to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no independent source has verified such
assumptions. If any of our assumptions or estimates, or these publications, research, surveys or studies prove to be inaccurate, then the actual market for
any of our product candidates may be smaller than we expect, and as a result our product revenue may be limited and it may be more difficult for us to
achieve or maintain profitability.
If we are unable to establish sales, marketing and distribution capabilities or enter into sales, marketing and distribution agreements with third parties,
we may not be successful in commercializing our product candidates if and when they are approved.
We do not have a sales or marketing infrastructure and have no experience in the sale, marketing or distribution of pharmaceutical products. To
achieve commercial success for any product for which we have obtained marketing approval, we will need to establish a sales, marketing and distribution
organization, either ourselves or through collaborations or other arrangements with third parties.
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In the future, we expect to build a focused, specialty sales and marketing infrastructure to market some of our product candidates in the United
States, if and when they are approved. There are risks involved with establishing our own sales, marketing and distribution capabilities. For example,
recruiting and training a sales force is expensive and time-consuming and could delay any product launch. If the commercial launch of a product candidate
for which we recruit a sales force and establish marketing capabilities is delayed or does not occur for any reason, we would have prematurely or
unnecessarily incurred these commercialization expenses. These efforts may be costly, and our investment would be lost if we cannot retain or reposition
our sales and marketing personnel.
Factors that may inhibit our efforts to commercialize our products on our own include:
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our inability to recruit, train and retain adequate numbers of effective sales, marketing, coverage or reimbursement, customer service, medical
affairs and other support personnel;
the inability of sales personnel to obtain access to physicians or persuade adequate numbers of physicians to prescribe any future products;
the inability of reimbursement professionals to negotiate arrangements for formulary access, reimbursement and other acceptance by payors;
the inability to price our products at a sufficient price point to ensure an adequate and attractive level of profitability;
restricted or closed distribution channels that make it difficult to distribute our products to segments of the patient population;
the lack of complementary products to be offered by sales personnel, which may put us at a competitive disadvantage relative to companies
with more extensive product lines; and
unforeseen costs and expenses associated with creating an independent sales and marketing organization.
If we are unable to establish our own sales, marketing and distribution capabilities and we enter into arrangements with third parties to perform these
services, our product revenues and our profitability, if any, are likely to be lower than if we were to market, sell and distribute any products that we develop
ourselves. In addition, we may not be successful in entering into arrangements with third parties to sell, market and distribute our product candidates or
may be unable to do so on terms that are acceptable to us. We likely will have little control over such third parties, and any of them may fail to devote the
necessary resources and attention to sell and market our products effectively. If we do not establish sales, marketing and distribution capabilities
successfully, either on our own or in collaboration with third parties, we will not be successful in commercializing our product candidates.
We face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully than we
do.
The development and commercialization of new drug products is highly competitive. We face competition with respect to our current product
candidates, and will face competition with respect to any product candidates that we may seek to develop or commercialize in the future, from major
pharmaceutical companies, specialty pharmaceutical companies and biotechnology companies worldwide. There are a number of large pharmaceutical and
biotechnology companies that currently market and sell products or are pursuing the development of products for the treatment of many of the disease
indications for which we are developing our product candidates. Some of these competitive products and therapies are based on scientific approaches that
are the same as or similar to our approach, and others are based on entirely different approaches. Potential competitors also include academic institutions,
government agencies and other public and private research organizations that conduct research, seek patent protection and establish collaborative
arrangements for research, development, manufacturing and commercialization.
For example, we are aware of several product candidates in clinical development that could be competitive with product candidates that we may
successfully develop and commercialize. bluebird, Aruvant Sciences, Inc., Novo Nordisk A/S, Imara, Inc., Agios Pharmaceuticals, Inc., Forma
Therapeutics Holdings, Inc., Global Blood Therapeutics, Inc., Takeda Pharmaceutical Company Limited, Pfizer, Inc., CSL Behring, Intellia Therapeutics,
Inc., Editas Medicine, Inc., Sangamo Therapeutics Inc., or Sangamo (in collaboration with Bioverativ Inc.) and CRISPR Therapeutics AG (in collaboration
with Vertex Pharmaceuticals, Inc.) are developing therapeutic approaches for patients with SCD. Acceleron (in collaboration with Celgene), Bellicum
Pharmaceuticals, Inc., Silence Therapeutics plcImara Inc., Agios Pharmaceuticals, Inc., Forma Therapeutics Holdings, Inc., Ionis Pharmaceuticals, Inc.,
Orchard Therapeutics plc, Sangamo (in collaboration with
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Bioverativ, Inc.) and CRISPR Therapeutics AG (in collaboration with Vertex Pharmaceuticals, Inc.) are developing therapeutic approaches for patients with
ß-thalassemia.
Our commercial opportunity could be reduced or eliminated if our 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. Our competitors also may obtain
FDA 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. In addition, our ability to compete may be affected in many cases by insurers or other third-
party payors seeking to encourage the use of generic products. If our product candidates achieve marketing approval, we expect that they will be priced at a
significant premium over competitive generic products.
Many of the companies against which we are competing or against which we may compete in the future have significantly greater financial
resources and expertise in research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and
marketing approved products than we do.
Mergers and acquisitions in the pharmaceutical and biotechnology industries may result in even more resources being concentrated among a smaller
number of our competitors. Smaller and other early-stage companies may also prove to be significant competitors, particularly through collaborative
arrangements with large and established companies. These third parties compete with us in recruiting and retaining qualified scientific and management
personnel, establishing clinical trial sites and patient registration for clinical trials, as well as in acquiring technologies complementary to, or necessary for,
our programs.
If the market opportunities for our product candidates are smaller than we believe they are, our revenue may be adversely affected, and our business
may suffer. Because certain of the target patient populations of our product candidates are small, and the addressable patient population even smaller,
we must be able to successfully identify patients and capture a significant market share to achieve profitability and growth.
We primarily focus our research and product development on treatments for genetically-defined rare diseases. Given the small number of patients
who have the rare diseases that we are targeting, it is critical to our ability to grow and become profitable that we continue to successfully identify patients
with these rare diseases. Our projections of both the number of people who have these diseases, as well as the subset of people with these diseases who
have the potential to benefit from treatment with our product candidates, are based on our beliefs and estimates. These estimates have been derived from a
variety of sources, including the scientific literature, surveys of clinics, patient foundations or market research that we conducted, and may prove to be
incorrect or contain errors. New studies may change the estimated incidence or prevalence of these diseases. The number of patients may turn out to be
lower than expected. The effort to identify patients with diseases we seek to treat is in early stages, and we cannot accurately predict the number of patients
for whom treatment might be possible. Additionally, the potentially addressable patient population for each of our product candidates may be limited or
may not be amenable to treatment with our product candidates, and new patients may become increasingly difficult to identify or gain access to, which
would adversely affect our results of operations and our business. Further, even if we obtain significant market share for our product candidates, because
the potential target populations for many of the indications we are evaluating are very small, we may never achieve profitability despite obtaining such
significant market share.
The target patient populations for some of the indications we are evaluating are relatively small, and there is currently no standard of care treatment
directed at some of our target indications, such as FSHD. As a result, the pricing and reimbursement of our product candidates, if approved, is uncertain,
but must be adequate to support commercial infrastructure. If we are unable to obtain adequate levels of reimbursement, our ability to successfully market
and sell our product candidates will be adversely affected.
We rely, and expect to continue to rely, on CMOs to manufacture our product candidates. If we are unable to enter into such arrangements as expected
or if such organizations do not meet our supply requirements, development and/or commercialization of our product candidates may be delayed.
We do not have any manufacturing facilities and rely, and expect to continue to rely, on third parties to manufacture clinical supplies of our product
candidates and we expect to rely on third parties to manufacture commercial supplies of our products, if and when approved for marketing by applicable
regulatory authorities, as well as for packaging, sterilization, storage, distribution and other production logistics. If we are unable to enter into such
arrangements on the terms or timeline we expect, development and/or commercialization of our product candidates may be delayed.
If these third parties do not successfully carry out their contractual duties, meet expected deadlines or manufacture our product candidates in
accordance with regulatory requirements, if there are disagreements between us and such parties or if such parties are unable to expand capacities to
support commercialization of any of our product candidates for which we obtain marketing approval, we may not be able to fulfill, or may be delayed in
producing sufficient product candidates to
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meet, our supply requirements, or we may be forced to manufacture the materials ourselves, for which we may not have the capabilities or resources, or
enter into an agreement with a different manufacturer, which we may not be able to do on reasonable terms, if at all. In either scenario, our clinical trial
supply could be delayed significantly as we establish alternative supply sources. In some cases, the technical skills required to manufacture our products or
product candidates may be unique or proprietary to the original manufacturer and we may have difficulty, or there may be contractual restrictions
prohibiting us from, transferring such skills to a back-up or alternate supplier, or we may be unable to transfer such skills at all.
In addition, if we are required to change manufacturers for any reason, we will be required to verify that the new manufacturer maintains facilities
and procedures that comply with quality standards and with all applicable regulations. We will also need to verify, such as through a manufacturing
comparability study, that any new manufacturing process will produce our product candidate according to the specifications previously submitted to the
FDA or another regulatory authority. The delays associated with the verification of a new manufacturer could negatively affect our ability to develop
product candidates or commercialize our products in a timely manner or within budget. Furthermore, a manufacturer may possess technology related to the
manufacture of our product candidate that such manufacturer owns independently. This would increase our reliance on such manufacturer or require us to
obtain a license from such manufacturer in order to have another manufacturer manufacture our product candidates. In addition, changes in manufacturers
often involve changes in manufacturing procedures and processes, which could require that we conduct bridging studies between our prior clinical supply
used in our clinical trials and that of any new manufacturer. We may be unsuccessful in demonstrating the comparability of clinical supplies which could
require the conduct of additional clinical trials. These facilities may also be affected by natural disasters, such as floods or fire, as well as public health
issues (for example, an outbreak of a contagious disease such as COVID-19), or such facilities could face manufacturing issues, such as contamination or
regulatory concerns following a regulatory inspection of such facility.
Our third-party manufacturers will be subject to inspection and approval by the FDA before we can commence the manufacture and sale of any of
our product candidates, and thereafter subject to FDA inspection from time to time. Failure by our third-party manufacturers to pass such inspections and
otherwise satisfactorily complete the FDA approval regimen with respect to our product candidates may result in regulatory actions such as the issuance of
FDA Form 483 notices of observations, warning letters or injunctions or the loss of operating licenses.
We or our third-party manufacturers may also encounter shortages in the raw materials or API necessary to produce our product candidates in the
quantities needed for our clinical trials or, if our product candidates are approved, in sufficient quantities for commercialization or to meet an increase in
demand, as a result of capacity constraints or delays or disruptions in the market for the raw materials or API, including shortages caused by the purchase
of such raw materials or API by our competitors or others. The failure of us or our third-party manufacturers to obtain the raw materials or API necessary to
manufacture sufficient quantities of our product candidates, may have a material adverse effect on our business.
Our reliance on third parties increases the risk that we will not have sufficient quantities of our product candidates or products or such quantities at an
acceptable cost or quality, which could delay, prevent or impair our development or commercialization efforts.
We do not have any manufacturing facilities. Although we believe we have obtained sufficient losmapimod tablets from GSK to complete our
ongoing Phase 2 clinical trials of losmapimod for the treatment of FSHD, we cannot be sure we have correctly estimated our drug product and API
requirements or that such drug product or API will not expire before we want to use it. We have also engaged CMOs to prepare our own API and to
manufacture losmapimod tablets. Although we believe we have produced sufficient losmapimod tablets to complete our planned Phase 3 registrational trial,
we cannot be sure we have correctly estimated our drug product and API requirements or that such drug product or API will not expire before we want to
use it. In addition, although we believe we have obtained sufficient quantities of FTX-6058 from a CMO for the completion of our ongoing Phase 1 clinical
trial, our ongoing Phase 1b clinical trial for SCD, and our planned Phase 1b trial in non-SCD hemoglobinopathies, including ß-thalassemia, we cannot be
sure we have correctly estimated our drug product requirements, which could delay, prevent or impair our development efforts.
We expect to rely on third parties for the manufacture of FTX-6058 for any future clinical trials and for the manufacture of any future product
candidates for preclinical and clinical testing. We also expect to rely on third-party manufacturers or third-party collaborators for the manufacture of
commercial supply of any other product candidates for which we or our collaborators obtain marketing approval. This reliance on third parties increases the
risk that we will not have sufficient quantities of our product candidates or products or such quantities at an acceptable cost or quality, which could delay,
prevent or impair our development or commercialization efforts.
Our product candidates and any products that we may develop may compete with other product candidates and products for access to manufacturing
facilities. There are a limited number of manufacturers that operate under cGMP regulations and that might be capable of manufacturing for us.
Any performance failure on the part of our existing or future manufacturers could delay clinical development or marketing approval. We do not
currently have arrangements in place for redundant supply or a source for bulk drug
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substance. If any of our future contract manufacturers cannot perform as agreed, we may be required to replace such manufacturers. Although we believe
that there are several potential alternative manufacturers who could manufacture our product candidates, we may incur added costs and delays in
identifying and qualifying any such replacement.
Our current and anticipated future dependence upon others for the manufacture of our product candidates or products may adversely affect our
future profit margins and our ability to commercialize any products that receive marketing approval on a timely and competitive basis.
Even if we are able to commercialize any product candidates, the products may become subject to unfavorable pricing regulations, third-party coverage
or reimbursement practices or healthcare reform initiatives, which could harm our business.
The regulations that govern marketing approvals, pricing, coverage and reimbursement for new drug products vary widely from country to country.
Current and future legislation may significantly change the approval requirements in ways that could involve additional costs and cause delays in obtaining
approvals. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after
marketing or product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing
governmental control even after initial approval is granted. As a result, we might obtain marketing approval for a product in a particular country, but then
be subject to price regulations that delay our commercial launch of the product, possibly for lengthy time periods, and negatively impact the revenues we
are able to generate from the sale of the product in that country. Adverse pricing limitations may hinder our ability to recoup our investment in one or more
product candidates, even if our product candidates obtain marketing approval. See the section entitled “Business — Pharmaceutical Insurance Coverage
and Health Care Reform”.
Our ability to commercialize any product candidates successfully also will depend in part on the extent to which coverage and adequate
reimbursement for these products and related treatments will be available from government health administration authorities, private health insurers and
other organizations. Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which
medications they will pay for and establish reimbursement levels. A primary trend in the U.S. healthcare industry and elsewhere is cost containment.
Government authorities and third-party payors have attempted to control costs by limiting coverage and the amount of reimbursement for particular
medications. Increasingly, third-party payors are requiring that drug companies provide them with predetermined discounts from list prices and are
challenging the prices charged for medical products. Coverage and reimbursement may not be available for any product that we commercialize and, even if
these are available, the level of reimbursement may not be satisfactory. Reimbursement may affect the demand for, or the price of, any product candidate
for which we obtain marketing approval. Obtaining and maintaining adequate reimbursement for our products may be difficult. We may be required to
conduct expensive pharmacoeconomic studies to justify coverage and reimbursement or the level of reimbursement relative to other therapies. If coverage
and adequate reimbursement are not available or reimbursement is available only to limited levels, we may not be able to successfully commercialize any
product candidate for which we obtain marketing approval. Coverage and reimbursement by a third-party payor may depend upon a number of factors,
including the third-party payor’s determination that use of a product is:
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a covered benefit under its health plan;
safe, effective and medically necessary;
appropriate for the specific patient;
cost-effective; and
neither experimental nor investigational.
There may be significant delays in obtaining coverage and reimbursement for newly approved drugs, and coverage may be more limited than the
purposes for which the drug is approved by the FDA or similar regulatory authorities outside of the United States. Moreover, eligibility for coverage and
reimbursement does not imply that a drug will be paid for in all cases or at a rate that covers our costs, including research, development, manufacture, sale
and distribution expenses. Interim reimbursement levels for new drugs, if applicable, may also not be sufficient to cover our costs and may not be made
permanent. Reimbursement rates may vary according to the use of the drug and the clinical setting in which it is used, may be based on reimbursement
levels already set for lower cost drugs and may be incorporated into existing payments for other services. Net prices for drugs may be reduced by
mandatory discounts or rebates required by government healthcare programs or private payors and by any future relaxation of laws that presently restrict
imports of drugs from countries where they may be sold at lower prices than in the United States. Third-party payors often rely upon Medicare coverage
policy and payment limitations in setting their own reimbursement policies. Our inability to promptly obtain coverage and adequate
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reimbursement rates from both government-funded and private payors for any approved products that we develop could have a material adverse effect on
our operating results, our ability to raise capital needed to commercialize products and our overall financial condition.
There can be no assurance that our product candidates, even if they are approved for sale in the United States or in other countries, will be
considered medically reasonable and necessary for a specific indication or cost-effective by third-party payors, or that coverage and an adequate level of
reimbursement will be available or that third-party payors’ reimbursement policies will not adversely affect our ability to sell our product candidates
profitably.
Our future growth depends, in part, on our ability to penetrate foreign markets, where we would be subject to additional regulatory burdens and other
risks and uncertainties that, if they materialize, could harm our business.
Our future profitability will depend, in part, on our ability to commercialize our product candidates in markets outside of the United States and the
European Union. If we commercialize our product candidates in foreign markets, we will be subject to additional risks and uncertainties, including:
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economic weakness, including inflation, or political instability in particular economies and markets;
the burden of complying with complex and changing foreign regulatory, tax, accounting and legal requirements, many of which vary between
countries;
different medical practices and customs in foreign countries affecting acceptance in the marketplace;
tariffs and trade barriers, as well as other governmental controls and trade restrictions;
other trade protection measures, import or export licensing requirements or other restrictive actions by U.S. or foreign governments;
longer accounts receivable collection times;
longer lead times for shipping;
compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;
workforce uncertainty in countries where labor unrest is common;
language barriers for technical training;
reduced protection of intellectual property rights in some foreign countries, and related prevalence of generic alternatives to therapeutics;
foreign currency exchange rate fluctuations and currency controls;
differing foreign reimbursement landscapes;
uncertain and potentially inadequate reimbursement of our products; and
the interpretation of contractual provisions governed by foreign laws in the event of a contract dispute.
If risks related to any of these uncertainties materializes, it could have a material adverse effect on our business.
Clinical trial and product liability lawsuits against us could divert our resources and could cause us to incur substantial liabilities and to limit
commercialization of any products that we may develop.
We face an inherent risk of clinical trial and product liability exposure related to the testing of our product candidates in human clinical trials, and
we will face an even greater risk if we commercially sell any products that we may develop. While we currently have no products that have been approved
for commercial sale, the current and future use of product candidates by us in clinical trials, and the sale of any approved products in the future, may expose
us to liability claims. These claims might be made by patients that use the product, healthcare providers, pharmaceutical companies or others selling such
products. If we cannot successfully defend ourselves against claims that our product candidates or products caused injuries, we will incur substantial
liabilities. Regardless of merit or eventual outcome, liability claims may result in:
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decreased demand for any product candidates or products that we may develop;
injury to our reputation and significant negative media attention;
withdrawal of clinical trial participants;
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significant costs to defend any related litigation;
substantial monetary awards to trial participants or patients;
loss of revenue;
reduced resources of our management to pursue our business strategy; and
the inability to commercialize any products that we may develop.
We currently hold $10 million in clinical trial liability insurance coverage in the aggregate, with a per incident limit of $10 million, which may not
be adequate to cover all liabilities that we may incur. We may need to increase our insurance coverage as we expand our clinical trials or if we commence
commercialization of our product candidates. Insurance coverage is increasingly expensive. We may not be able to maintain insurance coverage at a
reasonable cost or in an amount adequate to satisfy any liability that may arise. If a successful clinical trial or product liability claim or series of claims is
brought against us for uninsured liabilities or in excess of insured liabilities, our assets may not be sufficient to cover such claims and our business
operations could be impaired.
Risks Related to our Dependence on Third Parties
We rely, and expect to continue to rely, on third parties to conduct our clinical trials, and those third parties may not perform satisfactorily, including
failing to meet deadlines for the completion of such trials, which may harm our business.
We currently rely on third-party contract CROs to conduct our ongoing clinical trials of losmapimod and FTX-6058. We plan to rely on third-party
CROs or third-party research collaboratives to conduct any future clinical trials. We do not plan to independently conduct clinical trials of our other product
candidates. We expect to continue to rely on third parties, such as CROs, clinical data management organizations, medical institutions and clinical
investigators, to conduct our clinical trials. These agreements might terminate for a variety of reasons, including a failure to perform by the third parties. If
we need to enter into alternative arrangements, our product development activities might be delayed.
Our reliance on these third parties for research and development activities will reduce our control over these activities but will not relieve us of our
responsibilities.
If these third parties do not successfully carry out their contractual duties, meet expected deadlines or conduct our clinical trials in accordance with
regulatory requirements or our stated protocols, we will not be able to obtain, or may be delayed in obtaining, marketing approvals for our product
candidates and will not be able to, or may be delayed in our efforts to, successfully develop and commercialize our product candidates. Furthermore, these
third parties may also have relationships with other entities, some of which may be our competitors.
We also rely, and expect to continue to rely on other third parties to store and distribute drug supplies for our clinical trials. Any performance failure
on the part of our distributors could delay clinical development or marketing approval of our product candidates or commercialization of our products,
producing additional losses and depriving us of potential product revenue.
We have entered into, and may in the future enter into, collaborations with third parties for the discovery, development or commercialization of our
product candidates. If our collaborations are not successful, we may not be able to capitalize on the market potential of these product candidates and
our business could be adversely affected.
We have collaboration and license agreements with Acceleron (with a targeted indication within the pulmonary disease space) and MyoKardia (for
certain genetically defined cardiomyopathies). See “Business—License Agreements and Collaborations”. While we have retained all rights to and are
developing on our own our current product candidates, we may in the future enter into development, distribution or marketing arrangements with third
parties with respect to our other existing or future product candidates. Our likely collaborators for any such sales, marketing, distribution, development,
licensing or broader collaboration arrangements include large and mid-size pharmaceutical companies, regional and national pharmaceutical companies and
biotechnology companies. If we enter into any such arrangements with any third parties in the future, we will likely have limited control over the amount
and timing of resources that our collaborators dedicate to the development or commercialization of our product candidates. Our ability to generate revenues
from these arrangements will depend on our collaborators’ abilities and efforts to successfully perform the functions assigned to them in these
arrangements.
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Collaborations that we enter into, including our collaborations with Acceleron and MyoKardia, may not be successful, and any success will depend
heavily on the efforts and activities of such collaborators. Collaborations pose a number of risks, including the following:
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collaborators have significant discretion in determining the amount and timing of efforts and resources that they will apply to these
collaborations;
collaborators may not perform their obligations as expected;
collaborators may not pursue development of our product candidates or may elect not to continue or renew development programs based on
results of clinical trials or other studies, changes in the collaborators’ strategic focus or available funding, or external factors, such as an
acquisition, that divert resources or create competing priorities;
collaborators may not pursue commercialization of any product candidates that achieve regulatory approval or may elect not to continue or
renew commercialization programs based on results of clinical trials or other studies, changes in the collaborators’ strategic focus or available
funding, or external factors, such as an acquisition, that may divert resources or create competing priorities;
collaborators may delay clinical trials, provide insufficient funding for a clinical trial program, 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 stockholders about the status of such product
candidates on a discretionary basis;
collaborators could independently develop, or develop with third parties, products that compete directly or indirectly with our product
candidates and products if the collaborators believe that the competitive products are more likely to be successfully developed or can be
commercialized under terms that are more economically attractive than ours;
product candidates discovered 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 may fail to comply with applicable regulatory requirements regarding the development, manufacture, distribution or marketing
of a product candidate or product;
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 such product or products;
disagreements with collaborators, including disagreements over intellectual property or proprietary rights, contract interpretation or the
preferred course of development, might cause delays or terminations of the research, development or commercialization of product candidates,
might lead to additional responsibilities for us with respect to product candidates, or might result in litigation or arbitration, any of which
would be time-consuming and expensive;
collaborators may not properly obtain, maintain, enforce, defend or protect our intellectual property or proprietary rights or may use our
proprietary information in such a way as to potentially lead to disputes or legal proceedings 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, misappropriate or otherwise violate the intellectual property or proprietary 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.
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Collaboration agreements may not lead to development or commercialization of product candidates in the most efficient manner, or at all. If any
collaborations that we enter into 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 the collaboration. If we do not receive the
funding we expect under these agreements, our development of our product candidates could be delayed and we may need additional resources to develop
our product candidates. All of the risks relating to product development, regulatory approval and commercialization described herein also apply to the
activities of our collaborators.
Additionally, subject to its contractual obligations to us, if a collaborator of ours is involved in a business combination, the collaborator might
deemphasize or terminate the development or commercialization of any product candidate licensed to it by us. For example, in November 2020, subsequent
to our entering into the MyoKardia collaboration agreement, MyoKardia was acquired by Bristol-Myers Squibb Company. Bristol-Myers Squibb Company
could determine to reprioritize MyoKardia’s development programs such that it ceases to diligently pursue the development of our programs and/or cause
the agreement between MyoKardia and us to terminate. Additionally, in November 2021, subsequent to our entering into the Acceleron collaboration
agreement, Acceleron was acquired by Merck & Co., Inc. Merck & Co., Inc. could determine to reprioritize Acceleron's development programs such that it
ceases to diligently pursue the development of our programs and/or cause the agreement between Acceleron and us to terminate. If one of our collaborators
terminates its agreement with us, we may find it more difficult to attract new collaborators and our perception in the business and financial communities
could be adversely affected.
If we are not able to establish or maintain collaborations, we may have to alter our development and commercialization plans and our business could
be adversely affected.
For some of our product candidates, we may decide to collaborate with pharmaceutical or biotechnology companies for the development and
potential commercialization of those product candidates. For example, in December 2019, we entered into a collaboration and license agreement with
Acceleron to identify biological targets to modulate specific pathways associated with a targeted indication within the pulmonary disease space, and in July
2020, we entered into a collaboration and license agreement with MyoKardia to identify and validate potential biological targets for the potential treatment
of certain genetically defined cardiomyopathies. We face significant competition in seeking appropriate collaborators, and a number of more established
companies may also be pursuing strategies to license or acquire third-party intellectual property rights that we consider attractive. These established
companies may have a competitive advantage over us due to their size, financial resources and greater clinical development and commercialization
capabilities. In addition, companies that perceive us to be a competitor may be unwilling to assign or license rights to us. Whether we reach a definitive
agreement for a collaboration 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 a number of factors. Those factors may include the design or results of clinical
trials, the likelihood of approval by the FDA or similar regulatory authorities outside the United States, the potential market for the subject product
candidate, the costs and complexities of manufacturing and delivering such product candidate to patients, the potential of competing products, the existence
of uncertainty with respect to our ownership of technology, which can exist if there is a challenge to such ownership without regard to the merits of the
challenge, and industry and market conditions generally. The collaborator may also consider alternative product candidates or technologies for similar
indications that may be available to collaborate on and whether such a collaboration could be more attractive than the one with us for our product
candidate.
We may also be restricted under existing or future license agreements from entering into agreements on certain terms with potential collaborators.
For example, we are restricted by GSK’s right of first negotiation under our current license agreement with them. We are also restricted under our
collaboration with Acceleron from, directly or indirectly, researching, developing, manufacturing, commercializing, using or otherwise exploiting any
compound or product for the treatment, prophylaxis, or diagnosis of a targeted indication within the pulmonary disease space, other than for Acceleron,
while we are performing the research activities pursuant to the research plan and for a specified period thereafter. Additionally, we are restricted under our
collaboration with Acceleron from researching, developing, manufacturing, commercializing, using, or otherwise exploiting any compound or product for
the treatment, prophylaxis, or diagnosis of a targeted indication within the pulmonary disease space that is directed against certain specified biological
targets identified by us in the performance of the research activities while we are performing the research activities pursuant to the research plan and for a
specified period thereafter. Under our collaboration with MyoKardia, we are restricted from researching, developing, manufacturing, commercializing,
using, or otherwise exploiting any compound or product (a) that is a compound or product under the agreement that is directed against certain targets
identified by us in the performance of the research activities for the treatment, prophylaxis, or diagnosis of any indication or (b) for the treatment of any
genetically defined cardiomyopathies shown to be related to certain specified genes of interest that are modulated by the targets chosen by MyoKardia
under our collaboration, in each case , while we are performing the research activities pursuant to the research plan and for a specified period thereafter.
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Collaborations are complex and time-consuming to negotiate and document. In addition, there have been a significant number of recent business
combinations among large pharmaceutical and biotechnology companies that have resulted in a reduced number of potential future collaborators.
If we are unable to reach agreements with suitable collaborators on a timely basis, on acceptable terms or at all, we may have to curtail the
development of a product candidate, reduce or delay its development program or one or more of our other development programs, delay its potential
commercialization or reduce the scope of any sales or marketing activities, or increase our expenditures and undertake development or commercialization
activities at our own expense. If we elect to fund and undertake development or commercialization activities on our own, we may need to obtain additional
expertise and additional capital, which may not be available to us on acceptable terms or at all. If we fail to enter into collaborations and do not have
sufficient funds or expertise to undertake the necessary development and commercialization activities, we may not be able to further develop our product
candidates or bring them to market or continue to develop our product engine.
Risks Related to our Intellectual Property
If we are unable to obtain, maintain, enforce and protect patent protection for our technology and product candidates or if the scope of the patent
protection obtained is not sufficiently broad, our competitors could develop and commercialize technology and products similar or identical to ours,
and our ability to successfully develop and commercialize our technology and product candidates may be adversely affected.
Our success depends in large part on our ability to obtain and maintain protection of the intellectual property we may own solely and jointly with
others or may license from others, particularly patents, in the United States and other countries with respect to any proprietary technology and product
candidates we develop. We seek to protect our proprietary position by filing patent applications in the United States and abroad related to our product
candidates that are important to our business and by in-licensing intellectual property related to our technologies and product candidates. If we are unable to
obtain or maintain patent protection with respect to any proprietary technology or product candidate, our business, financial condition, results of operations
and prospects could be materially harmed.
The patent prosecution process is expensive, time-consuming and complex, and we may not be able to file, prosecute, maintain, defend or license all
necessary or desirable patent applications at a reasonable cost or in a timely manner. It is also possible that we will fail to identify patentable aspects of our
research and development output before it is too late to obtain patent protection. Moreover, in some circumstances, we do not have the right to control the
preparation, filing and prosecution of patent applications, or to maintain, enforce and defend the patents, covering technology that we license from third
parties. Therefore, these in-licensed patents and applications may not be prepared, filed, prosecuted, maintained, defended and enforced in a manner
consistent with the best interests of our business.
The patent position of pharmaceutical and biotechnology companies generally is highly uncertain, involves complex legal and factual questions and
has in recent years been the subject of much litigation. In addition, the scope of patent protection outside of the United States is uncertain and laws of
foreign countries may not protect our rights to the same extent as the laws of the United States or vice versa. For example, European patent law restricts the
patentability of methods of treatment of the human body more than United States law does. With respect to both owned and in-licensed patent rights, we
cannot predict whether the patent applications we and our licensors are currently pursuing will issue as patents in any particular jurisdiction or whether the
claims of any issued patents will provide sufficient protection from competitors. Further, we may not be aware of all third-party intellectual property rights
potentially relating to our product candidates. In addition, publications of discoveries in the scientific literature often lag behind the actual discoveries, and
patent applications in the United States and other jurisdictions are typically not published until 18 months after filing, or in some cases not published at all.
Therefore, neither we nor our licensors can know with certainty whether either we or our licensors were the first to make the inventions claimed in the
patents and patent applications we own or in-license now or in the future, or that either we or our licensors were the first to file for patent protection of such
inventions. As a result, the issuance, scope, validity, enforceability and commercial value of our owned and in-licensed patent rights are highly uncertain.
Moreover, our owned and in-licensed pending and future patent applications may not result in patents being issued which protect our technology and
product candidates, in whole or in part, or which effectively prevent others from commercializing competitive technologies and products. Changes in either
the patent laws or interpretation of the patent laws in the United States and other countries may diminish the value of our patents and our ability to obtain,
protect, maintain, defend and enforce our patent rights, narrow the scope of our patent protection and, more generally, could affect the value or narrow the
scope of our patent rights. For information relating to our patent portfolio, see Item 1 “Business-Intellectual Property” in this Annual Report on Form 10-K.
Moreover, we or our licensors may be subject to a third-party preissuance submission of prior art to the United States Patent and Trademark Office,
or USPTO, or become involved in opposition, derivation, revocation, reexamination, inter
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partes review, post-grant review or interference proceedings challenging our patent rights or the patent rights of others. An adverse determination in any
such submission, proceeding or litigation could reduce the scope of, or invalidate, our patent rights, allow third parties to commercialize our technology or
product candidates and compete directly with us, without payment to us, or result in our inability to manufacture or commercialize drugs without infringing
third-party patent rights. If the breadth or strength of protection provided by our patents and patent applications is threatened, regardless of the outcome, it
could dissuade companies from collaborating with us to license, develop or commercialize current or future product candidates. For example, while we
believe that the specific and generic claims contained in our U.S. patent provide protection for the method of using losmapimod for the treatment of FSHD
and while we also believe that the specific and generic claims contained in our issued and pending U.S. non-provisional and provisional applications
provide protection for the pharmaceutical compositions and methods of use for FTX-6058, third parties may nevertheless challenge such claims. If any
such claims are invalidated or rendered unenforceable for any reason, we will lose valuable intellectual property rights and our ability to prevent others
from competing with us would be impaired.
Additionally, the coverage claimed in a patent application can be significantly reduced before the patent is issued, and its scope can be reinterpreted
after issuance. Even if our owned and in-licensed patent applications issue as patents, they may not issue in a form that will provide us with any meaningful
protection, prevent competitors from competing with us or otherwise provide us with any competitive advantage. The issuance of a patent is not conclusive
as to its inventorship, scope, validity or enforceability, and our owned and in-licensed patents may be challenged in the courts or patent offices in the
United States and abroad. Such challenges may result in loss of exclusivity or freedom to operate or in patent claims being narrowed, invalidated or held
unenforceable, in whole or in part, which could limit our ability to stop others from using or commercializing similar or identical technology and products,
or limit the duration of the patent protection of our technology and product candidates. Such proceedings also may result in substantial cost and require
significant time from our management and employees, even if the eventual outcome is favorable to us. 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. Furthermore, our competitors may be able to circumvent our owned or in-licensed patents by developing similar or
alternative technologies or products in a non-infringing manner. As a result, our owned and in-licensed patent portfolio may not provide us with sufficient
rights to exclude others from commercializing technology and products similar or identical to any of our technology and product candidates.
Patent terms may be inadequate to protect our competitive position on our product candidates for an adequate amount of time.
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 product candidates are obtained, once the patent life has expired, we may be open to competition from competitive products,
including generics or biosimilars. 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 similar or identical to ours. For example, the composition of
matter patents covering losmapimod, licensed from GSK, are expected to expire on February 10, 2023. As soon as the patents covering the composition of
matter expire on February 10, 2023, or are no longer in-force, the GSK-licensed patents will no longer be a barrier to entry for any new uses not covered by
our other patents and patent applications. Given the near term expiration date of these patents, and the fact that safe harbor protections in many jurisdictions
permit third parties to engage in development, including clinical trials, these patents may not provide us with any meaningful competitive advantage.
If we are unable to obtain licenses from third parties on commercially reasonable terms or fail to comply with our obligations under such agreements,
our business could be harmed.
It may be necessary for us to use the patented or proprietary technology of third parties to commercialize our products, in which case we would be
required to obtain a license from these third parties. If we are unable to license such technology, or if we are forced to license such technology on
unfavorable terms, our business could be materially harmed. If we are unable to obtain a necessary license, we may be unable to develop or commercialize
the affected product candidates, which could materially harm our business and the third parties owning such intellectual property rights could seek either an
injunction prohibiting our sales or an obligation on our part to pay royalties and/or other forms of compensation. Even if we are able to obtain a license, it
may be non-exclusive, thereby giving our competitors access to the same technologies licensed to us.
If we are unable to obtain rights to required third-party intellectual property rights or maintain the existing intellectual property rights we have, we
may be required to expend significant time and resources to redesign our technology, product
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candidates, or the methods for manufacturing them or to develop or license replacement technology, all of which may not be feasible on a technical or
commercial basis. If we are unable to do so, we may be unable to develop or commercialize the affected technology and product candidates, which could
harm our business, financial condition, results of operations and prospects significantly.
Additionally, if we fail to comply with our obligations under license agreements, our counterparties may have the right to terminate these
agreements, in which event we might not be able to develop, manufacture or market, or may be forced to cease developing, manufacturing or marketing,
any product that is covered by these agreements or may face other penalties under such agreements. Such an occurrence could materially adversely affect
the value of the product candidate being developed under any such agreement. Termination of these agreements or reduction or elimination of our rights
under these agreements, or restrictions on our ability to freely assign or sublicense our rights under such agreements when it is in the interest of our
business to do so, may result in our having to negotiate new or reinstated agreements with less favorable terms, cause us to lose our rights under these
agreements, including our rights to important intellectual property or technology or impede, or delay or prohibit the further development or
commercialization of one or more product candidates that rely on such agreements.
If we do not obtain patent term extension in the United States under the Hatch-Waxman Act and in foreign countries under similar legislation, our
business may be materially harmed.
In the United States, the patent term of a patent that covers an FDA-approved drug may be eligible for limited patent term extension of up to five
years beyond the expiration of the patent. The length of the patent term extension is related to, among other factors, the length of time the drug is under
regulatory review, but such patent extension cannot extend the remaining term of a patent beyond a total of 14 years from the date of product approval, and
only one eligible patent may be extended. Similar provisions are available in Europe and certain other jurisdictions outside the United States. If and when
our product candidates receive FDA approval, we expect to apply for patent term extensions where applicable, but there is no guarantee that the applicable
governmental authorities will agree with our assessment of whether such extensions should be granted, and even if granted, the length of such extensions.
We may not be granted patent term extension either in the United States or in any foreign country because of, for example, failing to exercise due diligence
during the testing phase or regulatory review process, failing to apply within applicable deadlines, failing to apply prior to expiration of relevant patents or
otherwise failing to satisfy applicable requirements. If we are unable to obtain any patent term extension or the term of any such extension is less than we
request, our competitors may obtain approval of competing products following the expiration of our patent rights, and our business, financial condition,
results of operations and prospects could be materially harmed.
Further, for our licensed patents, we may not have the right to control prosecution, including filing with the USPTO a petition for patent term
extension thus if one of our licensed patents is eligible for patent term extension, we may not be able to control whether a petition to obtain a patent term
extension is filed, or obtained, from the USPTO.
There are detailed rules and requirements regarding the patents that may be submitted to the FDA for listing in the Orange Book. We may be unable
to obtain patents covering our product candidates that contain one or more claims that satisfy the requirements for listing in the Orange Book. Even if we
submit a patent for listing in the Orange Book, the FDA may decline to list the patent, or a manufacturer of generic drugs may challenge the listing. If one
of our product candidates is approved and a patent covering that product candidate is not listed in the Orange Book, an ANDA applicant would not have to
provide notice to us with respect to that patent. See “Business—Intellectual Property” for additional information regarding patent laws and patent
protection.
Changes to patent laws in the United States and other jurisdictions could diminish the value of patents in general, thereby impairing our ability to
protect our products.
Changes in either the patent laws or interpretation of patent laws in the United States, including patent reform legislation such as the Leahy-Smith
America Invents Act, or the Leahy-Smith Act, could increase the uncertainties and costs surrounding the prosecution of our owned and in-licensed patent
applications and the maintenance, enforcement or defense of our owned and in-licensed issued patents. The Leahy-Smith Act includes a number of
significant changes to United States patent law. These changes include provisions that affect the way patent applications are prosecuted, redefine prior art,
provide more efficient and cost-effective avenues for competitors to challenge the validity of patents, and enable third-party submission of prior art to the
USPTO during patent prosecution and additional procedures to attack the validity of a patent at USPTO-administered post-grant proceedings, including
post-grant review, inter partes review, and derivation proceedings. Assuming that other requirements for patentability are met, prior to March 2013, in the
United States, the first to invent the claimed invention was entitled to the patent, while outside the United States, the first to file a patent application was
entitled to the patent. After March 2013, under the Leahy-Smith Act, the United States transitioned to a first-to-file system in which,
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assuming that the other statutory requirements for patentability are met, the first inventor to file a patent application will be entitled to the patent on an
invention regardless of whether a third party was the first to invent the claimed invention. As such, the Leahy-Smith Act and its implementation could
increase the uncertainties and costs surrounding the prosecution of our patent applications and the enforcement or defense of our issued patents, all of
which could have a material adverse effect on our business, financial condition, results of operations and prospects.
In addition, the patent positions of companies in the development and commercialization of biologics and pharmaceuticals are particularly uncertain.
Recent U.S. Supreme Court rulings have narrowed the scope of patent protection available in certain circumstances and weakened the rights of patent
owners in certain situations. This combination of events has created uncertainty with respect to the validity and enforceability of patents once obtained.
Depending on future actions by the U.S. Congress, the federal courts, and the USPTO, the laws and regulations governing patents could change in
unpredictable ways that could have a material adverse effect on our patent rights and our ability to protect, defend and enforce our patent rights in the
future.
Although we or our licensors are not currently involved in any litigation, we may become involved in lawsuits to protect or enforce our patent or other
intellectual property rights, which could be expensive, time-consuming and unsuccessful.
Competitors and other third parties may infringe, misappropriate or otherwise violate our or our licensor’s issued patents or other intellectual
property. As a result, we or our licensors may need to file infringement, misappropriation or other intellectual property related claims, which can be
expensive and time-consuming. Any claims we assert against perceived infringers could provoke such parties to assert counterclaims against us alleging
that we infringe, misappropriate or otherwise violate their intellectual property. In addition, in a patent infringement proceeding, such parties could
counterclaim that the patents we or our licensors have asserted are 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, or non-enablement. Grounds for an unenforceability assertion could be an allegation that
someone connected with prosecution of the patent withheld relevant information from the USPTO, or made a misleading statement, during prosecution.
Third parties may institute such 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, interference proceedings, derivation proceedings, and equivalent proceedings in foreign
jurisdictions (e.g., opposition proceedings). The outcome following legal assertions of invalidity and unenforceability is unpredictable.
An adverse result in any such proceeding could put one or more of our owned or in-licensed patents at risk of being invalidated or interpreted
narrowly, and could put any of our owned or in-licensed patent applications at risk of not yielding an issued patent. A court may also refuse to stop the third
party from using the technology at issue in a proceeding on the grounds that our owned or in-licensed patents do not cover such technology. 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 or trade secrets could be compromised by disclosure during this type of litigation. Any of the foregoing could allow such third parties to
develop and commercialize competing technologies and products and have a material adverse impact on our business, financial condition, results of
operations and prospects.
Interference or derivation proceedings provoked by third parties or brought by us or declared by the USPTO may be necessary to determine the
priority of inventions with respect to our patents or patent applications. An unfavorable outcome could require us to cease using the related technology or to
attempt to license rights to it from the prevailing party. Our business could be harmed if the prevailing party does not offer us a license on commercially
reasonable terms or at all, or if a non-exclusive license is offered and our competitors gain access to the same technology. Our defense of litigation or
interference or derivation proceedings may fail and, even if successful, may result in substantial costs and distract our management and other employees. In
addition, the uncertainties associated with litigation could have a material adverse effect on our ability to raise the funds necessary to continue our clinical
trials, continue our research programs, license necessary technology from third parties, or enter into development partnerships that would help us bring our
product candidates to market.
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 this type of 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 our common stock.
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Third parties may initiate legal proceedings alleging that we are infringing, misappropriating or otherwise violating their intellectual property rights,
the outcome of which would be uncertain and could have a material adverse effect on the success of our business.
Our commercial success depends upon our ability and the ability of our collaborators to develop, manufacture, market and sell our product
candidates and use our proprietary technologies without infringing, misappropriating or otherwise violating the intellectual property and proprietary rights
of third parties. There is considerable patent and other intellectual property litigation in the pharmaceutical and biotechnology industries. We may become
party to, or threatened with, adversarial proceedings or litigation regarding intellectual property rights with respect to our technology and product
candidates, including interference proceedings, post grant review, inter partes review, and derivation proceedings before the USPTO and similar
proceedings in foreign jurisdictions such as oppositions before the European Patent Office. Numerous U.S. and foreign issued patents and pending patent
applications, which are owned by third parties, exist in the fields in which we are pursuing development candidates. As the biotechnology and
pharmaceutical industries expand and more patents are issued, the risk increases that our technologies or product candidates that we may identify may be
subject to claims of infringement of the patent rights of third parties.
The legal threshold for initiating litigation or contested proceedings is low, so that even lawsuits or proceedings with a low probability of success
might be initiated and require significant resources to defend. Litigation and contested proceedings can also be expensive and time-consuming, and our
adversaries in these proceedings may have the ability to dedicate substantially greater resources to prosecuting these legal actions than we can. The risks of
being involved in such litigation and proceedings may increase if and as our product candidates near commercialization and as we gain the greater visibility
associated with being a public company. Third parties may assert infringement claims against us based on existing patents or patents that may be granted in
the future, regardless of merit. We may not be aware of all such intellectual property rights potentially relating to our technology and product candidates
and their uses, or we may incorrectly conclude that third party intellectual property is invalid or that our activities and product candidates do not infringe
such intellectual property. Thus, we do not know with certainty that our technology and product candidates, or our development and commercialization
thereof, do not and will not infringe, misappropriate or otherwise violate any third party’s intellectual property.
Third parties may assert that we are employing their proprietary technology without authorization. There may be third-party patents or patent
applications with claims to materials, formulations or methods, such as methods of manufacture or methods for treatment, related to the discovery, use or
manufacture of the product candidates that we may identify or related to our technologies. Because patent applications can take many years to issue, there
may be currently pending patent applications which may later result in issued patents that the product candidates that we may identify may infringe. In
addition, third parties may obtain patents in the future and claim that use of our technologies infringes upon these patents. Moreover, as noted above, there
may be existing patents that we are not aware of or that we have incorrectly concluded are invalid or not infringed by our activities. If any third-party
patents were held by a court of competent jurisdiction to cover, for example, the manufacturing process of the product candidates that we may identify, any
molecules formed during the manufacturing process or any final product itself, the holders of any such patents may be able to block our ability to
commercialize such product candidate unless we obtained a license under the applicable patents, or until such patents expire.
Parties making claims against us may obtain injunctive or other equitable relief, which could effectively block our ability to further develop and
commercialize the product candidates that we may identify. Defense of these claims, regardless of their merit, would involve substantial litigation expense
and would be a substantial diversion of employee resources from our business. In the event of a successful claim of infringement against us, we may have
to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign our infringing products or obtain
one or more licenses from third parties, which may be impossible or require substantial time and monetary expenditure.
We may choose to take a license or, if we are found to infringe, misappropriate or otherwise violate a third party’s intellectual property rights, we
could also be required to obtain a license from such third party to continue developing, manufacturing and marketing our technology and product
candidates. However, we may not be able to obtain any required license on commercially reasonable terms or at all. Even if we were able to obtain a
license, it could be non-exclusive, thereby giving our competitors and other third parties access to the same technologies licensed to us and could require us
to make substantial licensing and royalty payments. We could be forced, including by court order, to cease developing, manufacturing and commercializing
the infringing technology or product. In addition, we could be found liable for significant monetary damages, including treble damages and attorneys’ fees,
if we are found to have willfully infringed a patent or other intellectual property right and could be forced to indemnify our customers or collaborators. A
finding of infringement could prevent us from commercializing our product candidates or force us to cease some of our business operations, which could
materially harm our business. In addition, we may be forced to redesign our product candidates, seek new regulatory approvals and indemnify third parties
pursuant to contractual agreements. Claims that we have misappropriated the confidential information or trade secrets of third parties could have a similar
material adverse effect on our business, financial condition, results of operations and prospects.
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Intellectual property litigation or other legal proceedings relating to intellectual property could cause us to spend substantial resources and distract our
personnel from their normal responsibilities.
Even if resolved in our favor, litigation or other legal proceedings relating to intellectual property claims may cause us to incur significant expenses,
and could distract our technical and management personnel from their normal responsibilities. In addition, there could be public announcements of the
results of hearings, motions or other interim proceedings or developments and if securities analysts or investors perceive these results to be negative, it
could have a substantial adverse effect on the price of our common stock. Such litigation or proceedings could substantially increase our operating losses
and reduce the resources available for development activities or any future sales, marketing or distribution activities. We may not have sufficient financial
or other resources to conduct such litigation or proceedings adequately. Some of our competitors may be able to sustain the costs of such litigation or
proceedings more effectively than we can because of their greater financial resources and may also have an advantage in such proceedings due to their
more mature and developed intellectual property portfolios. Uncertainties resulting from the initiation and continuation of intellectual property litigation or
other proceedings could compromise our ability to compete in the marketplace.
Obtaining and maintaining patent protection depends on compliance with various procedural, document submission, fee payment and other
requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these
requirements.
Periodic maintenance, renewal and annuity fees and various other government fees on any issued patent and pending patent application must be paid
to the USPTO and foreign patent agencies in several stages or annually over the lifetime of our owned and in-licensed patents and patent applications. The
USPTO and various foreign governmental patent agencies require compliance with a number of procedural, documentary, fee payment and other similar
provisions during the patent application process. In certain circumstances, we rely on our licensing partners to pay these fees to, or comply with the
procedural and documentary rules of, the relevant patent agency. With respect to our patents, we rely on an annuity service, outside firms and outside
counsel to remind us of the due dates and to make payment after we instruct them to do so. While an inadvertent lapse can in many cases be cured by
payment of a late fee or by other means in accordance with the applicable rules, there are situations in which noncompliance can result in abandonment or
lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the relevant jurisdiction. Non-compliance events that could
result in abandonment or lapse of a patent or patent application include failure to respond to official actions within prescribed time limits, non-payment of
fees and failure to properly legalize and submit formal documents. In such an event, potential competitors might be able to enter the market with similar or
identical products or technology. If we or our licensors fail to maintain the patents and patent applications covering our product candidates, it would have a
material adverse effect on our business, financial condition, results of operations and prospects.
If we fail to comply with our obligations in our intellectual property licenses and funding arrangements with third parties, or otherwise experience
disruptions to our business relationships with our licensors, we could lose intellectual property rights that are important to our business.
We are party to license and funding agreements, such as the our agreement with GSK, and we may enter into additional licensing and funding
arrangements with third parties that, that impose or may impose diligence, development and commercialization timelines, milestone payment, royalty,
insurance and other obligations on us. Under our existing licensing and funding agreements, we are obligated to pay royalties on net product sales of
product candidates or related technologies to the extent they are covered by the agreements. If we fail to comply with such obligations under current or
future license and funding agreements, our counterparties may have the right to terminate these agreements or require us to grant them certain rights. Such
an occurrence could materially adversely affect the value of any product candidate being developed under any such agreement. Termination of these
agreements or reduction or elimination of our rights under these agreements may result in our having to negotiate new or reinstated agreements with less
favorable terms, or cause us to lose our rights under these agreements, including our rights to important intellectual property or technology, which would
have a material adverse effect on our business, financial condition, results of operations and prospects. We also have licenses and agreements to certain
technologies used in our product engine, all of which are non-exclusive. While we still face all of the risks described herein with respect to those
agreements, we cannot prevent third parties from also accessing those technologies. In addition, our licenses may place restrictions on our future business
opportunities. For example, under our license with GSK, GSK has certain rights of first negotiation if we wish to sublicense any of the patent or data rights
licensed by GSK to us to a third party for use outside the United States. This may prevent or delay certain transactions, which could have an adverse effect
on the development and commercialization of losmapimod and on our business.
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Disputes may arise regarding intellectual property subject to a licensing agreement, including:
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the scope of rights granted under the license agreement and other interpretation related issues;
the extent to which our technology and processes infringe on intellectual property of the licensor that is not subject to the licensing agreement;
the sublicensing of patent and other rights under our collaborative development relationships;
our diligence obligations under the license agreement and what activities satisfy those diligence obligations;
the inventorship and ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our licensors
and us and our partners; and
the priority of invention of patented technology.
In addition, the agreements under which we currently license intellectual property or technology from third parties are complex, and certain
provisions in such agreements may be susceptible to multiple interpretations. The resolution of any contract interpretation disagreement that may arise
could narrow what we believe to be the scope of our rights to the relevant intellectual property or technology, or increase what we believe to be our
financial or other obligations under the relevant agreement, either of which could have a material adverse effect on our business, financial condition, results
of operations and prospects. Moreover, if disputes over intellectual property that we have licensed prevent or impair our ability to maintain our current
licensing arrangements on commercially acceptable terms, we may be unable to successfully develop and commercialize the affected technology and
product candidates, which could have a material adverse effect on our business, financial conditions, results of operations and prospects.
Our current or future licensors may have relied on third-party consultants or collaborators or on funds from third parties such that our licensors are
not the sole and exclusive owners of the patents and patent applications we in-license. If other third parties have ownership rights to patents or patent
applications we in-license, they may be able to license such patents to our competitors, and our competitors could market competing products and
technology. This could have a material adverse effect on our competitive position, business, financial conditions, results of operations and prospects.
In spite of our best efforts, our licensors might conclude that we have materially breached our license agreements and might therefore terminate the
license agreements, thereby removing our ability to develop and commercialize product candidates and technology covered by these license agreements. If
these in-licenses are terminated, or if the underlying intellectual property fails to provide the intended exclusivity, competitors would have the freedom to
seek regulatory approval of, and to market, products and technologies identical to ours. This could have a material adverse effect on our competitive
position, business, financial condition, results of operations and prospects.
We may not be able to protect our intellectual property and proprietary rights throughout the world.
Filing, prosecuting and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and the
laws of foreign countries may not protect our rights to the same extent as the laws of the United States. 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, and even where such protection is nominally
available, judicial and governmental enforcement of such intellectual property rights may be lacking. Consequently, we may not be able to prevent third
parties from practicing our inventions in all countries outside the United States, 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 have not obtained patent protection to develop
their own products and, further, may export otherwise infringing products to territories where we have patent protection or licenses but enforcement is not
as strong as that in the United States. These products may compete with our products, 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 intellectual property and proprietary rights generally. In addition, certain jurisdictions do not protect to the same
extent or at all inventions that constitute new methods of treatment.
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Proceedings to enforce our intellectual property and proprietary rights 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, could put 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 and proprietary rights
around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop or license.
Many countries have compulsory licensing laws under which a patent owner may be compelled to grant licenses to third parties. In addition, many
countries limit the enforceability of patents against government agencies or government contractors. In these countries, the patent owner may have limited
remedies, which could materially diminish the value of such patent. If we or any of our licensors is forced to grant a license to third parties with respect to
any patents relevant to our business, our competitive position may be impaired, and our business, financial condition, results of operations and prospects
may be adversely affected.
We may be subject to claims challenging the inventorship or ownership of our patents and other intellectual property.
We or our licensors may be subject to claims that former employees, collaborators or other third parties have an interest in our owned or in-licensed
patents, trade secrets or other intellectual property as an inventor or co-inventor. For example, we or our licensors may have inventorship disputes arise
from conflicting obligations of employees, consultants or others who are involved in developing our product candidates. Litigation may be necessary to
defend against these and other claims challenging inventorship or our or our licensors’ ownership of our owned or in-licensed patents, trade secrets or other
intellectual property. If we or our licensors fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual
property rights, such as exclusive ownership of, or right to use, intellectual property that is important to our product candidates. Even if we are successful in
defending against such claims, litigation could result in substantial costs and be a distraction to management and other employees. Any of the foregoing
could have a material adverse effect on our business, financial condition, results of operations and prospects.
We may be subject to claims by third parties asserting that our employees, consultants or contractors have wrongfully used or disclosed confidential
information of third parties, or we have wrongfully used or disclosed alleged trade secrets of their current or former employers or claims asserting we
have misappropriated their intellectual property, or claiming ownership of what we regard as our own intellectual property.
Many of our employees, consultants and contractors were previously employed at universities or other pharmaceutical or biotechnology companies,
including our competitors or potential competitors. Although we try to ensure that our employees, consultants and contractors 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.
In addition, while it is our policy to require our employees, consultants 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. Our intellectual property assignment agreements with them may not be self-executing or may
be breached, and we may be forced to bring claims against third parties, or defend claims they may bring against us, to determine the ownership of what we
regard as our intellectual property. Such claims could have a material adverse effect on our business, financial conditions, results of operations and
prospects.
If we fail in prosecuting or defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or
personnel, which could have a material adverse effect on our competitive business position and prospects. Such intellectual property rights could be
awarded to a third party, and we could be required to obtain a license from such third party to commercialize our technology or products, which license
may not be available on commercially reasonable terms, or at all, or such license may be non-exclusive. Even if we are successful in prosecuting or
defending against such claims, litigation could result in substantial costs and be a distraction to our management and employees.
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If we are unable to protect the confidentiality of our trade secrets, our business and competitive position would be harmed.
In addition to seeking patents for our product candidates, we also rely on trade secrets and confidentiality agreements to protect our unpatented
know-how, technology and other proprietary information, to maintain our competitive position, including certain aspects of our proprietary product engine.
We seek to protect our trade secrets and other proprietary technology, in part, by entering into non-disclosure and confidentiality agreements with parties
who have access to them, such as our employees, corporate collaborators, outside scientific collaborators, CROs, CMOs, consultants, advisors and other
third parties. We also enter into confidentiality and invention or patent assignment agreements with our employees and consultants, but we cannot
guarantee that we have entered into such agreements with each party that may have or has had access to our trade secrets or proprietary technology. Despite
these efforts, any of these parties may breach the agreements and disclose our proprietary information, including our trade secrets, and we may not be able
to obtain adequate remedies for such breaches. Detecting the disclosure or misappropriation of a trade secret and enforcing a claim that a party illegally
disclosed or misappropriated a trade secret is difficult, expensive and time-consuming, and the outcome is unpredictable. In addition, some courts inside
and outside of the United States are less willing or unwilling to protect trade secrets. 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 any of our trade secrets were to be disclosed to or independently developed by a competitor or other
third party, our competitive position would be materially and adversely harmed.
Intellectual property 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 may
not adequately protect our business or permit us to maintain our competitive advantage. For example:
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portions of our product engine are protected by trade secrets, but much of our product engine is not protected by intellectual property, including
patents, trade secrets and know-how, and we may not be able to develop, acquire or in-license any patentable technologies or other intellectual
property related to the unprotected portions of our product engine;
others may be able to make product candidates that are similar to ours but that are not covered by the claims of the patents that we own;
we, or our license partners or current or future collaborators, might not have been the first to make the inventions covered by the issued patent
or pending patent applications that we license or may own in the future;
we, or 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 our owned or in-
licensed intellectual property rights;
it is possible that our owned and in-licensed pending patent applications or those we may own or in-license in the future will not lead to issued
patents;
issued patents that we hold rights to may be held invalid or unenforceable, including as a result of legal challenges by our competitors;
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 cannot ensure that any of our patents, or any of our pending patent applications, if issued, or those of our licensors, will include claims
having a scope sufficient to protect our product candidates;
we cannot ensure that any patents issued to us or our licensors will provide a basis for an exclusive market for our commercially viable product
candidates or will provide us with any competitive advantages;
we cannot ensure that our commercial activities or product candidates will not infringe upon the patents of others;
we cannot ensure that we will be able to successfully commercialize our product candidates on a substantial scale, if approved, before the
relevant patents that we own or license expire;
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we may not develop additional proprietary technologies that are patentable;
the patents of others may harm our business; and
we may choose not to file a patent in order to maintain certain trade secrets or know-how, and a third party may subsequently file a patent
covering such intellectual property.
Should any of these events occur, they could have a material adverse effect on our business, financial condition, results of operations and prospects.
Risks Related to Regulatory Approval of our Product Candidates and Other Legal Compliance Matters
Even if we complete the necessary preclinical studies and clinical trials, the marketing approval process is expensive, time-consuming and uncertain,
and we may not obtain approvals for the commercialization of some or all of our product candidates. If we are not able to obtain, or if there are delays
in obtaining, required regulatory approvals, we will not be able to commercialize our product candidates, and our ability to generate revenue will be
materially impaired.
Marketing approval of drugs in the United States requires the submission of a new drug application, or NDA, to the FDA and we are not permitted
to market any drug candidate in the United States until we obtain approval of the NDA. An NDA must be supported by extensive clinical and preclinical
data, as well as extensive information regarding pharmacology, chemistry, manufacturing and controls. We have not submitted an application for or
received marketing approval for any of our product candidates in the United States or in any other jurisdiction.
We have only limited experience in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party
clinical research organizations or other third-party consultants or vendors to assist us in this process. Securing marketing approval requires the submission
of extensive preclinical and clinical data and supporting information, including manufacturing information, to regulatory authorities for each therapeutic
indication to establish the product candidate’s safety and efficacy. 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. If any of our product candidates receives marketing approval, the accompanying label may limit the approved use of our drug, which
could limit sales of the product.
The process of obtaining marketing approvals, both in the United States and abroad, is expensive, may take many years, 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. Regulatory authorities have substantial
discretion in the approval process and may refuse to accept any application or may decide that our data is insufficient for approval and require additional
preclinical, clinical or other studies. In addition, varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or
prevent marketing approval of a product candidate. Any marketing approval we ultimately obtain may be limited or subject to restrictions or post-approval
commitments that render the approved product not commercially viable.
Disruptions at the FDA and other agencies may prolong the time necessary for regulatory submissions to be reviewed and/or new drugs to be
approved by necessary government agencies, which would adversely affect our business. For example, over the last several years, the U.S. government has
shut down several times and certain regulatory agencies, such as the FDA, have had to furlough critical employees and stop critical activities. If a
prolonged government shutdown were to occur, it could significantly impact the ability of the FDA to timely review and process our regulatory
submissions, which could have a material adverse effect on our business.
In addition, since March 2020 when foreign and domestic inspections of facilities were largely placed on hold due to the COVID-19 pandemic, the
FDA has been working to resume routine surveillance, bioresearch monitoring and pre-approval inspections on a prioritized basis. Since April 2021, the
FDA has conducted limited inspections and employed remote interactive evaluations, using risk management methods, to meet user fee commitments and
goal dates. Ongoing travel restrictions and other uncertainties continue to impact oversight operations both domestic and abroad and it is unclear when
standard operational levels will resume. Should FDA determine that an inspection is necessary for approval and an inspection cannot be completed during
the review cycle due to restrictions on travel, and the FDA does not determine a remote interactive evaluation to be adequate, the Agency has stated that it
generally intends to issue, depending on the circumstances, a complete response letter or defer action on the application until an inspection can be
completed. During the COVID-19 public health emergency, a number of companies announced receipt of complete response letters due to the FDA’s
inability to complete required inspections for their applications. Regulatory authorities outside the U.S. may adopt
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similar restrictions or other policy measures in response to the ongoing COVID-19 pandemic and may experience delays in their regulatory activities.
If we experience delays in obtaining approval or if we fail to obtain approval of our product candidates, the commercial prospects for our product
candidates may be harmed and our ability to generate revenues will be materially impaired.
We may not be able to obtain or maintain orphan drug designation or exclusivity for our product candidates and, even if we do, that exclusivity may not
prevent the FDA or the EMA from approving other competing products.
Regulatory authorities in some jurisdictions, including the United States and Europe, may designate drugs for relatively small patient populations as
orphan drugs. The FDA and EMA have granted orphan drug designation to losmapimod for the treatment of FSHD. We may seek orphan drug designation
for our other current and future product candidates.
Generally, if a product with an orphan drug designation subsequently 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 the EMA from approving another marketing
application for the same drug for a certain time period. The applicable period is seven years in the United States and ten years in Europe. The exclusivity
period in Europe can be reduced to six years if a drug no longer meets the criteria for orphan drug designation or if the drug is sufficiently profitable so that
market exclusivity is no longer justified. Orphan drug exclusivity may be lost if the FDA or EMA determines that the request for designation was
materially defective or if the manufacturer is unable to assure sufficient quantity of the drug to meet the needs of patients with the rare disease or condition.
Even if we obtain orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because
competing drugs containing a different active ingredient can be approved for the same condition. In addition, the FDA can subsequently approve the same
drug for the same condition if the FDA concludes that the later drug is clinically superior to the first drug to obtain orphan drug exclusivity because it is
shown to be safer, more effective or makes a major contribution to patient care. Moreover, if we pursue and obtain approval for the same product for
another indication for which we are not entitled to or do not have orphan drug exclusivity, our period of orphan exclusivity will not prevent third parties
from obtaining approval for a competing drug containing the same active ingredient for use in this other, non-orphan indication. If that were to occur, the
protection we derive from orphan exclusivity may be adversely affected.
Special designation by the FDA, such as fast track or breakthrough therapy, may not lead to a faster development or regulatory review or approval
process, and it does not increase the likelihood that our product candidates will receive marketing approval.
The FDA granted fast track designation to losmapimod for the treatment of FSHD, and we may seek fast track designation for some of our other
product candidates as well as breakthrough therapy designation, including for losmapimod. If a drug is intended for the treatment of a serious or life-
threatening condition and the drug demonstrates the potential to address unmet medical needs for this condition, the drug sponsor may apply for FDA 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, we cannot assure stockholders that the FDA would decide to grant it. Even with fast track designation, we may not experience a faster
development process, review or approval compared to conventional FDA procedures. The FDA may withdraw fast track designation if it believes that the
designation is no longer supported by data from our clinical development program.
A breakthrough therapy is defined as a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-
threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies
on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
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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. Even if we receive
breakthrough therapy designation, the receipt of such 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 breakthrough therapies, the FDA may later decide that the products no longer meet the conditions
for qualification or decide that the time period for FDA review or approval will not be shortened.
Even if the FDA agrees that we may pursue an accelerated approval NDA submission, approval of the NDA is not assured, nor does submission of an
accelerated approval NDA ensure that the product candidate will have a faster development or regulatory review process.
We may seek approval of our product candidates using the FDA’s accelerated approval pathway. A product may be eligible for accelerated approval
if it treats a serious condition, generally provides a meaningful advantage over available therapies, and demonstrates an effect on a surrogate endpoint that
is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, or IMM, that is
reasonably likely to predict an effect on IMM or other clinical benefit (i.e., an intermediate clinical endpoint).
Prior to seeking such accelerated approval, we will seek feedback from the FDA and otherwise evaluate our ability to seek and receive such
accelerated approval.
There can be no assurance that, after feedback from FDA, we will continue to pursue or apply for accelerated approval or any other form of
expedited development, review or approval, even if we initially decide to do so. Furthermore, if we decide to submit an application for accelerated approval
or under another expedited regulatory designation, there can be no assurance that such submission or application will be accepted or that any expedited
review or approval will be granted on a timely basis, or at all.
Moreover, for drugs granted accelerated approval, the FDA typically requires confirmatory trials to verify the anticipated effect on IMM or other
clinical benefit. These confirmatory trials must be completed with due diligence. We may be required to evaluate additional or different clinical endpoints
in these post-marketing confirmatory trials. These confirmatory trials may require enrollment of more patients than we currently anticipate and will result
in additional costs, which may be greater than the estimated costs we currently anticipate. The FDA may withdraw approval of a product candidate
approved under the accelerated approval pathway if, for example, the trial required to verify the predicted clinical benefit of our product candidate fails to
verify such benefit or does not demonstrate sufficient clinical benefit to justify the risks associated with the drug. The FDA may also withdraw approval if
other evidence demonstrates that our product candidate is not shown to be safe or effective under the conditions of use, we fail to conduct any required post
approval trial of our product candidate with due diligence or we disseminate false or misleading promotional materials relating to our product candidate. A
failure to obtain accelerated approval or any other form of expedited development, review or approval for our product candidates would result in a longer
time period for commercialization of such product candidate, could increase the cost of development of such product candidate and could harm our
competitive position in the marketplace.
Failure to obtain marketing approval in foreign jurisdictions would prevent our product candidates from being marketed abroad.
In order to market and sell our products in the European Union and many other foreign jurisdictions, we or our potential third-party collaborators
must obtain separate marketing approvals and comply with numerous and varying regulatory requirements. The approval procedure varies among countries
and can involve additional testing. The time required to obtain approval may differ substantially from that required to obtain FDA approval. The regulatory
approval process outside of the United States generally includes all of the risks associated with obtaining FDA approval. In addition, in many countries
outside of the United States, it is required that the product be approved for reimbursement before the product can be approved for sale in that country. We
or our potential third-party collaborators may not obtain approvals, including conditional authorization, from regulatory authorities outside of the United
States on a timely basis, if at all. Approval by the FDA does not ensure approval by regulatory authorities in other countries or jurisdictions, and approval
by one regulatory authority outside of the United States does not ensure approval by regulatory authorities in other countries or jurisdictions or by the FDA.
However, a failure or delay in obtaining regulatory approval in one country may have a negative effect on the regulatory process in other countries. We may
not be able to file for marketing approvals and may not receive necessary approvals to commercialize our products in any market.
Additionally, we could face heightened risks with respect to seeking marketing approval in the United Kingdom as a result of the recent withdrawal
of the United Kingdom from the European Union, commonly referred to as Brexit. The United
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Kingdom and European Union entered into a Trade and Cooperation Agreement in connection with Brexit, which sets out certain procedures for approval
and recognition of medical products in each jurisdiction. Since the regulatory framework for pharmaceutical products in the United Kingdom covering the
quality, safety, and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales, and distribution of pharmaceutical
products is derived from European Union directives and regulations, Brexit could materially impact the future regulatory regime that applies to products
and the approval of product candidates in the United Kingdom. Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of the
Trade and Cooperation Agreement or otherwise, could prevent us from commercializing any product candidates in the United Kingdom and/or the
European Union and restrict our ability to generate revenue and achieve and sustain profitability. If any of these outcomes occur, we may be forced to
restrict or delay efforts to seek regulatory approval in the United Kingdom and/or European Union for any product candidates, which could significantly
and materially harm our business.
Any product candidate for which we obtain marketing approval could be subject to post-marketing restrictions or withdrawal from the market and we
may be subject to substantial penalties if we fail to comply with regulatory requirements or if we experience unanticipated problems with our products,
when and if any of them are approved.
Any product candidate for which we obtain marketing approval, along with the manufacturing processes, post-approval clinical data, labeling,
advertising and promotional activities for such product, will be subject to continual requirements of and review by the FDA and other regulatory
authorities. Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the
product may be marketed or to the conditions of approval, including the requirement to implement a REMS. If any of our product candidates receives
marketing approval, the accompanying label may limit the approved use of our drug, which could limit sales of the product.
The FDA may also impose requirements for costly post-marketing studies or clinical trials and surveillance to monitor the safety or efficacy of the
product, including the adoption and implementation of REMS. The FDA and other agencies, including the Department of Justice, or the DOJ, closely
regulate and monitor the post-approval marketing and promotion of drugs to ensure they are marketed and distributed only for the approved indications and
in accordance with the provisions of the approved labeling. Violations of the FDCA and other statutes, including the False Claims Act, relating to the
promotion and advertising of prescription drugs may lead to investigations and enforcement actions alleging violations of federal and state healthcare fraud
and abuse laws, as well as state consumer protection laws.
In addition, later discovery of previously unknown adverse events or other problems with our products, manufacturers or manufacturing processes,
or failure to comply with regulatory requirements, may have various consequences, including:
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suspension of or restrictions on such products, manufacturers or manufacturing processes;
restrictions and warnings on the labeling or marketing of a product;
restrictions on product distribution or use;
requirements to conduct post-marketing studies or clinical trials;
warning letters or untitled letters;
withdrawal of the products from the market;
refusal to approve pending applications or supplements to approved applications that we submit;
recall of products;
fines, restitution or disgorgement of profits or revenues;
suspension of any ongoing clinical trials;
suspension or withdrawal of marketing approvals;
damage to relationships with any potential collaborators;
unfavorable press coverage and damage to our reputation;
refusal to permit the import or export of our products;
product seizure or detention;
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injunctions or the imposition of civil or criminal penalties; or
litigation involving patients using our products.
Non-compliance with European Union requirements regarding safety monitoring or pharmacovigilance, and with requirements related to the
development of products for the pediatric population, can also result in significant financial penalties. Similarly, failure to comply with the European
Union’s requirements regarding the protection of personal information can also lead to significant penalties and sanctions.
In addition, manufacturers of approved products and those manufacturers’ facilities are required to comply with extensive FDA requirements,
including ensuring that quality control and manufacturing procedures conform to cGMPs applicable to drug manufacturers. We will also be subject to other
regulatory requirements, including submissions of safety and other post-marketing information and reports, registration and listing requirements,
requirements regarding the distribution of samples to clinicians, and recordkeeping.
Our relationships with healthcare providers, physicians and third-party payors will be subject to applicable anti-kickback, fraud and abuse, false
claims, transparency, health information privacy and security, and other healthcare laws and regulations, which, in the event of a violation, could
expose us to criminal sanctions, civil penalties, contractual damages, reputational harm, administrative burdens and diminished profits and future
earnings.
If we obtain regulatory approval and commercialize any products, healthcare providers, physicians and third-party payors will play a primary role in
the recommendation and prescription of any product candidates for which we obtain marketing approval. Our future arrangements with healthcare
providers, physicians and third-party payors may expose us to broadly applicable fraud and abuse and other healthcare laws and regulations that may
constrain the business or financial arrangements and relationships through which we market, sell and distribute any products for which we obtain marketing
approval. In addition, we may be subject to transparency laws and patient privacy regulation by U.S. federal and state governments and by governments in
foreign jurisdictions in which we conduct our business. See the section entitled “Business—Government Regulation and Product Approvals—Health Care
Law and Regulation”.
The distribution of pharmaceutical products is subject to additional requirements and regulations, including extensive record-keeping, licensing,
storage and security requirements intended to prevent the unauthorized sale of pharmaceutical products.
The scope and enforcement of each of these laws is uncertain and subject to rapid change in the current environment of healthcare reform, especially
in light of the lack of applicable precedent and regulations. Efforts to ensure that our business arrangements with third parties will comply with applicable
healthcare laws and regulations will involve substantial costs. It is possible that governmental authorities will conclude that our business practices may not
comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our
operations, including anticipated activities that would be conducted by our sales team, are found to be in violation of any of these laws or any other
governmental regulations that may apply to us, we may be subject to significant civil, criminal and administrative penalties, damages, fines, imprisonment,
exclusion of products from government funded healthcare programs, such as Medicare and Medicaid, and the curtailment or restructuring of our operations.
If any of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws,
they may be subject to criminal, civil or administrative sanctions, including exclusions from participation in government funded healthcare programs.
Compliance with global privacy and data security requirements could result in additional costs and liabilities to us or inhibit our ability to collect and
process data globally, and the failure to comply with such requirements could subject us to significant fines and penalties, which may have a material
adverse effect on our business, financial condition or results of operations.
The regulatory framework for the collection, use, safeguarding, sharing, transfer and other processing of information worldwide is rapidly evolving
and is likely to remain uncertain for the foreseeable future. Globally, virtually every jurisdiction in which we operate has established its own data security
and privacy frameworks with which we must comply. For example, the collection, use, disclosure, transfer, or other processing of personal data regarding
individuals in the EU, including personal health data, is subject to the GDPR, which took effect across all Member States of the EEA, on May 25, 2018.
Similar actions are either in place or under way in the United States. There are a broad variety of data protection laws that are applicable to our
activities, and a wide range of enforcement agencies at both the state and federal levels that can review companies for privacy and data security concerns
based on general consumer protection laws. The Federal Trade Commission and state Attorneys General all are aggressive in reviewing privacy and data
security protections for consumers.
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New laws also are being considered at both the state and federal levels. For example, the CCPA, which went into effect on January 1, 2020, is creating
similar risks and obligations as those created by the GDPR, and many other states are considering similar legislation. A broad range of legislative measures
also have been introduced at the federal level. Accordingly, failure to comply with federal and state laws (both those currently in effect and future
legislation) regarding privacy and security of personal information could expose us to fines and penalties under such laws. There also is the threat of
consumer class actions related to these laws and the overall protection of personal data. For more information regarding the GDPR, the CCPA and other
regulations, see Item 1 “Business –Government Regulation and Product Approvals” in this Annual Report on Form 10-K.
Given the breadth and depth of changes in data protection obligations, preparing for and complying with these requirements is rigorous and time
intensive and requires significant resources and a review of our technologies, systems and practices, as well as those of any third-party collaborators,
service providers, contractors or consultants that process or transfer personal data collected in the EEA. The GDPR and other changes in laws or
regulations associated with the enhanced protection of certain types of sensitive data, such as healthcare data or other personal information from our
clinical trials, could require us to change our business practices and put in place additional compliance mechanisms, may interrupt or delay our
development, regulatory and commercialization activities and increase our cost of doing business, and could lead to government enforcement actions,
private litigation and significant fines and penalties against us and could have a material adverse effect on our business, financial condition or results of
operations. Similarly, failure to comply with federal and state laws regarding privacy and security of personal information could expose us to fines and
penalties under such laws. Even if we are not determined to have violated these laws, government investigations into these issues typically require the
expenditure of significant resources and generate negative publicity, which could harm our reputation and our business.
Recently enacted and future legislation may increase the difficulty and cost for us to obtain marketing approval of and commercialize our product
candidates and affect the prices we may obtain for any products that are approved in the United States or foreign jurisdictions.
In the United States and some foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding
the healthcare system that could prevent or delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our
ability to profitably sell any product candidates for which we obtain marketing approval. The pharmaceutical industry has been a particular focus of these
efforts and has been significantly affected by legislative initiatives. Current laws, as well as other healthcare reform measures that may be adopted in the
future, may result in more rigorous coverage criteria and in additional downward pressure on the price that we receive for any FDA approved product. If
reimbursement of our products is unavailable or limited in scope, our business could be materially harmed. See Item 1 “Business—Government Regulation
and Product Approval—Pharmaceutical Insurance Coverage and Health Care Reform” in this Annual Report on Form 10-K.
We expect that these healthcare reforms, as well as other healthcare reform measures that may be adopted in the future, may result in additional
reductions in Medicare and other healthcare funding, more rigorous coverage criteria, new payment methodologies and additional downward pressure on
the price that we receive for any approved product and/or the level of reimbursement physicians receive for administering any approved product we might
bring to market. Reductions in reimbursement levels may negatively impact the prices we receive or the frequency with which our products are prescribed
or administered. Any reduction in reimbursement from Medicare or other government programs may result in a similar reduction in payments from private
payors.
Governments outside of the United States tend to impose strict price controls, which may adversely affect our revenues, if any.
In countries outside of the United States, particularly the countries of the European Union, the pricing of prescription pharmaceuticals is subject to
governmental control. In these countries, pricing negotiations with governmental authorities can take considerable time after the receipt of marketing
approval for a product. To obtain reimbursement or pricing approval in some countries, we may be required to conduct a clinical trial that compares the
cost-effectiveness of our product candidate to other available therapies. If reimbursement of our products is unavailable or limited in scope or amount, or if
pricing is set at unsatisfactory levels, our business could be harmed, possibly materially.
If we or any third-party manufacturers we engage now or in the future fail to comply with environmental, health and safety laws and regulations, we
could become subject to fines or penalties or incur costs or liabilities that could harm our business.
We and third-party manufacturers we engage now are, and any third-party manufacturers we may engage in the future will be, 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.
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Liability under certain environmental laws governing the release and cleanup of hazardous materials is joint and several and could be imposed without
regard to fault. We also could incur significant costs associated with civil or criminal fines and penalties or become subject to injunctions limiting or
prohibiting our activities for failure to comply with such laws and regulations.
Although we maintain general liability insurance as well as 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, this insurance may not provide adequate coverage against potential liabilities.
We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us in connection with our storage or disposal of
biological, hazardous or radioactive materials.
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. Our failure to comply with these laws and regulations
also may result in substantial fines, penalties or other sanctions.
Further, with respect to the operations of our current and any future third-party contract manufacturers, it is possible that if they fail to operate in
compliance with applicable environmental, health and safety laws and regulations or properly dispose of wastes associated with our products, we could be
held liable for any resulting damages, suffer reputational harm or experience a disruption in the manufacture and supply of our product candidates or
products. In addition, our supply chain may be adversely impacted if any of our third-party contract manufacturers become subject to injunctions or other
sanctions as a result of their non-compliance with environmental, health and safety laws and regulations.
We are subject to anti-corruption laws, as well as export control laws, customs laws, sanctions laws and other laws governing our operations. If we fail
to comply with these laws, we could be subject to civil or criminal penalties, other remedial measures and legal expenses, be precluded from developing
manufacturing and selling certain products outside the United States or be required to develop and implement costly compliance programs, which
could adversely affect our business, results of operations and financial condition.
Our operations are subject to anti-corruption laws, including the U.K. Bribery Act 2010, or Bribery Act, the U.S. Foreign Corrupt Practices Act, or
FCPA, and other anti-corruption laws that apply in countries where we do business and may do business in the future. The Bribery Act, FCPA and these
other laws generally prohibit us, our officers, and our employees and intermediaries from bribing, being bribed or making other prohibited payments to
government officials or other persons to obtain or retain business or gain some other business advantage. Compliance with the FCPA, in particular, is
expensive and difficult, particularly in countries in which corruption is a recognized problem. In addition, the FCPA presents particular challenges in the
pharmaceutical industry, because, in many countries, hospitals are operated by the government, and doctors and other hospital employees are considered
foreign officials. Certain payments to hospitals in connection with clinical trials and other work have been deemed to be improper payments to government
officials and have led to FCPA enforcement actions.
We may in the future operate in jurisdictions that pose a high risk of potential Bribery Act or FCPA violations, and we may participate in
collaborations and relationships with third parties whose actions could potentially subject us to liability under the Bribery Act, FCPA or local anti-
corruption laws. 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. If we expand our operations outside of the United States, we will need to
dedicate additional resources to comply with numerous laws and regulations in each jurisdiction in which we plan to operate.
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 on
countries and persons, customs requirements and currency exchange regulations, collectively referred to as the Trade Control laws. In addition, various
laws, regulations and executive orders also restrict the use and dissemination outside of the United States, or the sharing with certain non-U.S. nationals, of
information classified for national security purposes, as well as certain products and technical data relating to those products. If we expand our presence
outside of the United States, it will require us to dedicate additional resources to comply with these laws, and these laws may preclude us from developing,
manufacturing, or selling certain products and product candidates outside of the United States, which could limit our growth potential and increase our
development costs.
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. The Securities and Exchange
Commission, or SEC, also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions. Any
investigation of any potential violations of the Bribery Act, the FCPA, other anti-corruption laws or Trade Control laws by United Kingdom, U.S. or other
authorities could also have an adverse impact on our reputation, our business, results of operations and financial condition.
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Our employees, independent contractors, consultants and vendors may engage in misconduct or other improper activities, including non-compliance
with regulatory standards and requirements and insider trading, which could cause significant liability for us and harm our reputation.
We are exposed to the risk of fraud or other misconduct by our employees, independent contractors, consultants and vendors. Misconduct by these
partners could include intentional failures to comply with FDA regulations or similar regulations of comparable foreign regulatory authorities, provide
accurate information to the FDA or comparable foreign regulatory authorities, comply with manufacturing standards, comply with federal and state
healthcare fraud and abuse laws and regulations and similar laws and regulations established and enforced by comparable foreign regulatory authorities,
report financial information or data accurately or disclose unauthorized activities to us. Employee misconduct could also involve the improper use of
information obtained in the course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation. This could include
violations of HIPAA, other U.S. federal and state law, and requirements of non-U.S. jurisdictions, including the European Union Data Protection Directive.
We are also exposed to risks in connection with any insider trading violations by employees or others affiliated with us. 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 failure to be in compliance with such
laws, standards, regulations, guidance or codes of conduct. 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 and results of operations, including the imposition of significant fines or
other sanctions.
Our internal computer systems, or those of our collaborators or other contractors or consultants, may fail or suffer security breaches, which could
result in a material disruption of our product development programs.
Our internal computer systems and those of any collaborators, contractors or consultants are vulnerable to damage from computer viruses,
unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures. Such systems are also vulnerable to service
interruptions or to security breaches from inadvertent or intentional actions by our employees, third-party vendors and/or business partners, or from cyber-
attacks by malicious third parties. Cyber-attacks are increasing in their frequency, sophistication and intensity, and have become increasingly difficult to
detect. Cyber-attacks could include the deployment of harmful malware, ransomware, denial-of-service attacks, unauthorized access to or deletion of files,
social engineering and other means to affect service reliability and threaten the confidentiality, integrity and availability of information. For example, we
make extensive use of cloud-based storage systems, and in October 2018, we experienced a breach of one such system. While this breach did not result in
the permanent loss or theft of any of our critical information or any other material consequences, it could have, and while we took steps to remediate this
breach, such as establishing multi-factor authentication and implementing improvements to our data securities protocols, we cannot guarantee that the
measures we have taken to date, and actions we may take in the future, will be sufficient to remediate any future breaches. Cyber-attacks also could include
phishing attempts or e-mail fraud to cause payments or information to be transmitted to an unintended recipient.
While we have not experienced any material system failure, accident, cyber-attack or security breach to date, if such an event were to occur and
cause interruptions in our 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 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.
Risks Related to Employee Matters and Managing Growth
Our future success depends on our ability to retain key executives and to attract, retain and motivate qualified personnel.
We are highly dependent on the research and development, clinical, financial, operational and other business expertise of our executive officers, as
well as the other principal members of our management, scientific and clinical teams. Although we have entered into employment offer letters with our
executive officers, each of them may terminate their employment with us at any time. We do not maintain “key person” insurance for any of our executives
or other employees. Recruiting and retaining qualified scientific, clinical, manufacturing, accounting, legal and sales and marketing personnel will also be
critical to our success.
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We have had recent executive transitions, including of our chief executive officer, chief scientific officer and chief financial officer. We cannot
predict the likelihood, timing or effect of future transitions among our executive leadership. The loss of the services of our executive officers or other key
employees could impede the achievement of our research, development and commercialization objectives and seriously harm our ability to successfully
implement our business strategy. Furthermore, replacing executive officers and key employees may be difficult and may take an extended period of time
because of the limited number of individuals in our industry with the breadth of skills and experience required to successfully develop, gain regulatory
approval of and commercialize products. Competition to hire from this limited pool is intense, and we may be unable to hire, train, retain or motivate these
key personnel on acceptable terms given the competition among numerous pharmaceutical and biotechnology companies for similar personnel. We also
experience competition for the hiring of scientific and clinical personnel from universities and research institutions. In addition, we rely on consultants and
advisors, including scientific and clinical advisors, to assist us in formulating our research and development and commercialization strategy. Our
consultants and advisors may be employed by employers other than us and may have commitments under consulting or advisory contracts with other
entities that may limit their availability to us. Our success as a public company also depends on implementing and maintaining internal controls and the
accuracy and timeliness of our financial reporting. If we are unable to continue to attract and retain high quality personnel, our ability to pursue our growth
strategy will be limited.
We expect to expand our development and regulatory capabilities and potentially implement sales, marketing and distribution capabilities, and as a
result, we may encounter difficulties in managing our growth, which could disrupt our operations.
We expect to experience significant growth in the number of our employees and the scope of our operations, particularly in the areas of drug
development, clinical, regulatory affairs and, if any of our product candidates receives marketing approval, sales, marketing and distribution. To manage
our anticipated future growth, we must continue to implement and improve our managerial, operational and financial systems, expand our facilities and
continue to recruit and train additional qualified personnel. Due to our limited financial resources and the limited experience of our management team in
managing a company with such anticipated growth, we may not be able to effectively manage the expansion of our operations or recruit and train additional
qualified personnel. The expansion of our operations may lead to significant costs and may divert our management and business development resources.
Any inability to manage growth could delay the execution of our business plans or disrupt our operations.
Risks Related to our Common Stock
Our executive officers, directors and principal stockholders, if they choose to act together, have the ability to control or significantly influence all
matters submitted to stockholders for approval.
As of February 24, 2022, our executive officers and directors and our stockholders who owned more than 5% of our outstanding common stock in
the aggregate beneficially owned shares representing approximately 56.1% of our capital stock. As a result, if these stockholders were to choose to act
together, they would be able to control or significantly influence all matters submitted to our stockholders for approval, as well as our management and
affairs. For example, these persons, if they choose to act together, would control the election of directors and approval of any merger, consolidation or sale
of all or substantially all of our assets.
This concentration of ownership control may:
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delay, defer or prevent a change in control;
entrench our management and board of directors; or
delay or prevent a merger, consolidation, takeover or other business combination involving us that other stockholders may desire.
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Provisions in our corporate charter documents and under Delaware law could make an acquisition of our company, which may be beneficial to our
stockholders, more difficult and may prevent attempts by our stockholders to replace or remove our current directors and members of management.
Provisions in our certificate of incorporation and our bylaws may discourage, delay or prevent a merger, acquisition or other change in control of our
company that stockholders may consider favorable, including transactions in which stockholders might otherwise receive a premium for their shares. These
provisions could also limit the price that investors might be willing to pay in the future for shares of our common stock, thereby depressing the market price
of our common stock. In addition, because our board of directors is responsible for appointing the members of our management team, these provisions may
frustrate or prevent any attempts by our stockholders to replace or remove our current management by making it more difficult for stockholders to replace
members of our board of directors. Among other things, these provisions:
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establish a classified board of directors such that only one of three classes of directors is elected each year;
allow the authorized number of our directors to be changed only by resolution of our board of directors;
limit the manner in which stockholders can remove directors from our board of directors;
establish advance notice requirements for stockholder proposals that can be acted on at stockholder meetings and nominations to our board of
directors;
require that stockholder actions must be effected at a duly called stockholder meeting and prohibit actions by our stockholders by written
consent;
limit who may call stockholder meetings;
authorize our board of directors to issue preferred stock without stockholder approval, which could be used to institute a “poison pill” that
would work to dilute the stock ownership of a potential hostile acquirer, effectively preventing acquisitions that have not been approved by our
board of directors; and
require the approval of the holders of at least 75% of the votes that all our stockholders would be entitled to cast to amend or repeal specified
provisions of our certificate of incorporation or bylaws.
Moreover, because we are incorporated in Delaware, we are governed by the provisions of Section 203 of the Delaware General Corporation Law,
or the DGCL, which prohibits a person who owns in excess of 15% of our outstanding voting stock from merging or combining with us for a period of
three years after the date of the transaction in which the person acquired in excess of 15% of our outstanding voting stock, unless the merger or
combination is approved in a prescribed manner.
If securities analysts do not publish or cease publishing research or reports or publish misleading, inaccurate or unfavorable research about our
business or if they publish negative evaluations of our stock, the price and trading volume of our stock could decline.
The trading market for our common stock relies, in part, on the research and reports that industry or financial analysts publish about us or our
business. There can be no assurance that existing analysts will continue to cover us or that new analysts will begin to cover us. There is also no assurance
that any covering analyst will provide favorable coverage. Although we have obtained analyst coverage, if one or more of the analysts covering our
business downgrade their evaluations of our stock or publish inaccurate or unfavorable research about our business, or provides more favorable relative
recommendations about our competitors, the price of our stock could decline. If one or more of these analysts cease to cover our stock, we could lose
visibility in the market for our stock, which in turn could cause our stock price and trading volume to decline.
The price of our common stock may be volatile and fluctuate substantially, which could result in substantial losses for our stockholders.
The trading price of our common stock has been, and is likely to continue to be volatile and could be subject to wide fluctuations in response to
various factors, some of which are beyond our control. The stock market in general and the market for smaller biopharmaceutical companies in particular
have experienced extreme volatility that has often been unrelated to
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the operating performance of particular companies. The market price for our common stock may be influenced by many factors, including:
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results of or developments in preclinical studies and clinical trials of our product candidates or those of our competitors or potential
collaborators;
our success in commercializing our product candidates, if and when approved;
the success of competitive products or technologies;
regulatory or legal developments in the United States and other countries;
developments or disputes concerning patent applications, issued patents or other intellectual property or proprietary rights;
the recruitment or departure of key personnel;
the level of expenses related to any of our product candidates or clinical development programs;
the results of our efforts to discover, develop, acquire or in-license products, product candidates, technologies or data referencing rights, the
costs of commercializing any such products and the costs of development of any such product candidates or technologies;
actual or anticipated changes in estimates as to financial results, development timelines or recommendations by securities analysts;
variations in our financial results or the financial results of companies that are perceived to be similar to us;
changes in the structure of healthcare payment systems;
market conditions in the pharmaceutical and biotechnology sectors;
general economic, industry and market conditions; and
the other factors described in this “Risk Factors” section.
In the past, following periods of volatility in the market price of a company’s securities, securities class-action litigation has often been instituted
against that company. Any lawsuit to which we are a party, with or without merit, may result in an unfavorable judgment. We also may decide to settle
lawsuits on unfavorable terms. Any such negative outcome could result in payments of substantial damages or fines, damage to our reputation or adverse
changes to our offerings or business practices. Such litigation may also cause us to incur other substantial costs to defend such claims and divert
management’s attention and resources. Furthermore, negative public announcements of the results of hearings, motions or other interim proceedings or
developments could have a negative effect on the market price of our common stock.
A significant portion of our total outstanding shares are eligible to be sold into the market in the near future, which could cause the market price of our
common stock to drop significantly, even if our business is doing well.
Sales of a substantial number of shares of our common stock in the public market, or the perception in the market that the holders of a large number
of shares intend to sell shares, could reduce the market price of our common stock. Persons who were our stockholders prior to our initial public offering
continue to hold a substantial number of shares of our common stock. If such persons sell, or indicate an intention to sell, substantial amounts of our
common stock in the public market, the trading price of our common stock could decline.
Moreover, holders of a substantial number of shares of our common stock have rights, subject to specified conditions, to require us to file
registration statements covering their shares or to include their shares in registration statements that we may file for ourselves or other stockholders.
In June 2020, we issued and sold 4,029,411 shares of common stock to investors in a private placement. We have filed a registration statement
covering the resale of these shares by the purchasers in the private placement and have agreed to keep such registration statement effective until the date the
shares covered by the registration statement have been sold or can be resold without restriction under Rule 144 of the Securities Act of 1933, as amended,
or the Securities Act.
We currently have on file with the SEC a universal shelf registration statement which allows us to offer and sell registered common stock, preferred
stock, debt securities, depositary shares, warrants and/or units from time to time pursuant to one or more offerings up to an aggregate of $250 million, at
prices and terms to be determined at the time of sale.
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In addition, we have filed or intend to file registration statements registering all shares of common stock that we may issue under our equity
compensation plans or pursuant to equity awards made to newly hired employees outside of equity compensation plans. Such registered shares can be
freely sold in the public market upon issuance, subject to volume limitations applicable to affiliates.
We are an “emerging growth company,” and the reduced disclosure requirements applicable to emerging growth companies may make our common
stock less attractive to investors.
We are an “emerging growth company,” or EGC, as defined in the Jumpstart Our Business Startups Act of 2012, or the JOBS Act. We may remain
an EGC until December 31, 2024, although if the market value of our common stock that is held by non-affiliates exceeds $700 million as of any June 30
before that time or if we have annual gross revenues of $1.07 billion or more in any fiscal year, we would cease to be an EGC as of December 31 of the
applicable year. We also would cease to be an EGC if we issue more than $1 billion of non-convertible debt over a three-year period. For so long as we
remain an EGC, we are permitted and intend to rely on exemptions from certain disclosure requirements that are applicable to other public companies that
are not EGCs. These exemptions include:
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not being required to comply with the auditor attestation requirements in the assessment of our internal control over financial reporting;
not being required to comply with any requirement that may be adopted by the Public Company Accounting Oversight Board regarding
mandatory audit firm rotation or a supplement to the auditor’s report providing additional information about the audit and the financial
statements;
reduced disclosure obligations regarding executive compensation; and
exemptions from the requirements of holding a nonbinding advisory vote on executive compensation and stockholder approval of any golden
parachute payments not previously approved.
We may choose to take advantage of some or all of the available exemptions. We cannot predict whether investors will find our common stock less
attractive if we rely on these exemptions. If some investors find our common stock less attractive as a result, there may be a less active trading market for
our common stock and our stock price may be more volatile.
In addition, the JOBS Act permits an EGC to take advantage of an extended transition period to comply with new or revised accounting standards
applicable to public companies until those standards would otherwise apply to private companies. We have elected not to “opt out” of such extended
transition period, which means that when a standard is issued or revised and it has different application dates for public or private companies, we will adopt
the new or revised standard at the time private companies adopt the new or revised standard and will do so until such time that we either (i) irrevocably
elect to “opt out” of such extended transition period or (ii) no longer qualify as an EGC.
We have incurred and will continue to incur increased costs as a result of operating as a public company, and our management will be required to
devote substantial time to new compliance initiatives and corporate governance practices.
As a public company we have incurred, and particularly after we are no longer an EGC, we will continue to incur significant legal, accounting and
other expenses that we did not incur as a private company. The Sarbanes-Oxley Act of 2002, the Dodd-Frank Wall Street Reform and Consumer Protection
Act, the listing requirements of the Nasdaq Global Market and other applicable securities rules and regulations impose various requirements on public
companies, including establishment and maintenance of effective disclosure and financial controls and corporate governance practices. Our management
and other personnel will need to devote a substantial amount of time to these compliance initiatives. Moreover, these rules and regulations will increase our
legal and financial compliance costs, particularly as we hire additional financial and accounting employees to meet public company internal control and
financial reporting requirements, and will make some activities more time-consuming and costly. For example, we expect that these rules and regulations
may make it more difficult and more expensive for us to obtain director and officer liability insurance, which in turn could make it more difficult for us to
attract and retain qualified members of our board of directors.
We are evaluating these rules and regulations, and cannot predict or estimate the amount of additional costs we may incur or the timing of such
costs. These rules and regulations are often subject to varying interpretations, in many cases due to their lack of specificity, and, as a result, their application
in practice may evolve over time as new guidance is provided by regulatory and governing bodies. This could result in continuing uncertainty regarding
compliance matters and higher costs necessitated by ongoing revisions to disclosure and governance practices.
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Pursuant to Section 404 of the Sarbanes-Oxley Act of 2002, or Section 404, we are required to furnish a report by our management on our internal
control over financial reporting. However, while we remain an EGC or a smaller reporting company with less than $100 million in revenue, we will not be
required to include an attestation report on internal control over financial reporting issued by our independent registered public accounting firm. To achieve
compliance with Section 404 within the prescribed period, we will be engaged in a process to document and evaluate our internal control over financial
reporting, which is both costly and challenging. In this regard, we will need to continue to dedicate internal resources, including through hiring additional
financial and accounting personnel, potentially engage outside consultants and adopt a detailed work plan to assess and document the adequacy of internal
control over financial reporting, continue steps to improve control processes as appropriate, validate through testing that controls are functioning as
documented and implement a continuous reporting and improvement process for internal control over financial reporting. Despite our efforts, there is a risk
that we will not be able to conclude, within the prescribed timeframe or at all, that our internal control over financial reporting is effective as required by
Section 404. If we identify one or more material weaknesses in our internal control over financial reporting, it could result in an adverse reaction in the
financial markets due to a loss of confidence in the reliability of our financial statements.
Because we do not anticipate paying any cash dividends on our capital stock in the foreseeable future, capital appreciation, if any, will be our
stockholders’ sole source of gain.
We have never declared or paid cash dividends on our capital stock. We currently intend to retain all of our future earnings, if any, to finance the
growth and development of our business. As a result, capital appreciation, if any, of our common stock will be our stockholders’ sole source of gain for the
foreseeable future.
Our certificate of incorporation designates the state courts in the State of Delaware as the sole and exclusive forum for certain types of actions and
proceedings that may be initiated by our stockholders, which could discourage lawsuits against the company and our directors, officers and employees.
Our certificate of incorporation provides that, unless we consent in writing to the selection of an alternative forum, the Court of Chancery of the
State of Delaware (or, if the Court of Chancery of the State of Delaware does not have jurisdiction, the federal district court for the District of Delaware)
will be the sole and exclusive forum for (1) any derivative action or proceeding brought on our behalf, (2) any action asserting a claim of breach of a
fiduciary duty owed by any of our directors, officers, employees or stockholders to our company or our stockholders, (3) any action asserting a claim
arising pursuant to any provision of the DGCL or as to which the DGCL confers jurisdiction on the Court of Chancery of the State of Delaware or (4) any
action asserting a claim arising pursuant to any provision of our certificate of incorporation or bylaws (in each case, as they may be amended from time to
time) or governed by the internal affairs doctrine. This exclusive forum provision will not apply to actions arising under the Securities Act or the Securities
Exchange Act of 1934, as amended.
This exclusive forum provision may limit the ability of our stockholders to bring a claim in a judicial forum that such stockholders find favorable for
disputes with us or our directors, officers or employees, which may discourage such lawsuits against us and our directors, officers and employees.
Alternatively, if a court were to find the choice of forum provision contained in our certificate of incorporation to be inapplicable or unenforceable in an
action, we may incur additional costs associated with resolving such action in other jurisdictions, which could materially adversely affect our business,
financial condition and operating results.
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Item 1B. Unresolved Staff Comments.
Not applicable.
Item 2. Properties.
Our principal facilities consist of office and laboratory space. We occupy approximately 28,731 square feet of office space in Cambridge,
Massachusetts under a lease that currently expires in June 2028.
Item 3. Legal Proceedings.
We are not currently a party to any material legal proceedings.
Item 4. Mine Safety Disclosures.
Not applicable.
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PART II
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities.
Market Information
Our common stock trades under the symbol “FULC” on the Nasdaq Global Market and has been publicly traded since July 18, 2019. Prior to this
time, there was no public market for our common stock.
Holders of Our Common Stock
As of February 24, 2022, there were approximately 22 holders of record of shares of our common stock. This number does not include stockholders
for whom shares are held in “nominee” or “street” name.
Dividends
We have never declared or paid any cash dividends on our capital stock. We currently intend to retain all available funds and any future earnings for
use in the operation of our business and do not anticipate paying any dividends on our common stock in the foreseeable future. Any future determination to
declare dividends will be made at the discretion of our board of directors and will depend on our financial condition, operating results, capital requirements,
general business conditions and other factors that our board of directors may deem relevant.
Unregistered Sales of Equity Securities and Use of Proceeds
Recent Sales of Unregistered Securities
Effective September 7, 2021, we granted one employee an option to purchase 140,000 shares of our common stock at an exercise price of $28.49 per
share. Effective September 30, 2021, we granted one employee an option to purchase 58,000 shares of our common stock at an exercise price of $28.21 per
share. These options were inducement grants in accordance with Nasdaq Listing Rule 5635(c)(4), which were made outside of our 2019 Stock Incentive
Plan. The options have a ten-year term and vest over four years, with 25% of the shares underlying the option grants vesting on the first anniversary of the
respective employee’s start date and an additional 6.25% of the shares vesting in equal quarterly installments over the twelve successive quarters following
the first anniversary of the respective start date, subject to such employee’s continued service with us through the applicable vesting dates. We filed a
registration statement on a Form S-8 to register the shares of common stock underlying these options.
No underwriters were involved in the foregoing issuances of securities. The securities were issued pursuant to Section 4(a)(2) under the Securities
Act of 1933, as amended, relating to transactions by an issuer not involving any public offering. The recipients either received adequate information about
us or had access, through other relationships, to such information.
Other than as reported in a Current Report on Form 8-K, we did not sell any securities that were not registered under the Securities Act during the
year ended December 31, 2021.
Item 6. Reserved.
Not applicable.
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Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations.
The following discussion and analysis of our financial condition and results of operations should be read together with our consolidated financial
statements and related notes appearing at the end of this Annual Report on Form 10-K. Some of the information contained in this discussion and analysis
or set forth elsewhere in this Annual Report on Form 10-K, including information with respect to our plans and strategy for our business, includes forward-
looking statements that involve risks and uncertainties. As a result of many factors, including those factors set forth in the “Risk Factors” section of this
Annual Report on Form 10-K, our actual results could differ materially from the results described in or implied by the forward-looking statements
contained in the following discussion and analysis.
Overview
We are a clinical-stage biopharmaceutical company focused on improving the lives of patients with genetically defined rare diseases in areas of high
unmet medical need. Our most advanced product candidate, losmamipod, is in development to treat the root cause of FSHD. Our other clinical product
candidate is FTX-6058, which is being developed for the treatment of certain hemoglobinopathies, including SCD and ß-thalassemia. We expect to initiate
REACH, a randomized, double-blind, placebo-controlled, multi-national Phase 3 clinical trial of losmapimod, our product candidate for FSHD, in the
second quarter of 2022. We initiated a Phase 1b clinical trial of FTX-6058 in people with SCD in the fourth quarter of 2021, and we expect to report initial
data from that Phase 1b trial in the second quarter of 2022. Additionally, we submitted an IND in the fourth quarter of 2021 for FTX-6058 in other select
hemoglobinopathies, including ß-thalassemia, and expect to initiate a Phase 1b study in the second quarter of 2022.
We have developed a proprietary product engine, FulcrumSeek, that we employ to systematically identify and validate cellular drug targets that can
potentially modulate gene expression to treat the known root cause of genetically defined diseases. Our product engine integrates patient-derived tissue-
and disease-relevant cell models that we interrogate using our pharmacologically diverse and highly annotated small-molecule compound library and
customized CRISPR and RNAi libraries. These screens generate tens of millions of data points and high-content imaging. We then apply computational
biology and analytics to identify targets with specificity and selectivity accompanied by a comprehensive data set that significantly accelerates
development. This approach led to the identification of both losmapimod for FSHD and FTX-6058 for hemoglobinopathies, as well as a robust discovery
pipeline. We expect to nominate our next development candidate this year to support our fourth IND by the end of the first quarter of 2023.
Since inception, our operations have focused on organizing and staffing our company, business planning, raising capital, establishing our intellectual
property, building our discovery platform, including our proprietary compound library and product engine, identifying drug targets and potential product
candidates, in-licensing assets, producing drug substance and drug product material for use in clinical trials and conducting preclinical studies and clinical
trials. To date, we have funded our operations primarily from the sale of shares of our common stock in public offerings, a private placement, and in the
ATM Offering, through issuances of convertible preferred stock, and from upfront payments received under our collaboration and license agreements.
In January 2021, we issued and sold 4,600,000 shares of our common stock in a public offering at a public offering price of $11.00 per share, which
includes 600,000 shares issued upon the exercise in full by the underwriters of their option to purchase additional shares at the public offering price, less
underwriting discounts and commissions. The net proceeds of the offering were $47.4 million, after deducting underwriting discounts and commissions and
offering expenses.
In August 2021, we issued and sold 7,590,000 shares of our common stock in a public offering at a public offering price of $19.00 per share, which
includes 990,000 shares issued upon the exercise in full by the underwriters of their option to purchase additional shares at the public offering price, less
underwriting discounts and commissions. The net proceeds of the offering were $135.5 million, after deducting underwriting discounts and commissions
and offering expenses.
94
We have incurred significant operating losses since our inception and we expect to continue to incur significant operating losses for the foreseeable
future. Our ability to generate product revenue sufficient to achieve profitability, if ever, will depend heavily on the successful development and eventual
commercialization of one or more of our product candidates. Our net losses were $80.8 million and $70.8 million for the years ended December 31, 2021
and 2020, respectively. As of December 31, 2021, we had an accumulated deficit of $302.5 million. We expect our expenses and operating losses will
increase substantially over the next several years in connection with our ongoing activities, as we:
•
•
•
•
•
•
•
•
•
•
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•
continue our clinical development of losmapimod and FTX-6058;
continue our ongoing preclinical studies;
advance clinical-stage product candidates into later stage trials;
pursue the discovery of drug targets for other genetically-defined rare diseases and the subsequent development of any resulting product
candidates;
seek regulatory approvals for any product candidates that successfully complete clinical trials;
scale up our manufacturing processes and capabilities, or arrange for a third party to do so on our behalf, to support our clinical trials of our
product candidates and commercialization of any of our product candidates for which we obtain marketing approval;
establish a sales, marketing and distribution infrastructure to commercialize any products for which we may obtain regulatory approval;
acquire or in-license products, product candidates, technologies and/or data referencing rights;
make any milestone payments to affiliates of GSK under our right of reference and license agreement with GSK upon the achievement of
specified clinical or regulatory milestones;
maintain, expand, enforce, defend and protect our intellectual property;
hire additional clinical, quality control and scientific personnel; and
add operational, financial and management information systems and personnel, including personnel to support our product development and
planned future commercialization efforts and our operations as a public company.
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, strategic alliances and marketing, distribution or licensing arrangements. We may be unable to raise additional funds or enter into such other
agreements or arrangements when needed on favorable terms, or at all. If we fail to raise capital or enter into such agreements as, and when, needed, we
may have to significantly delay, scale back or discontinue the development and commercialization of one or more of our product candidates, or grant rights
to develop and market our product candidates even if we would otherwise prefer to develop and market such product candidates ourselves.
Because of the numerous risks and uncertainties associated with drug development, we are unable to predict the timing or amount of increased
expenses or the timing of when or if we will be able to achieve or maintain profitability. Even if we are able to generate product sales, 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.
As of December 31, 2021, we had $218.2 million in cash, cash equivalents, and marketable securities. We believe that our existing cash, cash
equivalents, and marketable securities will enable us to fund our operating expenses and capital expenditure requirements into 2024. 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. See “—Liquidity and
Capital Resources.”
95
Components of Results of Operations
Revenue
We have not generated any revenue from product sales and do not expect to generate revenue from the sale of products for several years, if at all. If
our development efforts for our current or future product candidates are successful and result in marketing approval, we may generate revenue in the future
from product sales. We cannot predict if, when or to what extent we will generate revenue from the commercialization and sale of our product candidates.
We may never succeed in obtaining regulatory approval for any of our product candidates.
In December 2019, we entered into a collaboration and license agreement with Acceleron to identify biological targets to modulate specific
pathways associated with a targeted indication within the pulmonary disease space. Under the collaboration agreement, we granted Acceleron an exclusive
worldwide license under certain intellectual property rights to make, have made, use, sell, have sold, import, export, distribute and have distributed, market,
have marketed, promote, have promoted, or otherwise exploit molecules and products directed against or expressing certain biological targets identified by
us for the treatment, prophylaxis, or diagnosis of a targeted indication within the pulmonary disease space. Acceleron was subsequently acquired by Merck
in November 2021. The primary goal of the collaboration is to identify and validate potential biological targets for further research in order to support the
development, manufacture and commercialization of product candidates by Acceleron for the targeted indication by leveraging our proprietary product
engine.
Under the terms of the collaboration agreement, we received a $10.0 million upfront payment from Acceleron in December 2019 and in December
2020, achieved $2.0 million of specified research milestones. We are also eligible to receive up to $436.5 million in the aggregate in milestone payments
with respect to certain research, developmental, clinical, regulatory and sales-related milestones, and tiered royalty payments based on Acceleron’s (and
any of its affiliates’ and sublicensees’) annual worldwide net sales of products directed to any identified targets.
For the years ended December 31, 2021 and 2020 we recognized $9.6 million and $6.3 million, respectively, of collaboration revenue under the
Acceleron collaboration agreement. As of December 31, 2021 and December 31, 2020, we recorded $0.6 million and $7.9 million, respectively, of deferred
revenue associated with the Acceleron collaboration agreement, which is classified as either current or net of current portion in our consolidated balance
sheets based on the period over which the revenue is expected to be recognized. As of December 31, 2021, we had received $3.9 million of cost
reimbursement payments and $2.0 million of milestone payments under the Acceleron collaboration agreement. As of December 31, 2021, we recorded
unbilled accounts receivable of $0.7 million related to reimbursable research and development costs under the Acceleron collaboration agreement for
activities performed during the three months ended December 31, 2021.
In the future, we will recognize additional revenue associated with the $10.0 million upfront payment and the $2.0 million of specified research
milestones achieved in December 2020 as we satisfy our performance obligation, and from reimbursement of costs incurred under the Acceleron
collaboration agreement. In the future, we may also generate additional revenue from milestones and royalty payments under the Acceleron collaboration
agreement. We expect that our revenue will fluctuate from quarter-to-quarter and year-to-year based upon our pattern of performance under the Acceleron
collaboration agreement and as a result of the timing, amount, and achievement of milestones and reimbursement of costs incurred under the Acceleron
collaboration agreement.
On July 20, 2020, we entered into a collaboration and license agreement with MyoKardia, pursuant to which we granted to MyoKardia an exclusive
worldwide license under certain intellectual property rights to research, develop, make, have made, use, have used, sell, have sold, offer for sale, have
offered for sale, import, have imported, export, have exported, distribute, have distributed, market, have marketed, promote, have promoted, or otherwise
exploit products directed against certain biological targets identified by us that are capable of modulating up to a certain number of genes of interest with
relevance to certain genetically defined cardiomyopathies. MyoKardia was subsequently acquired by Bristol-Myers Squibb Company in November 2020.
The primary goal of the collaboration is to identify and validate potential biological targets for further research, in order to support the development,
manufacture and commercialization of product candidates by MyoKardia for the potential treatment of certain genetically defined cardiomyopathies.
Under the terms of the MyoKardia collaboration agreement, we received a $10.0 million upfront payment and a $2.5 million payment as prepaid
research funding in July 2020. MyoKardia will also reimburse us for the costs of the research activities not covered by the prepaid research funding, up to a
maximum amount of total research funding (including the prepaid research funding). Upon the achievement of specified preclinical, development and sales
milestones, we will be entitled to preclinical milestone payments, development milestone payments and sales milestone payments of up to $298.5
96
million in the aggregate per target for certain potential cardiomyopathy gene targets, and of up to $150.0 million in the aggregate per target for certain other
potential cardiomyopathy gene targets. To date, we have achieved a $2.5 million specified preclinical milestone. MyoKardia will also pay us tiered
royalties ranging from a mid single-digit percentage to a low double-digit percentage based on MyoKardia’s, and any of its affiliates’ and sublicensees’,
annual worldwide net sales of products under the MyoKardia collaboration agreement directed against any identified target. The royalties are payable on a
product-by-product basis during a specified royalty term, and may be reduced in specified circumstances.
For the years ended December 31, 2021 and 2020 we recognized $9.6 million and $2.5 million, respectively, of collaboration revenue under the
MyoKardia collaboration agreement. As of December 31, 2021 and 2020, we have recorded $4.1 million and $10.0 million, respectively, of deferred
revenue associated with the MyoKardia collaboration agreement, which is classified as either current or net of current portion in our consolidated balance
sheets based on the period over which the revenue is expected to be recognized. As of December 31, 2021, we had received $0.7 million of cost
reimbursement payments and $2.5 million of milestone payments under the MyoKardia collaboration agreement, as well as the $2.5 million payment as
prepaid research funding in July 2020. As of December 31, 2021, we recorded $2.5 million of accounts receivable associated with the achievement of a
preclinical milestone in December 2021. As of December 31, 2021, we recorded unbilled accounts receivable of $0.5 million related to reimbursable
research and development costs under the MyoKardia collaboration agreement for activities performed during the three months ended December 31, 2021.
In the future, we will recognize additional revenue associated with the $10.0 million upfront payment and the $2.5 million preclinical milestone
achieved in December 2021, and from reimbursement of costs incurred under the MyoKardia collaboration agreement. In the future, we may also generate
additional revenue from milestones and royalty payments under the MyoKardia collaboration agreement. We expect that our revenue will fluctuate from
quarter-to-quarter and year-to-year based upon our pattern of performance under the MyoKardia collaboration agreement and as a result of the timing,
amount, and achievement of milestones and reimbursement of costs incurred under the MyoKardia collaboration agreement.
We may also in the future enter into additional license or collaboration agreements for our product candidates or intellectual property, and we may
generate revenue in the future from payments as a result of such license or collaboration agreements.
Operating Expenses
Research and Development Expenses
Research and development expenses represent costs incurred by us for the discovery, development, and manufacture of our product candidates and
include:
•
•
•
•
•
external research and development expenses incurred under agreements with contract research organizations, CMOs, and consultants;
salaries, payroll taxes, employee benefits and stock-based compensation expenses for individuals involved in research and development efforts;
laboratory supplies;
costs related to compliance with regulatory requirements; and
facilities, depreciation and other allocated expenses, which include direct and allocated expenses for rent, maintenance of facilities, insurance
and other operating costs.
We expense research and development costs as incurred. We recognize expenses for certain development activities, such as clinical trials and
manufacturing, based on an evaluation of the progress to completion of specific tasks using data such as patient enrollment or other information provided to
us by our vendors. Payments for these activities are based on the terms of the individual agreements, which may differ from the pattern of expenses
incurred. Non-refundable advance payments for goods or services to be received in the future for use in research and development activities are recorded as
prepaid expenses. These amounts are recognized as an expense as the goods are delivered or the related services are performed, or until it is no longer
expected that the goods will be delivered or the services rendered.
External costs represent a significant portion of our research and development expenses, which we track on a program-by-program basis following
the nomination of a development candidate. Our internal research and development expenses consist primarily of personnel-related expenses, including
stock-based compensation expense. We do not track our internal research and development expenses on a program-by-program basis as the resources are
deployed across multiple projects.
97
The following table summarizes our external research and development expenses by program following nomination as a development candidate for
the years ended December 31, 2021 and 2020. Pre-development candidate expenses, unallocated expenses and internal research and development expenses
are classified separately.
(in thousands)
Losmapimod external expenses
FTX-6058 external expenses
Pre-development candidate expenses and unallocated expenses
Internal research and development expenses
Total research and development expenses
Year Ended
December 31,
2021
2020
19,128 $
14,041
16,100
20,432
69,701 $
22,954
5,538
14,775
15,775
59,042
$
$
The successful development of our product candidates is highly uncertain. At this time, we cannot reasonably estimate or know the nature, timing,
and estimated costs of the efforts that will be necessary to complete the remainder of the development of our product candidates. We are also unable to
predict when, if ever, material net cash inflows will commence from our product candidates, if approved. This is due to the numerous risks and
uncertainties associated with developing our product candidates, including the uncertainty related to:
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•
•
•
•
•
•
•
•
•
•
the timing and progress of preclinical and clinical development activities, including in light of the ongoing COVID-19 pandemic;
the number and scope of preclinical and clinical programs we decide to pursue;
our ability to raise additional funds necessary to complete clinical development of and commercialize our product candidates;
our ability to maintain our current research and development programs and to establish new ones;
our ability to establish new licensing or collaboration arrangements;
the progress of the development efforts of parties with whom we may enter into collaboration arrangements;
the successful initiation and completion of clinical trials with safety, tolerability and efficacy profiles that are satisfactory to the FDA or any
comparable foreign regulatory authority;
the receipt and related terms of regulatory approvals from applicable regulatory authorities;
the availability of raw materials and active pharmaceutical ingredient, or API, for use in production of our product candidates;
our ability to establish and operate a manufacturing facility, or secure manufacturing supply through relationships with third parties;
our ability to consistently manufacture our product candidates in quantities sufficient for use in clinical trials;
our ability to obtain and maintain intellectual property protection and regulatory exclusivity, both in the United States and internationally;
our ability to maintain, enforce, defend and protect our rights in our intellectual property portfolio;
the commercialization of our product candidates, if and when approved;
our ability to obtain and maintain third-party coverage and adequate reimbursement for our product candidates, if approved;
the acceptance of our product candidates, if approved, by patients, the medical community and third-party payors;
competition with other products; and
a continued acceptable safety profile of our products following receipt of any regulatory approvals.
A change in the outcome of any of these variables with respect to the development of any of our product candidates would significantly change the
costs and timing associated with the development of that product candidate, and potentially other candidates.
98
Research and development activities account for a significant portion of our operating expenses. We expect our research and development expenses
to increase significantly in future periods as we continue to implement our business strategy, which includes advancing losmapimod for the treatment of
FSHD, advancing FTX-6058 for the treatment of certain hemoglobinopathies, expanding our research and development efforts, including hiring additional
personnel to support our research and development efforts, and seeking regulatory approvals for our product candidates that successfully complete clinical
trials. In addition, product candidates in later stages of clinical development generally incur higher development costs than those in earlier stages of clinical
development, primarily due to the increased size and duration of later-stage clinical trials. As a result, we expect our research and development expenses to
increase as our product candidates advance into later stages of clinical development. However, we do not believe that it is possible at this time to accurately
project total program-specific expenses through commercialization. There are numerous factors associated with the successful commercialization of any of
our product candidates, including future trial design and various regulatory requirements, many of which cannot be determined with accuracy at this time
based on our stage of development.
General and Administrative Expenses
General and administrative expenses consist of personnel-related costs, including salaries, benefits and stock-based compensation expense, for our
personnel in executive, finance and accounting, human resources, business operations and other administrative functions, legal fees related to patent,
intellectual property and corporate matters, fees paid for accounting and tax services, consulting fees and facility-related costs not otherwise included in
research and development expenses.
We expect our general and administrative expenses will increase for the foreseeable future to support our expanded infrastructure and increased
costs of expanding our operations and operating as a public company. These increases will likely include increased expenses related to accounting, audit,
legal, regulatory and tax-related services associated with maintaining compliance with exchange listing and SEC requirements, director and officer
insurance premiums, and investor relations costs associated with operating as a public company.
Other Income, Net
Other income, net consists primarily of interest income related to our investments in cash equivalents and marketable securities.
Results of Operations
Comparison of the Years Ended December 31, 2021 and 2020
The following summarizes our results of operations for the years ended December 31, 2021 and 2020, along with the changes in those items in
dollars:
(in thousands)
Collaboration revenue
Operating expenses:
Research and development
General and administrative
Total operating expenses
Loss from operations
Other income, net
Net loss
Year Ended
December 31,
2021
2020
Change
$
$
19,163 $
8,823 $
10,340
69,701
30,516
100,217
(81,054 )
207
(80,847 ) $
59,042
21,392
80,434
(71,611 )
792
(70,819 ) $
10,659
9,124
19,783
(9,443 )
(585 )
(10,028 )
$
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Collaboration Revenue
Collaboration revenue increased by $10.3 million from $8.8 million for the year ended December 31, 2020 to $19.2 million for the year ended
December 31, 2021. We recognize revenue under each of the Acceleron and MyoKardia collaboration agreements based on our pattern of performance
related to the respective identified performance obligation, which is the period over which we will perform research services under each of the agreements.
For the years ended December 31, 2021 and 2020, we recognized $9.6 million and $6.3 million, respectively, of collaboration revenue under the Acceleron
collaboration agreement and $9.6 million and $2.5 million of collaboration revenue, respectively, under the MyoKardia collaboration agreement.
Research and Development Expenses
The following table summarizes our research and development expenses for the years ended December 31, 2021 and 2020:
(in thousands)
External research and development
Employee compensation
Laboratory supplies
Facility costs
Other
Total research and development expenses
Year Ended
December 31,
2021
2020
Change
$
$
$
37,624 $
20,432
4,425
5,552
1,668
69,701 $
31,409 $
15,776
4,586
5,507
1,764
59,042 $
6,215
4,656
(161 )
45
(96 )
10,659
Research and development expense increased by $10.7 million from $59.0 million for the year ended December 31, 2020 to $69.7 million for the
year ended December 31, 2021. The increase in research and development expense was primarily attributable to the following:
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$6.2 million in increased external research and development costs, primarily associated with the advancement of FTX-6058 for the treatment
of certain hemoglobinopathies, partially offset by decreased costs associated with losmapimod as we completed the ReDUX4 trial in January
2021;
$4.7 million in increased employee compensation costs, including a $1.1 million increase in stock-based compensation expense, primarily
due to increased research and development headcount; and
$0.1 million in increased facilities costs, offset by a $0.2 million decrease in laboratory supplies costs and a $0.1 million decrease in other
costs.
General and Administrative Expenses
The following table summarizes our general and administrative expenses for the years ended December 31, 2021 and 2020:
(in thousands)
Employee compensation
Professional services
Facility costs
Other
Total general and administrative expenses
Year Ended
December 31,
2021
2020
Change
$
$
$
14,801 $
12,488
960
2,267
30,516 $
10,083 $
8,965
851
1,493
21,392 $
4,718
3,523
109
774
9,124
General and administrative expenses increased by $9.1 million from $21.4 million for the year ended December 31, 2020 to $30.5 million for the
year ended December 31, 2021. The increase in general and administrative expenses was primarily attributable to the following:
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$4.7 million in increased employee compensation costs, including a $2.6 million increase in stock-based compensation expense, primarily due
to increased general and administrative headcount;
$3.5 million in increased professional services, primarily due to increased use of consulting services;
$0.8 million in increased other costs; and
$0.1 million in increased facility-related costs, including depreciation and other utility and maintenance costs.
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Other Income, Net
Other income, net decreased by $0.6 million from $0.8 million for the year ended December 31, 2020 to $0.2 million for the year ended December
31, 2021. The decrease in other income, net was primarily attributable to a decrease in investment income on our cash, cash equivalents, and marketable
securities as a result of an overall decreased rate of return.
Liquidity and Capital Resources
Sources of Liquidity
We have incurred significant operating losses since our inception and expect to continue to incur significant operating losses for the foreseeable
future and may never become profitable. We have not yet commercialized any of our product candidates, which are in various phases of preclinical and
clinical development, and we do not expect to generate revenue from sales of any products for several years, if at all. As of December 31, 2021, we have
funded our operations primarily with aggregate gross proceeds of $501.2 million from the sale of shares of our common stock in public offerings, a private
placement, and the ATM Offering, through issuances of convertible preferred stock, and from upfront payments received under our collaboration and
license agreements. As of December 31, 2021, we had cash, cash equivalents, and marketable securities of $218.2 million.
In August 2020, we entered into an Equity Distribution Agreement with Piper Sandler & Co., or Piper Sandler, as sales agent, pursuant to which we
may offer and sell shares of our common stock with an aggregate offering price of up to $75.0 million under the ATM Offering. As of December 31, 2021,
we have issued and sold 550,000 shares of common stock under the ATM Offering, resulting in net proceeds of $5.7 million after deducting offering costs.
On January 22, 2021, we completed a public offering of our common stock and issued and sold 4,600,000 shares of common stock at a public
offering price of $11.00 per share, resulting in net proceeds of $47.4 million after deducting underwriting discounts and commissions and offering
expenses.
On August 16, 2021, we completed a public offering of our common stock and issued and sold 7,590,000 shares of common stock at a public
offering price of $19.00 per share, resulting in net proceeds of $135.5 million after deducting underwriting discounts and commissions and offering
expenses.
Cash Flows
The following table provides information regarding our cash flows for the years ended December 31, 2021 and 2020:
(in thousands)
Net cash used in operating activities
Net cash used in investing activities
Net cash provided by financing activities
Net decrease in cash, cash equivalents, and restricted cash
Year Ended
December 31,
2021
2020
$
$
(78,478 ) $
(129,669 )
186,507
(21,640 ) $
(53,655 )
(57,138 )
71,132
(39,661 )
Net Cash Used in Operating Activities
Net cash used in operating activities was $78.5 million during the year ended December 31, 2021 compared to net cash used in operating activities of $53.7
million during the year ended December 31, 2020. The increase in net cash used in operating activities of $24.8 million was primarily due to increased
external research and development costs as we continue to advance our lead programs, increased employee compensation costs, and increased general and
administrative costs to support the growth of our organization.
Net Cash Used in Investing Activities
Net cash used in investing activities was $129.7 million during the year ended December 31, 2021 compared to net cash used in investing activities
of $57.1 million during the year ended December 31, 2020. The increase in net cash used in investing activities of $72.6 million was primarily due to
higher net purchases of marketable securities during the year ended December 31, 2021.
101
Net Cash Provided by Financing Activities
Net cash provided by financing activities was $186.5 million during the year ended December 31, 2021 compared to net cash provided by financing
activities of $71.1 million during the year ended December 31, 2020. Net cash provided by financing activities during the year ended December 31, 2021
primarily consisted of net proceeds of approximately $182.9 million from the completion of the public offerings of our common stock in January 2021 and
August 2021. Net cash provided by financing activities during the year ended December 31, 2020 primarily consisted of net proceeds of approximately
$64.2 million from the issuance of common stock in a private placement in June 2020 and net proceeds of $5.7 million received under our ATM Offering.
Funding Requirements
We expect our expenses to increase substantially in connection with our ongoing research and development activities, particularly as we continue the
research and development of, initiate clinical trials of, and seek marketing approval for, our product candidates. In addition, we expect to incur additional
costs to support the growth of our organization. As a result, we expect to incur substantial operating losses and negative operating cash flows for the
foreseeable future.
Based on our current operating plan, we believe that our existing cash, cash equivalents, and marketable securities as of December 31, 2021 will
enable us to fund our operating expenses and capital expenditure requirements into 2024. However, we have based this estimate on assumptions that may
prove to be wrong and we could exhaust our capital resources sooner than we expect.
Our funding requirements and timing and amount of our operating expenditures will depend largely on:
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•
•
the progress, costs and results of our clinical trials of losmapimod and FTX-6058;
the scope, progress, costs and results of discovery research, preclinical development, laboratory testing and clinical trials for our current
product candidates in additional indications or for any future product candidates that we may pursue;
the impact of the ongoing COVID-19 pandemic on our business and operations;
the number of and development requirements for other product candidates that we pursue;
the costs, timing and outcome of regulatory review of our product candidates;
our ability to enter into contract manufacturing arrangements for supply of API and manufacture of our product candidates and the terms of
such arrangements;
the success of our collaborations with Acceleron and MyoKardia;
our ability to establish and maintain additional strategic collaborations, licensing or other arrangements and the financial terms of such
arrangements;
the payment or receipt of milestones, royalties and other collaboration-based revenues, if any;
the costs and timing of future commercialization activities, including product manufacturing, sales, marketing and distribution, for any of our
product candidates for which we may receive marketing approval;
the amount and timing of revenue, if any, received from commercial sales of our product candidates for which we receive marketing approval;
the costs and timing of preparing, filing and prosecuting patent applications, maintaining and enforcing our intellectual property and
proprietary rights and defending any intellectual property-related claims; and
the extent to which we acquire or in-license other products, product candidates, technologies or data referencing rights.
A change in the outcome of any of these or other variables with respect to the development of any of our product candidates could significantly
change the costs and timing associated with the development of that product candidate. We will need to continue to rely on additional financing to achieve
our business objectives.
In addition to the variables described above, if and when any of our product candidates successfully complete development, we will incur substantial
additional costs associated with regulatory filings, marketing approval, post-marketing requirements, maintaining our intellectual property rights, and
regulatory protection, in addition to other commercial costs. We cannot reasonably estimate these costs at this time.
102
Until such time, if ever, as we can generate substantial product revenue, we expect to finance our cash needs through a combination of equity
offerings, debt financings, collaboration arrangements, strategic alliances and marketing, distribution or licensing arrangements. We currently have no
credit facility or committed sources of capital. To the extent that we raise additional capital through the future sale of equity securities, the ownership
interests of our stockholders will be diluted, and the terms of these securities may include liquidation or other preferences that adversely affect the rights of
our existing common stockholders. If we raise additional funds through the issuance of debt securities, these securities could contain covenants that would
restrict our operations. We may require additional capital beyond our currently anticipated amounts, and additional capital may not be available on
reasonable terms, or at all. If we raise additional funds through collaboration arrangements, strategic alliances or marketing, distribution or licensing
arrangements in the future, we may have to relinquish valuable rights to our technologies, future revenue streams or product candidates, or grant licenses on
terms that may not be favorable to us. If we are unable to raise additional funds through equity or debt financings when needed, we may be required to
delay, limit, reduce or terminate development or future commercialization efforts or grant rights to develop and market product candidates that we would
otherwise prefer to develop and market ourselves.
Critical Accounting Policies and Estimates
Our management’s discussion and analysis of our financial condition and results of operations are based on our consolidated financial statements,
which have been prepared in accordance with generally accepted accounting principles in the United States. The preparation of these consolidated financial
statements requires us to make judgments and estimates 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 expenses during the reporting periods. Our estimates are based
on our historical experience, known trends and events, and on various other factors that we believe are reasonable under the circumstances, the results of
which form the basis for making judgments about the carrying value of assets and liabilities and amount of expense recognized that are not readily apparent
from other sources. Actual results may differ from these estimates under different assumptions or conditions. We evaluate our estimates and assumptions on
an ongoing basis. The effects of material revisions in estimates, if any, will be reflected in the consolidated financial statements prospectively from the date
of change in estimates.
We believe that the accounting policies discussed below are critical to understanding our historical and future performance, as these policies relate to
the most significant areas involving management’s judgments and estimates. See Note 2 to our consolidated financial statements included elsewhere in this
Annual Report on Form 10-K for a description of our other significant accounting policies.
Revenue Recognition
Under the Financial Accounting Standards Board Accounting Standards Codification, or ASC, 606, Revenue from Contracts with Customers, an
entity recognizes revenue when its customer obtains control of promised goods or services, in an amount that reflects the consideration that the entity
expects to receive in exchange for those goods or services. In applying ASC 606, we perform the following five steps:
1) Identify the contract with the customer
A contract with a customer exists when (i) we enter into an enforceable contract with a customer that defines each party’s rights regarding the goods
or services to be transferred and identifies the related payment terms, (ii) the contract has commercial substance and (iii) we determine that collection of
substantially all consideration for goods and services that are transferred is probable based on the customer’s intent and ability to pay the promised
consideration.
2) Identify the promises and performance obligations in the contract
Performance obligations promised in a contract are identified based on the goods and services that will be transferred to the customer that are both
capable of being distinct, whereby the customer can benefit from the good or service either on its own or together with other readily available resources,
and are distinct in the context of the contract, whereby the transfer of the good or service is separately identifiable from other promises in the contract. To
the extent a contract includes multiple promised goods and services, we must apply judgment to determine whether promised goods and services are
capable of being distinct and distinct in the context of the contract. In assessing whether a promised good or service is distinct, we consider factors such as
the research, manufacturing and commercialization capabilities of the customer and the availability of the associated expertise in the marketplace. We also
consider the intended benefit of the contract in assessing whether a promised good or service is separately identifiable from other promises in the contract.
If these criteria are not met, the promised goods and services are accounted for as a combined performance obligation.
103
3) Determine the transaction price
The transaction price is determined based on the consideration to which we will be entitled in exchange for transferring goods and services to the
customer. If the consideration promised in a contract includes a variable amount, we estimate the amount of consideration to which we will be entitled in
exchange for transferring the promised goods or services to a customer. We determine the amount of variable consideration by using the expected value
method or the most likely amount method. We include the unconstrained amount of estimated variable consideration in the transaction price. The amount
included in the transaction price is constrained to the amount for which it is probable that a significant reversal of cumulative revenue recognized will not
occur. At the end of each subsequent reporting period, we re-evaluate the estimated variable consideration included in the transaction price and any related
constraint, and if necessary, adjust our estimate of the overall transaction price. Any such adjustments are recorded on a cumulative catch-up basis in the
period of adjustment. Changes to the constraint of variable consideration can have a material effect on the amount of revenue recognized in the period.
If an arrangement includes research and development milestone payments, we evaluate whether the milestones are considered probable of being
reached and estimate the amount to be included in the transaction price using the most likely amount method. If it is probable that a significant revenue
reversal would not occur, the associated milestone value is included in the transaction price. Milestone payments that are based on the occurrence of events
not within our control, such as regulatory approvals, are generally not considered probable of being achieved until the underlying events occur or the
associated approvals are received.
For arrangements with licenses of intellectual property that include sales-based royalties, including milestone payments based on the level of sales,
and the license is deemed to be the predominant item to which the royalties relate, we recognize royalty revenue and sales-based milestones at the later of
(i) when the related sales occur, or (ii) when the performance obligation to which the royalty has been allocated has been satisfied.
In determining the transaction price, we adjust consideration for the effects of the time value of money if the timing of payments provides us with a
significant benefit of financing. We assess our revenue generating arrangements in order to determine whether a significant financing component exists.
4) Allocate the transaction price to the performance obligations in the contract
If the contract contains a single performance obligation, the entire transaction price is allocated to the single performance obligation. Contracts that
contain multiple performance obligations require an allocation of the transaction price to each performance obligation on a relative standalone selling price
basis, except for any variable consideration that meets the criteria to be allocated entirely to a single performance obligation or to a distinct service that
forms part of a single performance obligation.
5) Recognize revenue when or as the Company satisfies a performance obligation
We may satisfy performance obligations over time or at a point in time, depending on the nature of the performance obligation. Revenue is
recognized over time if the customer simultaneously receives and consumes the benefits provided by the entity’s performance, the entity’s performance
creates or enhances an asset that the customer controls as the asset is created or enhanced, or the entity’s performance does not create an asset with an
alternative use to the entity and the entity has an enforceable right to payment for performance completed to date. If the entity does not satisfy a
performance obligation over time, the related performance obligation is satisfied at a point in time by transferring the control of a promised good or service
to a customer.
For revenue that we recognize over time, we assess whether an input or an output method is the appropriate measure of progress associated with the
satisfaction of the performance obligation. In determining the appropriate method for measuring progress, we consider the nature of the good or service that
we have promised to transfer to the customer. Output methods recognize revenue on the basis of direct measurements of the value to the customer of the
goods or services transferred to date relative to the remaining goods or services promised under the contract. Input methods recognize revenue on the basis
of the entity’s efforts or inputs to the satisfaction of a performance obligation. Estimates inherent to our measurement of progress associated with the
satisfaction of performance obligations based on an input method include the total estimated costs to satisfy the associated performance obligation.
See Note 10, “Collaboration and License Agreements” to our audited consolidated financial statements included elsewhere in this Annual Report on
Form 10-K for further information on the application of ASC 606 to the Acceleron and MyoKardia collaboration agreements.
104
Accrued Research and Development Expenses
As part of the process of preparing our consolidated financial statements, we are required to estimate our accrued expenses as of each balance sheet
date. 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 the actual cost. The majority of our service providers invoice us monthly in arrears for services performed or when contractual
milestones are met. We make estimates of our accrued expenses as of each balance sheet date based on facts and circumstances known to us at that time.
We periodically confirm the accuracy of our estimates with the service providers and make adjustments if necessary. The significant estimates in our
accrued research and development expenses include the costs incurred for services performed by our vendors in connection with research and development
activities for which we have not yet been invoiced.
We base our expenses related to research and development activities on our estimates of the services received and efforts expended pursuant to
quotes and contracts with vendors that conduct research and development 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 research and development expense. 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 our estimate, we adjust the accrual or prepaid expense accordingly. Non-refundable advance payments for goods and services that will be
used in future research and development activities are expensed when the activity has been performed or when the goods have been received rather than
when the payment is made.
Although we do not expect our estimates to be materially different from amounts actually incurred, if our estimates of the status and timing of
services performed differ from the actual status and timing of services performed, it could result in us reporting amounts that are too high or too low in any
particular period. To date, there have been no material differences between our estimates of such expenses and the amounts actually incurred.
Stock-Based Compensation
We measure stock-based compensation expense related to all restricted stock awards and stock options based on the fair value of the award on the
date of grant. We recognize compensation expense for these awards over the requisite service period, which is generally the vesting period of the respective
award. Generally, we issue awards with only service-based vesting conditions and record the expense for these awards using the straight-line method. We
have also granted certain stock-based awards with performance-based vesting conditions. We recognize compensation expense for awards with
performance-based vesting conditions over the remaining service period using an accelerated attribution method when management determines that
achievement of the performance condition is probable. At each reporting date, we evaluate if the achievement of a performance-based milestone is probable
based on the expected satisfaction of the performance conditions.
We determine the fair value of restricted stock awards based on the estimated fair value of our common stock on the date of grant, less any
applicable purchase price. We estimate the fair value of stock options granted using the Black-Scholes option-pricing model. The determination of the grant
date fair value of stock options using an option pricing model is affected principally by our estimated fair value of our common stock and requires
management to make a number of other assumptions, including the expected term of the option, the estimated volatility of the underlying shares, the risk-
free interest rate, and expected dividends. The assumptions used in the determination of the grant date fair value of stock options represent management’s
best estimates at the time of measurement. Given the lack of public market for our common stock prior to the closing of our IPO and a lack of company-
specific historical and implied volatility data, we based the estimate of expected volatility on the historical volatility of a representative group of publicly
traded companies for which historical information is available. The historical volatility is calculated based on a period of time commensurate with the
assumption used for the expected term. We use the simplified method to calculate the expected term for all stock options. We utilize this method as we do
not have sufficient historical exercise data to provide a reasonable basis upon which to estimate the expected term. 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 dividend yield is assumed to be zero as we
have never paid dividends and do not have current plans to pay any dividends on common stock.
In future periods, we expect stock-based compensation expense to increase, due in part to our existing unrecognized stock-based compensation
expense and as we grant additional stock-based awards to continue to attract and retain our employees.
105
Income Taxes
We account for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for the
expected future tax consequences of events that have been recognized in the consolidated financial statements or in our tax returns. Under this method,
deferred tax assets and liabilities are determined based on differences between the financial statement carrying amounts and the tax bases of the assets and
liabilities using the enacted tax rates in effect in the years in which the differences are expected to reverse. A valuation allowance against deferred tax
assets is recorded if, based on the weight of the available evidence, it is more likely than not that some or all of the deferred tax assets will not be realized.
Potential for recovery of deferred tax assets is evaluated by considering several factors, including estimating the future taxable profits expected, estimating
future reversals of existing taxable temporary differences, considering taxable profits in carryback periods, and considering prudent and feasible tax
planning strategies.
We account for uncertain tax positions using a more-likely-than-not threshold for recognizing and resolving uncertain tax positions. The evaluation
of uncertain tax positions is based on factors including, but not limited to, changes in the law, the measurement of tax positions taken or expected to be
taken in tax returns, the effective settlement of matters subject to audit, new audit activity, and changes in facts or circumstances related to a tax position.
As of each balance sheet date, we did not have any uncertain tax positions.
Recently Issued Accounting Pronouncements
A description of recently issued accounting pronouncements that may potentially impact our financial position and results of operations is disclosed
in Note 2 to our audited consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K.
Emerging Growth Company Status
The Jumpstart Our Business Startups Act of 2012 permits an “emerging growth company” such as us to take advantage of an extended transition
period to comply with new or revised accounting standards applicable to public companies until those standards would otherwise apply to private
companies. We have elected not to “opt out” of such extended transition period, which means that when a standard is issued or revised and it has different
application dates for public or private companies, we will adopt the new or revised standard at the time private companies adopt the new or revised
standard and will do so until such time that we either (i) irrevocably elect to “opt out” of such extended transition period or (ii) no longer qualify as an
emerging growth company.
Item 7A. Quantitative and Qualitative Disclosures About Market Risk.
Our primary exposure to market risk is interest rate sensitivity, which is affected by changes in the general level of U.S. interest rates, particularly
because our cash equivalents are in the form of money market funds that are invested in U.S. Treasury securities and our investments are in short-term
marketable securities, such as corporate bonds and commercial paper. As of December 31, 2021, we had cash, cash equivalents, and marketable securities
of $218.2 million. Interest income is sensitive to changes in the general level of interest rates; however, due to the nature of these investments, an
immediate 10% change in interest rates would not have a material effect on the fair market value of our investment portfolio.
We are also exposed to market risk related to changes in foreign currency exchange rates. We contract with vendors that are located outside of the
United States and certain invoices are denominated in foreign currencies. We are subject to fluctuations in foreign currency rates in connection with these
arrangements. We do not currently hedge our foreign currency exchange rate risk. As of December 31, 2021, we had minimal or no liabilities denominated
in foreign currencies.
Inflation generally affects us by increasing our cost of labor and clinical trial costs. We do not believe that inflation had a material effect on our
business, financial condition or results of operations during the years ended December 31, 2021 and 2020.
Item 8. Financial Statements and Supplementary Data.
Our consolidated financial statements, together with the independent registered public accounting firm report thereon, are presented beginning on
page F-1 of this Annual Report on Form 10-K.
Item 9. Changes in and Disagreements With Accountants on Accounting and Financial Disclosure.
None.
106
Item 9A. Controls and Procedures.
Evaluation of Disclosure Controls and Procedures
Our management, with the participation of our Chief Executive Officer and Chief Financial Officer (our principal executive officer and principal
financial officer, respectively), evaluated the effectiveness of our disclosure controls and procedures as of December 31, 2021. The term “disclosure
controls and procedures,” as defined in Rules 13a-15(e) and 15d-15(e) under the Securities Exchange Act of 1934, as amended, or the Exchange Act,
means controls and other procedures of a company that are designed to ensure that information required to be disclosed by a company in the reports that it
files or submits under the Exchange Act is recorded, processed, summarized and reported, within the time periods specified in the SEC’s rules and forms.
Disclosure controls and procedures include, without limitation, controls and procedures designed to ensure that information required to be disclosed by a
company in the reports that it files or submits under the Exchange Act is accumulated and communicated to the company’s management, including its
principal executive and principal financial officers, or persons performing similar functions, as appropriate to allow timely decisions regarding required
disclosure. 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 our management necessarily applies its judgment in evaluating the cost-benefit relationship of possible controls
and procedures. Based on the evaluation of our disclosure controls and procedures as of December 31, 2021, our Chief Executive Officer and Chief
Financial Officer concluded that, as of such date, our disclosure controls and procedures were effective at the reasonable assurance level.
Management’s Annual Report on Internal Control over Financial Reporting
Our management is responsible for establishing and maintaining adequate internal control over financial reporting for the company. Internal control
over financial reporting is defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act as a process designed by, or under the supervision of, a
company’s principal executive officer and principal financial officer, or persons performing similar functions, and effected by a company’s board of
directors, management, and other personnel, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial
statements for external purposes in accordance with generally accepted accounting principles and includes those policies and procedures that:
•
•
•
pertain to the maintenance of records that in reasonable detail accurately and fairly reflect the transactions and dispositions of a
company’s assets;
provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in accordance with
generally accepted accounting principles, and that a company’s receipts and expenditures are being made only in accordance with
authorizations of a company’s management and directors; and
provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use or disposition of a company’s
assets that could have a material effect on the financial statements.
Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Therefore, even those systems
determined to be effective can provide only reasonable assurance with respect to financial statement preparation and presentation. 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 of and with the participation of our principal executive officer and principal financial officer, our management assessed the
effectiveness of our internal control over financial reporting as of December 31, 2021 based on the criteria set forth by the Committee of Sponsoring
Organizations of the Treadway Commission (COSO) in Internal Control—Integrated Framework (2013 framework). Based on this assessment,
management concluded that our internal control over financial reporting was effective as of December 31, 2021.
This Annual Report on Form 10-K does not include an attestation report of our independent registered public accounting firm due to an exemption
established by the JOBS Act for “emerging growth companies”.
Changes in Internal Control over Financial Reporting
There was no change in our internal control over financial reporting (as defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) that
occurred during the three months ended December 31, 2021 that has materially affected, or is reasonably likely to materially affect, our internal control
over financial reporting.
107
Item 9B. Other Information.
None.
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections.
Not applicable.
108
PART III
Item 10. Directors, Executive Officers and Corporate Governance.
Except to the extent provided below, the information required by this Item 10 will be included in our Definitive Proxy Statement to be filed with the
SEC, with respect to our 2022 Annual Meeting of Stockholders and is incorporated herein by reference.
We post our Code of Business Conduct and Ethics, which applies to our directors, officers and employees, including our principal executive officer,
principal financial officer, principal accounting officer or controller, or persons performing similar functions, in the “Corporate Governance” sub-section of
the “Investor Relations” section (ir.fulcrumtx.com) of our corporate website at www.fulcrumtx.com. We intend to disclose on our website any amendments
to, or waivers from, the Code of Business Conduct and Ethics that are required to be disclosed pursuant to the disclosure requirements of Item 5.05 of Form
8-K.
Item 11. Executive Compensation.
The information required by this Item 11 will be included in our Definitive Proxy Statement to be filed with the SEC with respect to our 2022
Annual Meeting of Stockholders and is incorporated herein by reference.
Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters.
The information required by this Item 12 will be included in our Definitive Proxy Statement to be filed with the SEC with respect to our 2022
Annual Meeting of Stockholders and is incorporated herein by reference.
Item 13. Certain Relationships and Related Transactions, and Director Independence.
The information required by this Item 13 will be included in our Definitive Proxy Statement to be filed with the SEC with respect to our 2022
Annual Meeting of Stockholders and is incorporated herein by reference.
Item 14. Principal Accountant Fees and Services.
The information required by this Item 14 will be included in our Definitive Proxy Statement to be filed with the SEC with respect to our 2022
Annual Meeting of Stockholders and is incorporated herein by reference.
109
Item 15. Exhibits and Financial Statement Schedules.
(1) Consolidated Financial Statements
PART IV
The following documents are included on pages F-1 through F-31 attached hereto and are filed as part of this Annual Report on Form 10-K.
Report of Independent Registered Public Accounting Firm (PCAOB ID: 42)
Consolidated Balance Sheets
Consolidated Statements of Operations and Comprehensive Loss
Consolidated Statements of Stockholders’ Equity
Consolidated Statements of Cash Flows
Notes to Consolidated Financial Statements
(2) Financial Statement Schedules
Page
F-2
F-3
F-4
F-5
F-6
F-7
All financial statement schedules have been omitted because they are not applicable, not required, or the information required is shown in the
consolidated financial statements or the notes thereto.
(3) Exhibits
The exhibits required by Item 601 of Regulation S-K and Item 15(b) of this Annual Report on Form 10-K are listed in the Exhibit Index
immediately preceding the signature page of this Annual Report on Form 10-K. The exhibits listed in the Exhibit Index are incorporated by reference
herein.
Item 16. Form 10-K Summary
None.
110
INDEX TO CONSOLIDATED FINANCIAL STATEMENTS
Report of Independent Registered Public Accounting Firm (PCAOB ID: 42)
Consolidated Balance Sheets
Consolidated Statements of Operations and Comprehensive Loss
Consolidated Statements of Stockholders’ Equity
Consolidated Statements of Cash Flows
Notes to Consolidated Financial Statements
F-1
Page
F-2
F-3
F-4
F-5
F-6
F-7
Report of Independent Registered Public Accounting Firm
To the Stockholders and the Board of Directors of Fulcrum Therapeutics, Inc.
Opinion on the Financial Statements
We have audited the accompanying consolidated balance sheets of Fulcrum Therapeutics, Inc. (the Company) as of December 31, 2021 and 2020, the
related consolidated statements of operations and comprehensive loss, stockholders’ equity and cash flows for the years then ended, and 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 at December 31, 2021 and 2020, and the results of its operations and its cash flows for the years then ended,
in conformity with U.S. generally accepted accounting principles.
Basis for Opinion
These financial statements are the responsibility of the Company’s management. Our responsibility is to express an opinion on the Company’s 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 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 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 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 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 financial statements. We believe that our audits provide a reasonable basis for our opinion.
/s/ Ernst & Young LLP
We have served as the Company’s auditor since 2017.
Boston, Massachusetts
March 3, 2022
F-2
Fulcrum Therapeutics, Inc.
Consolidated Balance Sheets
(In thousands, except share and per share amounts)
Assets
Current assets:
Cash and cash equivalents
Marketable securities
Accounts receivable
Unbilled accounts receivable
Prepaid expenses and other current assets
Total current assets
Property and equipment, net
Restricted cash
Other assets
Total assets
Liabilities and stockholders’ equity
Current liabilities:
Accounts payable
Accrued expenses and other current liabilities
Deferred lease incentive, current portion
Deferred revenue, current portion
Total current liabilities
Deferred rent, excluding current portion
Deferred lease incentive, excluding current portion
Deferred revenue, excluding current portion
Total liabilities
Commitments and contingencies (Note 12)
Stockholders’ equity:
$
$
$
December 31,
2021
December 31,
2020
35,412 $
182,750
2,500
1,137
4,199
225,998
7,368
1,092
542
235,000 $
4,788 $
9,231
469
4,711
19,199
1,680
2,582
—
23,461
57,052
55,862
2,000
531
4,065
119,510
8,397
1,092
578
129,577
4,079
7,267
469
14,910
26,725
1,649
3,051
2,971
34,396
Preferred stock, $0.001 par value; 5,000,000 shares authorized; no shares issued or outstanding
Common stock, $0.001 par value; 200,000,000 shares authorized; 40,636,398 and 28,067,402 shares
issued as of December 31, 2021 and December 31, 2020, respectively; 40,626,224 and
27,941,566 shares outstanding as of December 31, 2021 and December 31, 2020, respectively
Treasury stock, at cost; no shares as of December 31, 2021 and December 31, 2020
Additional paid-in capital
Accumulated other comprehensive loss
Accumulated deficit
Total stockholders’ equity
Total liabilities and stockholders’ equity
$
—
—
41
—
514,362
(397 )
(302,467 )
211,539
235,000 $
28
—
316,775
(2 )
(221,620 )
95,181
129,577
The accompanying notes are an integral part of these financial statements.
F-3
Fulcrum Therapeutics, Inc.
Consolidated Statements of Operations and Comprehensive Loss
(In thousands, except per share data)
Collaboration revenue
Operating expenses:
Research and development
General and administrative
Total operating expenses
Loss from operations
Other income, net
Net loss
Net loss per share, basic and diluted
Weighted average common shares outstanding, basic and diluted
Comprehensive loss:
Net loss
Other comprehensive loss:
Unrealized loss on marketable securities
Total other comprehensive loss
Comprehensive loss
Year Ended
December 31,
2021
2020
$
19,163 $
69,701
30,516
100,217
(81,054 )
207
(80,847 ) $
(2.29 ) $
35,361
$
$
$
(80,847 ) $
(395 )
(395 )
(81,242 ) $
$
8,823
59,042
21,392
80,434
(71,611 )
792
(70,819 )
(2.79 )
25,354
(70,819 )
(2 )
(2 )
(70,821 )
The accompanying notes are an integral part of these financial statements.
F-4
Fulcrum Therapeutics, Inc.
Consolidated Statements of Stockholders’ Equity
(In thousands, except share amounts)
Common Stock
Treasury Stock
Amount
Shares
Amount
Additional
Paid-In
Capital
Accumulated
Other
Comprehensi
ve
Loss
Accumulat
ed
Total
Stockholder
s’
Deficit
— $ (150,801 )$
Equity
Balance at December 31, 2019
Issuance of common stock in connection
with private placement, net of placement
agent fees and offering costs
Issuance of common stock in "at-the-
market" offering, net of issuance costs
Issuance of common stock under
employee benefit plans
Vesting of restricted stock awards
Repurchase of unvested restricted stock
awards
Retirement of treasury shares
Stock-based compensation expense
Unrealized loss on marketable securities
Net loss
Balance at December 31, 2020
Issuance of common stock in connection
with public offerings, net of issuance
costs
Issuance of common stock under
employee benefit plans
Vesting of restricted stock awards
Repurchase of unvested restricted stock
awards
Retirement of treasury shares
Stock-based compensation expense
Unrealized loss on marketable securities
Net loss
Balance at December 31, 2021
Shares
22,654,444 $
4,029,411
550,000
182,359
525,352
—
—
—
—
—
27,941,566 $
12,190,000
381,967
112,691
—
—
—
—
—
40,626,224 $
23
— $
— $
237,931 $
4
1
—
—
—
—
—
—
—
28
12
1
—
—
—
—
—
—
41
—
—
—
—
29,882
(29,882 )
—
—
—
— $
—
—
—
2,971
(2,971 )
—
—
—
— $
—
—
—
—
—
—
—
—
—
— $
—
—
—
—
—
—
—
—
— $
64,314
5,735
1,430
15
—
—
7,350
—
—
316,775 $
182,845
3,667
5
—
—
11,070
—
—
514,362 $
87,153
64,318
5,736
1,430
15
—
—
7,350
(2 )
(70,819 )
95,181
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
(2 )
—
(70,819 )
(2 )$ (221,620 )$
—
—
—
—
182,857
—
—
3,668
5
—
—
—
(395 )
—
—
—
—
—
(80,847 )
(397 )$ (302,467 )$
—
—
11,070
(395 )
(80,847 )
211,539
The accompanying notes are an integral part of these financial statements.
F-5
Fulcrum Therapeutics, Inc.
Consolidated Statements of Cash Flows
(In thousands)
Operating activities
Net loss
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation expense
Stock-based compensation expense
Net amortization of premiums and discounts on marketable securities
Changes in operating assets and liabilities:
Accounts receivable
Unbilled accounts receivable
Prepaid expenses and other current assets
Other assets
Accounts payable
Accrued expenses and other liabilities
Deferred revenue
Deferred rent and deferred lease incentive
Net cash used in operating activities
Investing activities
Purchases of marketable securities
Maturities of marketable securities
Purchases of property and equipment
Net cash used in investing activities
Financing activities
Payment of initial public offering costs
Proceeds from issuance of common stock in connection with private placement, net of placement agent fees
and offering costs
Proceeds from issuance of common stock in connection with at-the-market offering, net of issuance costs
Proceeds from issuance of common stock in connection with public offerings, net of issuance costs
Principal payments on capital lease obligations
Proceeds from issuance of common stock under benefit plans, net
Net cash provided by financing activities
Net decrease in cash, cash equivalents and restricted cash
Cash, cash equivalents, and restricted cash, beginning of period
Cash, cash equivalents, and restricted cash, end of period
Supplemental cash flow information
Cash paid for interest
Non-cash investing and financing activities:
Property and equipment purchases unpaid at end of period
$
$
$
$
$
Year Ended
December 31,
2021
2020
$
(80,847 ) $
(70,819 )
2,515
11,070
673
(500 )
(606 )
(134 )
36
973
1,950
(13,170 )
(438 )
(78,478 ) $
(216,234 )
88,278
(1,713 )
(129,669 ) $
—
—
—
182,857
(18 )
3,668
186,507
(21,640 )
58,144
36,504 $
— $
37 $
2,379
7,350
(68 )
(2,000 )
(531 )
(697 )
(519 )
1,773
1,976
7,881
(380 )
(53,655 )
(124,270 )
68,474
(1,342 )
(57,138 )
(193 )
64,210
5,736
—
(50 )
1,429
71,132
(39,661 )
97,805
58,144
4
262
The following table provides a reconciliation of the cash, cash equivalents, and restricted cash balances as of each of the periods shown above:
Cash and cash equivalents
Restricted cash
Total cash, cash equivalents, and restricted cash
December 31,
2021
December 31,
2020
$
$
35,412 $
1,092
36,504 $
57,052
1,092
58,144
The accompanying notes are an integral part of these financial statements.
F-6
Fulcrum Therapeutics, Inc.
Notes to Consolidated Financial Statements
1. Nature of the Business and Basis of Presentation
Fulcrum Therapeutics, Inc. (the “Company” or “Fulcrum”) was incorporated in Delaware on August 18, 2015. The Company is focused on
improving the lives of patients with genetically-defined rare diseases in areas of high unmet medical need.
The Company is subject to a number of risks similar to other companies in the biotechnology industry, including, but not limited to, risks of failure
of preclinical studies and clinical trials, dependence on key personnel, protection of proprietary technology, reliance on third party organizations, risks of
obtaining regulatory approval for any product candidate that it may develop, development by competitors of technological innovations, compliance with
government regulations, and the need to obtain additional financing. Product candidates currently under development will require significant additional
research and development efforts, including extensive preclinical and clinical testing, and regulatory approval, prior to commercialization. These efforts
require significant amounts of additional capital, adequate personnel infrastructure and extensive compliance-reporting capabilities. Even if the Company’s
development efforts are successful, it is uncertain when, if ever, the Company will realize significant revenue from product sales.
Basis of Presentation
The accompanying consolidated financial statements have been prepared in conformity with generally accepted accounting principles in the United
States of America (“GAAP”). Any reference in these notes to applicable guidance is meant to refer to the authoritative GAAP as found in the Accounting
Standards Codification (“ASC”) and Accounting Standards Updates (“ASU”) of the Financial Accounting Standards Board (“FASB”).
Sales of Common Stock
On June 9, 2020, the Company issued and sold 4,029,411 shares of common stock to investors in a private placement at a price of $17.00 per share,
resulting in net proceeds of $64.3 million after deducting offering costs.
On August 11, 2020, the Company entered into an Equity Distribution Agreement with Piper Sandler & Co. (“Piper Sandler”), as sales agent,
pursuant to which the Company may offer and sell shares of its common stock with an aggregate offering price of up to $75.0 million under an “at-the-
market” offering program (the “ATM Offering”). The Equity Distribution Agreement provides that Piper Sandler will be entitled to a sales commission
equal to 3.0% of the gross sales price per share of all shares sold under the ATM Offering. From the initiation of the ATM Offering through December 31,
2021, the Company has issued and sold 550,000 shares under the ATM Offering, resulting in aggregate net proceeds of $5.7 million after deducting
issuance costs of $0.2 million.
On January 22, 2021, the Company completed a public offering of its common stock and issued and sold 4,600,000 shares of common stock at a
public offering price of $11.00 per share, resulting in net proceeds of $47.4 million after deducting underwriting discounts and commissions and offering
expenses.
On August 16, 2021, the Company completed a public offering of its common stock and issued and sold 7,590,000 shares of common stock at a
public offering price of $19.00 per share, resulting in net proceeds of $135.5 million after deducting underwriting discounts and commissions and offering
expenses.
Liquidity
The Company has incurred recurring losses and negative cash flows from operations since inception and has primarily funded its operations with
proceeds from the sale of shares of common stock in public offerings, a private placement, and the ATM Offering, through issuances of convertible
preferred stock, and from upfront payments received from the collaboration and license agreements with Acceleron Pharma Inc. (“Acceleron”), a wholly-
owned subsidiary of Merck & Co., Inc., and MyoKardia, Inc. (“MyoKardia”), a wholly-owned subsidiary of Bristol Myers Squibb Company. As of
December 31, 2021, the Company had an accumulated deficit of $302.5 million. The Company expects its operating losses and negative operating cash
flows to continue into the foreseeable future as it continues to expand its research and development efforts. The Company expects to finance its future cash
needs through a combination of equity offerings, debt financings, collaborations, strategic alliances and marketing, distribution or licensing arrangements.
F-7
The Company expects that its cash, cash equivalents, and marketable securities will be sufficient to fund its operating expenses and capital
expenditure requirements for at least twelve months from the date of issuance of these financial statements. However, the Company has based this estimate
on assumptions that may prove to be wrong, and its operating plan may change as a result of many factors currently unknown to it. As a result, the
Company could deplete its capital resources sooner than it currently expects. If the Company is unable to raise additional funds through equity or debt
financings when needed, it may be required to delay, limit, reduce or terminate development or future commercialization efforts or grant rights to develop
and market product candidates that it would otherwise prefer to develop and market itself.
2. Summary of Significant Accounting Policies
Principles of Consolidation
The accompanying consolidated financial statements include the accounts of the Company and its wholly-owned subsidiary, Fulcrum Therapeutics
Securities Corp., which is a Massachusetts subsidiary created to buy, sell, and hold securities. All intercompany transactions and balances have been
eliminated.
Use of Estimates
The preparation of financial statements in accordance with GAAP requires management to make certain estimates and assumptions that affect the
reported amounts of assets and liabilities and disclosure of contingent assets and liabilities as of the date of the financial statements, and the reported
amount of expenses during the reported periods. Estimates inherent in the preparation of these consolidated financial statements include, but are not limited
to, estimates related to revenue recognition, accrued expenses, stock-based compensation expense, and income taxes. The Company bases its estimates on
historical experience and other market specific or other relevant assumptions it believes to be reasonable under the circumstances. On an ongoing basis,
management evaluates its estimates as there are changes in circumstances, facts and experience. Actual results could differ from those estimates or
assumptions.
Cash and Cash Equivalents
Cash equivalents are highly liquid investments that are readily convertible into cash with original maturities of three months or less when purchased.
Cash equivalents include investments in money market funds that invest in U.S. Treasury obligations. The Company maintains its bank accounts at major
financial institutions.
Restricted Cash
Restricted cash represents cash held to secure a letter of credit associated with the Company’s facility lease.
Fair Value of Financial Instruments
The fair value of the Company’s financial assets and liabilities reflects the Company’s estimate of amounts that it would have received in connection
with the sale of the assets or paid in connection with the transfer of the liabilities in an orderly transaction between market participants at the measurement
date. In connection with measuring the fair value of its assets and liabilities, the Company seeks to maximize the use of observable inputs (market data
obtained from sources independent from the Company) and to minimize the use of unobservable inputs (the Company’s assumptions about how market
participants would price assets and liabilities). The following fair value hierarchy is used to classify assets and liabilities based on the observable inputs and
unobservable inputs used in order to value the assets and liabilities:
Level 1: Quoted prices in active markets for identical assets or liabilities. An active market for an asset or liability is a market in which transactions
for the asset or liability occur with sufficient frequency and volume to provide pricing information on an ongoing basis.
Level 2: Observable inputs other than Level 1 inputs. Examples of Level 2 inputs include quoted prices in active markets for similar assets or
liabilities and quoted prices for identical assets or liabilities in markets that are not active.
Level 3: Unobservable inputs based on the Company’s assessment of the assumptions that market participants would use in pricing the asset or
liability.
The Company’s cash equivalents and marketable securities are carried at fair value and are classified according to the fair value hierarchy described
above (Note 3). The cash equivalents and marketable securities are initially valued at the transaction price, and subsequently revalued at the end of each
reporting period, utilizing third-party pricing services. The
F-8
pricing services utilize industry standard valuation models, including both income and market-based approaches, to determine fair value.
Marketable Securities
The Company classifies securities with a remaining maturity when purchased of greater than three months as marketable securities. As of
December 31, 2021, the Company’s marketable securities consisted of investments in corporate bonds and commercial paper. Marketable securities are
classified as current assets on the consolidated balance sheets if the marketable securities are available to be converted into cash to fund current operations.
Marketable securities are carried at fair value with the unrealized gains and losses included in accumulated other comprehensive loss, which is a
component of stockholders’ equity, until such gains and losses are realized. Any premium arising at purchase is amortized to interest expense (a component
of other income, net) over the period of the earliest call date, and any discount arising at purchase is accreted to interest income (a component of other
income, net) over the life of the instrument. Realized gains and losses are determined using the specific identification method and are included in other
income, net.
If any adjustment to fair value reflects a decline in value of the investment, the Company considers all available evidence to evaluate the extent to
which the decline is “other-than-temporary” and, if so, marks the investment to market through a charge to the Company’s statement of operations and
comprehensive loss.
Property and Equipment
Property and equipment are recorded at cost, net of accumulated depreciation. Maintenance and repairs to an asset that do not improve or extend its
life are charged to operations. Depreciation expense is recorded using the straight-line method over the estimated useful life of the related asset as follows:
Lab equipment
Furniture and fixtures
Computer equipment
Software
Leasehold improvements
Estimated Useful Life (in years)
5
4
3
3
Shorter of useful life or remaining lease term
Construction-in-progress is stated at cost, which includes direct costs attributable to the setup or construction of the related asset. Depreciation
expense is not recorded on construction-in-progress until the relevant assets are completed and put into use. When assets are retired or otherwise disposed
of, the assets and related accumulated depreciation are eliminated from the accounts and any resulting gain or loss is reflected in the Company’s
consolidated statements of operations and comprehensive loss.
Impairment of Long-Lived Assets
Long-lived assets consist of property and equipment. The Company continually evaluates whether events or circumstances have occurred that
indicate that the estimated remaining useful life of its long-lived assets may warrant revision or that the carrying value of these assets may be impaired. An
impairment loss would be recognized when estimated undiscounted future cash flows expected to result from the use or disposition of 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,
determined based on discounted cash flows. The Company did not record any impairment losses on long-lived assets during the years ended December 31,
2021 and 2020.
Leases
Leases are classified at their inception as either operating or capital leases. The Company recognizes rent expense for its facility leases, which are
classified as operating leases, on a straight-line basis over the respective lease term, inclusive of rent escalation provisions and rent holidays. The difference
between rent payments made and straight-line rent expense is recorded as deferred rent. Additionally, the Company recognizes tenant improvement
allowances for its operating leases as a
F-9
deferred lease incentive and amortizes the lease incentive as a reduction to rent expense on a straight-line basis over the respective lease term.
Revenue Recognition
Under ASC 606, Revenue from Contracts with Customers, an entity recognizes revenue when its customer obtains control of promised goods or
services, in an amount that reflects the consideration that the entity expects to receive in exchange for those goods or services. In applying ASC 606, the
Company performs the following five steps:
1) Identify the contract with the customer
A contract with a customer exists when (i) the Company enters into an enforceable contract with a customer that defines each party’s rights
regarding the goods or services to be transferred and identifies the related payment terms, (ii) the contract has commercial substance and (iii) the Company
determines that collection of substantially all consideration for goods and services that are transferred is probable based on the customer’s intent and ability
to pay the promised consideration.
2) Identify the promises and performance obligations in the contract
Performance obligations promised in a contract are identified based on the goods and services that will be transferred to the customer that are both
capable of being distinct, whereby the customer can benefit from the good or service either on its own or together with other readily available resources,
and are distinct in the context of the contract, whereby the transfer of the good or service is separately identifiable from other promises in the contract. To
the extent a contract includes multiple promised goods and services, the Company must apply judgment to determine whether promised goods and services
are capable of being distinct and distinct in the context of the contract. In assessing whether a promised good or service is distinct, the Company considers
factors such as the research, manufacturing and commercialization capabilities of the customer and the availability of the associated expertise in the
marketplace. The Company also considers the intended benefit of the contract in assessing whether a promised good or service is separately identifiable
from other promises in the contract. If these criteria are not met, the promised goods and services are accounted for as a combined performance obligation.
3) Determine the transaction price
The transaction price is determined based on the consideration to which the Company will be entitled in exchange for transferring goods and
services to the customer. If the consideration promised in a contract includes a variable amount, the Company estimates the amount of consideration to
which it will be entitled in exchange for transferring the promised goods or services to a customer. The Company determines the amount of variable
consideration by using the expected value method or the most likely amount method. The Company includes the unconstrained amount of estimated
variable consideration in the transaction price. The amount included in the transaction price is constrained to the amount for which it is probable that a
significant reversal of cumulative revenue recognized will not occur. At the end of each subsequent reporting period, the Company re-evaluates the
estimated variable consideration included in the transaction price and any related constraint, and if necessary, adjusts the estimate of the overall transaction
price. Any such adjustments are recorded on a cumulative catch-up basis in the period of adjustment. Changes to the constraint of variable consideration
can have a material effect on the amount of revenue recognized in the period.
If an arrangement includes research and development milestone payments, the Company evaluates whether the milestones are considered probable
of being reached and estimates the amount to be included in the transaction price using the most likely amount method. If it is probable that a significant
revenue reversal would not occur, the associated milestone value is included in the transaction price. Milestone payments that are based on the occurrence
of events not within the Company’s control, such as regulatory approvals, are generally not considered probable of being achieved until the underlying
events occur or the associated approvals are received.
For arrangements with licenses of intellectual property that include sales-based royalties, including milestone payments based on the level of sales,
and the license is deemed to be the predominant item to which the royalties relate, the Company recognizes royalty revenue and sales-based milestones at
the later of (i) when the related sales occur, or (ii) when the performance obligation to which the royalty has been allocated has been satisfied.
In determining the transaction price, the Company adjusts consideration for the effects of the time value of money if the timing of payments
provides the Company with a significant benefit of financing. The Company assesses its revenue generating arrangements in order to determine whether a
significant financing component exists.
F-10
4) Allocate the transaction price to the performance obligations in the contract
If the contract contains a single performance obligation, the entire transaction price is allocated to the single performance obligation. Contracts that
contain multiple performance obligations require an allocation of the transaction price to each performance obligation on a relative standalone selling price
basis, except for any variable consideration that meets the criteria to be allocated entirely to a single performance obligation or to a distinct service that
forms part of a single performance obligation.
5) Recognize revenue when or as the Company satisfies a performance obligation
The Company may satisfy performance obligations over time or at a point in time, depending on the nature of the performance obligation. Revenue
is recognized over time if the customer simultaneously receives and consumes the benefits provided by the entity’s performance, the entity’s performance
creates or enhances an asset that the customer controls as the asset is created or enhanced, or the entity’s performance does not create an asset with an
alternative use to the entity and the entity has an enforceable right to payment for performance completed to date. If the entity does not satisfy a
performance obligation over time, the related performance obligation is satisfied at a point in time by transferring the control of a promised good or service
to a customer.
For revenue that the Company recognizes over time, the Company assesses whether an input or an output method is the appropriate measure of
progress associated with the satisfaction of the performance obligation. In determining the appropriate method for measuring progress, the Company
considers the nature of the good or service that it has promised to transfer to the customer. Output methods recognize revenue on the basis of direct
measurements of the value to the customer of the goods or services transferred to date relative to the remaining goods or services promised under the
contract. Input methods recognize revenue on the basis of the entity’s efforts or inputs to the satisfaction of a performance obligation. Estimates inherent to
the measurement of progress associated with the satisfaction of performance obligations based on an input method include the total estimated costs to
satisfy the associated performance obligation.
See Note 10, “Collaboration and License Agreements”, for further information on the application of ASC 606 to the collaboration and license
agreement with Acceleron (the “Acceleron Collaboration Agreement”) and the collaboration and license agreement with MyoKardia (the “MyoKardia
Collaboration Agreement”).
Research and Development Expenses
Research and development expenses include costs directly attributable to the conduct of research and development programs, including personnel-
related expenses such as salaries, payroll taxes, benefits, and stock-based compensation expense, manufacturing and external costs related to outside
vendors engaged to conduct both preclinical studies and clinical trials, laboratory supplies, depreciation on and maintenance of research equipment, and the
allocable portions of facility costs, such as rent, utilities, repairs and maintenance, depreciation, and general support services. Expenditures relating to
research and development are expensed in the period incurred. Non-refundable advance payments for goods and services that will be used in future
research and development activities are expensed when the activity has been performed or when the goods have been received rather than when the
payment is made.
Research Contract Costs and Accruals
The Company has entered into various research and development contracts with research institutions and other companies. The Company records
accruals for estimated ongoing research costs that have not yet been invoiced. When evaluating the adequacy of the accrued liabilities, the Company
analyzes progress of the studies or trials or the extent of services provided during the reporting periods, including invoices received and contracted costs.
Significant judgments and estimates are made in determining the accrued balances at each reporting period. Actual results could differ from the Company’s
estimates.
Patent-Related Costs
Patent-related costs incurred in connection with patent applications are expensed as incurred due to the uncertainty about the recovery of the
expenditure. Amounts incurred are classified as general and administrative expenses in the accompanying statements of operations.
F-11
Stock-Based Compensation
The Company measures stock-based awards based on the fair value on the date of grant. Compensation expense associated with those awards is
recognized over the requisite service period, which is generally the vesting period of the respective award. Generally, the Company issues awards with only
service-based vesting conditions and records the expense for these awards using the straight-line method.
The fair value of each restricted stock award is based on the fair value of the Company’s common stock on the grant date, less any applicable
purchase price. The fair value of each stock option is estimated on the grant date using the Black-Scholes option-pricing model, which requires inputs
based on certain subjective assumptions, including the expected stock price volatility, the expected term of the award, the risk-free interest rate, and
expected dividends. Expected volatility is calculated based on reported volatility data for a representative group of publicly traded companies for which
historical information is available. The historical volatility is calculated based on a period of time commensurate with the assumption used for the expected
term. The risk-free interest rate is based on the U.S. Treasury yield curve in effect at the time of grant commensurate with the expected term assumption.
The Company uses the simplified method, under which the expected term is presumed to be the midpoint between the vesting date and the end of the
contractual term. The Company utilizes this method due to the lack of historical exercise data and the plain nature of its stock-based awards. The expected
dividend yield is assumed to be zero as the Company has never paid dividends and has no current plans to pay any dividends on common stock.
The Company accounts for forfeitures as they occur. The Company classifies stock-based compensation expense in its statements of operations in
the same manner in which the award recipient’s payroll or service costs are classified.
Income Taxes
The Company accounts for income taxes using the asset and liability method, which requires the recognition of deferred tax assets and liabilities for
the expected future tax consequences of events that have been recognized in the consolidated financial statements or in the Company’s tax returns. Under
this method, deferred tax assets and liabilities are determined based on differences between the financial statement carrying amounts and the tax bases of
the assets and liabilities using the enacted tax rates in effect in the years in which the differences are expected to reverse. A valuation allowance against
deferred tax assets is recorded if, based on the weight of the available evidence, it is more likely than not that some or all of the deferred tax assets will not
be realized. Potential for recovery of deferred tax assets is evaluated by considering several factors, including estimating the future taxable profits expected,
estimating future reversals of existing taxable temporary differences, considering taxable profits in carryback periods, and considering prudent and feasible
tax planning strategies.
The Company accounts for uncertain tax positions using a more-likely-than-not threshold for recognizing and resolving uncertain tax positions. The
evaluation of uncertain tax positions is based on factors including, but not limited to, changes in the law, the measurement of tax positions taken or
expected to be taken in tax returns, the effective settlement of matters subject to audit, new audit activity, and changes in facts or circumstances related to a
tax position.
Comprehensive Loss
Comprehensive loss is defined as the change in equity of a business enterprise during a period from transactions and other events and circumstances
from non-owner sources. For the years ended December 31, 2021 and 2020, comprehensive loss consists of net loss and unrealized losses on investments.
Net Income (Loss) Per Share
Basic net income (loss) per share is computed by dividing the net income (loss) by the weighted average number of shares of common stock
outstanding for the period. Diluted net income (loss) per share is computed by dividing net income (loss) by the weighted average number of shares of
common stock outstanding for the period, including potential dilutive common shares. For purpose of this calculation, outstanding options to purchase
common stock and unvested restricted stock awards are considered potential dilutive common shares. The Company has generated a net loss in all periods
presented, and therefore the basic and diluted net loss per share are the same as the inclusion of the potentially dilutive securities would be anti-dilutive.
Off-Balance Sheet Risk and Concentrations of Credit Risk
The Company has no significant off-balance sheet risk such as foreign exchange contracts, option contracts, or other foreign hedging arrangements.
Financial instruments that potentially expose the Company to concentrations of credit risk
F-12
consist primarily of cash, cash equivalents, marketable securities, and restricted cash. The Company’s cash, cash equivalents, and restricted cash are
deposited in accounts at large financial institutions. The Company believes it is not exposed to significant credit risk due to the financial strength of the
depository institutions in which the cash, cash equivalents and restricted cash are held. The Company maintains its cash equivalents in money market funds
that invest in U.S. Treasury securities. The Company’s marketable securities primarily consist of corporate bonds and commercial paper, and potentially
subject the Company to concentrations of credit risk. The Company has adopted an investment policy that limits the amounts the Company may invest in
any one type of investment. The Company has not experienced any credit losses and does not believe it is exposed to any significant credit risk on these
funds.
Segment Information
Operating segments are defined as components of an enterprise about which separate discrete financial information is available for evaluation by the
chief operating decision-maker in making decisions regarding resource allocation and assessing performance. The Company and the Company’s chief
operating decision-maker, the Company’s chief executive officer, view the Company’s operations and manage its business as a single operating segment.
Emerging Growth Company Status
The Company is an emerging growth company (“EGC”), as defined in the Jumpstart Our Business Startups Act (the “JOBS Act”), and may take
advantage of certain exemptions from various reporting requirements that are applicable to other public companies that are not EGCs, including that an
EGC can take advantage of the extended transition period afforded by the JOBS Act for the implementation of new or revised accounting standards. The
Company has elected to use the extended transition period for complying with new or revised accounting standards, and as a result of this election, its
consolidated financial statements may not be comparable to companies that comply with public company effective dates for ASUs. The Company may take
advantage of these exemptions up until the last day of the fiscal year following the fifth anniversary of its initial public offering or such earlier time that it is
no longer an EGC.
Recent Accounting Pronouncements—To Be Adopted
In February 2016, the FASB issued ASU 2016-02, Leases (Topic 842) (“ASU 2016-02”), as amended by various subsequently issued ASUs. Lessees
are required to classify leases as either finance or operating leases. If the lease is effectively a financed-purchase by the lessee, it is classified as a financing
lease, otherwise it is classified as an operating lease. This classification will determine whether lease expense is recognized based on an effective interest
method or on a straight-line basis over the term of the lease. The standard requires lessees to recognize an operating lease with a term greater than one year
on their balance sheets as a right-of-use asset and corresponding lease liability, measured at the present value of the lease payments. In July 2018, the FASB
issued ASU 2018-11, Leases (Topic 842): Targeted Improvements (“ASU 2018-11”), which permits entities to continue applying legacy guidance in ASC
840, Leases, including its disclosure requirements, in the comparative periods presented in the year that the entity adopts the new leasing standard. In
November 2019, the FASB deferred the effective date of ASU 2016-02, as amended, for private companies to fiscal years beginning after December 15,
2020. In June 2020, the FASB further deferred the effective date of ASU 2016-02, as amended, for private companies to fiscal years beginning after
December 15, 2021. The new standard will become effective for the Company on January 1, 2022. The Company will apply the transition method
permitted by ASU 2018-11. The Company is currently evaluating the effect that adoption of the standard is expected to have on the Company’s
consolidated financial statements and related disclosures. The Company expects to take advantage of certain available expedients by electing the transition
package of practical expedients permitted within ASU 2016-02, as amended, which allows the Company to not reassess previous accounting conclusions
around whether arrangements are, or contain, leases, the classification of leases, and the treatment of initial direct costs. The Company also expects to make
an accounting policy election to exclude leases with an initial term of twelve months or less from the balance sheet. The Company expects that the adoption
of ASU 2016-02, as amended, will result in the recognition of material right-of-use assets and lease liabilities in its consolidated balance sheets. The
Company does not expect the adoption of ASU 2016-02, as amended, will have a material impact to its consolidated statements of operations and
comprehensive loss.
In June 2016, the FASB issued ASU No. 2016-13, Financial Instruments—Credit Losses (Topic 326): Measurement of Credit Losses on Financial
Instruments. The standard requires that credit losses be reported using an expected losses model rather than the incurred losses model that is currently used,
and establishes additional disclosures related to credit risks. For available-for-sale debt securities with unrealized losses, this standard requires allowances
to be recorded instead of reducing the amortized cost of the investment. The new standard will be effective for the Company on January 1, 2023. The
Company is currently evaluating the potential impact that this standard may have on its consolidated financial position and results of operations.
F-13
In December 2019, the FASB issued ASU No. 2019-12, Income Taxes-Simplifying the Accounting for Income Taxes. The standard eliminates certain
exceptions related to the approach for intraperiod tax allocation, the methodology for calculating income taxes in an interim period, and the recognition of
deferred tax liabilities for outside basis differences. The new guidance also simplifies aspects of the accounting for franchise taxes and enacted changes in
tax laws or rates and clarifies the accounting for transactions that result in a step-up in the tax basis of goodwill. The new standard will be effective for the
Company on January 1, 2023. The Company is currently evaluating the potential impact that this standard may have on its consolidated financial position
and results of operations.
3. Fair Value Measurements
The following tables present information about the Company’s financial assets measured at fair value on a recurring basis and indicate the fair value
hierarchy classification of such fair values as of December 31, 2021 and 2020 (in thousands):
Cash equivalents:
Money market funds
Marketable securities:
Corporate bonds
Commercial paper
Total
Cash equivalents:
Money market funds
Marketable securities:
Corporate bonds
Commercial paper
Total
Fair Value Measurements at
December 31, 2021
Total
Level 1
Level 2
Level 3
$
35,412 $
35,412 $
— $
101,368
81,382
218,162 $
—
—
35,412 $
101,368
81,382
182,750 $
$
Fair Value Measurements at
December 31, 2020
Total
Level 1
Level 2
Level 3
$
57,052 $
57,052 $
— $
23,339
32,523
112,914 $
—
—
57,052 $
23,339
32,523
55,862 $
$
—
—
—
—
—
—
—
—
There were no transfers between fair value levels during the years ended December 31, 2021 or 2020.
4. Cash Equivalents and Marketable Securities
Cash equivalents and marketable securities consisted of the following as of December 31, 2021 and December 31, 2020 (in thousands):
Cash equivalents:
Money market funds
Total cash equivalents
Marketable securities:
Corporate bonds
Commercial paper
Total marketable securities
Total cash equivalents and marketable securities
Fair Value Measurements at
December 31, 2021
Gross
Unrealized
Gains
Gross
Unrealized
Losses
Amortized
Cost
Fair Value
35,412 $
35,412
101,697
81,450
183,147
218,559 $
— $
—
—
—
—
— $
— $
—
(329 )
(68 )
(397 )
(397 ) $
35,412
35,412
101,368
81,382
182,750
218,162
$
$
F-14
Cash equivalents:
Money market funds
Total cash equivalents
Marketable securities:
Corporate bonds
Commercial paper
Total marketable securities
Total cash equivalents and marketable securities
Amortized
Cost
$
$
57,052 $
57,052
23,341
32,523
55,864
112,916 $
Fair Value Measurements at
December 31, 2020
Gross
Unrealized
Gains
Gross
Unrealized
Losses
— $
—
2
—
2
2 $
Fair Value
57,052
57,052
23,339
32,523
55,862
112,914
— $
—
(4 )
—
(4 )
(4 ) $
There were no sales of marketable securities during the year ended December 31, 2021. As of December 31, 2021, the aggregate fair value of
securities that were in an unrealized loss position for less than twelve months was $180.8 million. As of December 31, 2021, no securities were in an
unrealized loss position for greater than twelve months.
The Company determined that it did not hold any securities with any other-than-temporary impairment as of December 31, 2021. As of December
31, 2021, the aggregate fair value of securities with a remaining contractual maturity of greater than one year was $39.7 million. As of December 31, 2021,
the Company did not intend to sell, and would not be more likely than not be required to sell, the securities in an unrealized loss position before recovery of
their amortized cost bases.
5. Property and Equipment, Net
Property and equipment, net consisted of the following (in thousands):
Lab equipment
Furniture and fixtures
Computer equipment
Software
Leasehold improvements
Construction in process
Total property and equipment
Less: accumulated depreciation
Property and equipment, net
December 31,
2021
December 31,
2020
8,182 $
594
373
199
6,289
—
15,637
(8,269 )
7,368 $
6,877
594
373
199
6,210
262
14,515
(6,118 )
8,397
$
$
Depreciation expense for the years ended December 31, 2021 and 2020 was $2.5 million and $2.4 million, respectively. Total property and
equipment, gross, as of December 31, 2020 included $0.2 million of property and equipment recorded under capital leases. Accumulated depreciation as of
December 31, 2020 included $0.2 million for property and equipment recorded under capital leases. No property and equipment was recorded under capital
leases as of December 31, 2021.
6. Additional Balance Sheet Detail
Prepaid expenses and other current assets consisted of the following (in thousands):
Prepaid expenses
Prepaid sign-on bonuses subject to vesting provisions
Interest income receivable
Other
Total prepaid expenses and other current assets
F-15
December 31,
2021
December 31,
2020
$
$
3,400 $
326
473
—
4,199 $
3,668
147
176
74
4,065
Accrued expenses and other current liabilities consisted of the following (in thousands):
External research and development
Payroll and benefits
Professional services
Capital lease obligation, current portion
Other
Total accrued expenses and other current liabilities
December 31,
2021
December 31,
2020
$
$
3,171 $
4,990
996
—
74
9,231 $
4,082
2,928
196
17
44
7,267
7. Preferred Stock
As of December 31, 2021 and 2020, 5,000,000 shares of undesignated preferred stock were authorized. No shares of preferred stock were issued or
outstanding as of December 31, 2021 and 2020.
No dividends have been declared since inception.
8. Common Stock
As of December 31, 2021 and 2020, 200,000,000 shares of common stock, $0.001 par value per share, were authorized.
Each share of common stock entitles the holder to one vote on all matters submitted to a vote of the Company’s stockholders. Common stockholders
are not entitled to receive dividends, unless declared by the Company’s board of directors, subject to the preferential dividend rights of any preferred stock
then outstanding. No dividends have been declared or paid by the Company since its inception.
As of December 31, 2021 and 2020, the Company has reserved for future issuance the following number of shares of common stock:
Shares reserved for exercises of outstanding stock options
Shares reserved for future issuance under the 2019 Stock
Incentive Plan
Shares reserved for future issuance under the 2019
Employee Stock Purchase Plan
December 31,
2021
5,188,354
December 31,
2020
2,962,347
286,324
1,728,616
706,658
6,181,336
465,999
5,156,962
9. Stock-based Compensation Expense
2016 Stock Incentive Plan
In July 2016, the Company adopted the 2016 Stock Incentive Plan (the “2016 Plan”), which provided for the grant of restricted stock awards,
restricted stock units, incentive stock options, non-statutory stock options, and other stock-based awards to the Company’s eligible employees, officers,
directors, consultants, and advisors. As of the effective date of the 2019 Stock Incentive Plan (the “2019 Plan”), and as of December 31, 2021 and 2020, no
shares remained available for future issuance under the 2016 Plan. Any options or other awards outstanding under the 2016 Plan remain outstanding and
effective.
F-16
2019 Stock Incentive Plan
On July 2, 2019, the Company’s stockholders approved the 2019 Plan, which became effective on July 17, 2019. The 2019 Plan provides for the
grant of incentive stock options, non-statutory stock options, stock appreciation rights, restricted stock awards, restricted stock units and other stock-based
awards to the Company’s officers, employees, directors, consultants and advisors. The number of shares initially reserved for issuance under the 2019 Plan
was 2,017,142 shares, plus the shares of common stock remaining available for issuance under the 2016 Plan as of July 17, 2019. The number of shares
reserved was annually increased on January 1, 2020 and will be increased each January 1 thereafter through January 1, 2029 by the least of (i) 2,000,000
shares, (ii) 4% of the number of shares of the Company’s common stock outstanding on the first day of each such year or (iii) an amount determined by the
Company’s board of directors. As of December 31, 2021, there were 286,324 shares available for future issuance under the 2019 Plan. On January 1, 2022,
the number of shares reserved for issuance under the 2019 Plan was increased by 1,625,455 shares.
The shares of common stock underlying any awards that expire, terminate, or are otherwise surrendered, cancelled, forfeited or repurchased by the
Company under the 2016 Plan or the 2019 Plan will be added back to the shares of common stock available for issuance under the 2019 Plan. As of July
17, 2019, no further awards will be made under the 2016 Plan.
2022 Inducement Stock Incentive Plan
In February 2022, the Company's board of directors adopted the 2022 Inducement Stock Incentive Plan (the "Inducement Plan"), pursuant to which
the Company may grant, subject to the terms of the Inducement Plan and Nasdaq rules, nonstatutory stock options, stock appreciation rights, restricted
stock awards, restricted stock units, and other stock-based awards. The Company initially reserved a total of 1,750,000 shares of common stock for the
issuance of awards under the Inducement Plan. The number of shares reserved and available for issuance under the Inducement Plan can be increased at
any time with the approval of the Company’s board of directors. The Inducement Plan permits the board of directors, a delegated committee of the board of
directors, or a delegated officer of the Company to grant the stock-based awards available under the Inducement Plan to attract key employees for the
growth of the Company.
Restricted Stock
The Company may repurchase unvested shares at the original purchase price if employees or non-employees are terminated or cease their
employment or service relationship with the Company. Shares of common stock repurchased from employees and non-employees are shares held in the
Company’s treasury (“Treasury Shares”). The board of directors may, at its discretion, authorize that the Treasury Shares be returned to the pool of
authorized but unissued common stock.
The shares of common stock underlying restricted stock awards typically vest over a four-year period. The shares of common stock are recorded in
stockholders’ equity as they vest.
The following table summarizes the Company’s restricted stock activity under the 2019 Plan and 2016 Plan since December 31, 2019:
Unvested at December 31, 2019
Granted
Vested
Repurchased
Unvested at December 31, 2020
Granted
Vested
Repurchased
Unvested at December 31, 2021
F-17
Number of
Shares
Weighted
Average Grant
Date Fair
Value
346,423 $
—
(233,563 )
(29,882 )
82,978 $
—
(69,833 )
(2,971 )
10,174 $
3.05
—
3.00
3.05
3.19
—
3.17
3.22
3.35
Stock Options
Stock options granted by the Company typically vest over a four year period and have a ten year contractual term. Shares issued upon the exercise of
stock options are issued from the Company’s pool of authorized but unissued common stock. In addition to stock options granted under the 2019 Plan and
2016 Plan, the Company has granted stock options as material inducements to employment in accordance with Nasdaq Listing Rule 5635(c)(4), which were
granted outside of the 2019 Plan and 2016 Plan. The following table summarizes the Company’s stock option activity during the year ended December 31,
2021:
Outstanding at December 31, 2020
Granted
Exercised
Cancelled
Outstanding at December 31, 2021
Exercisable at December 31, 2021
Weighted
Average
Exercise
Price
Weighted
Average
Remaining
Contractual
Term
(in years)
Aggregate
Intrinsic
Value
11.57
15.56
9.74
12.44
13.91
11.54
8.55 $
5,767,895
8.57 $
7.70 $
27,082,052
9,083,995
Number of
Shares
2,962,347 $
2,976,667
(341,952 )
(408,708 )
5,188,354 $
1,476,669 $
The aggregate intrinsic value of stock options is calculated as the difference between the exercise price of the stock options and the fair value of the
Company’s common stock as of the balance sheet date for those options that had exercise prices lower than the fair value of the Company’s common stock.
The weighted average grant date fair value of stock options granted in the years ended December 31, 2021 and 2020 was $11.37 per share and $9.76
per share, respectively. The total intrinsic value of stock options exercised in the years ended December 31, 2021 and 2020 was $3.5 million and $1.4
million, respectively.
The fair value of stock options granted during the years ended December 31, 2021 and 2020 has been calculated on the date of grant using the
following weighted average assumptions:
Risk-free interest rate
Expected dividend yield
Expected term (years)
Expected stock price volatility
Year
Ended
December 31, 2021
Year
Ended
December 31, 2020
0.9 %
0.0 %
6.1
87.3 %
1.2 %
0.0 %
6.0
77.6 %
F-18
Restricted Stock Grants Outside of the 2016 Plan and the 2019 Plan
The following table summarizes the Company’s restricted stock activity outside of the 2019 Plan and 2016 Plan since December 31, 2019:
Unvested at December 31, 2019
Granted
Vested
Repurchased
Unvested at December 31, 2020
Granted
Vested
Repurchased
Unvested at December 31, 2021
Number of
Shares
Weighted
Average Grant
Date Fair
Value
334,647 $
—
(291,789 )
—
42,858 $
—
(42,858 )
—
— $
2.94
—
2.94
—
2.93
—
2.94
—
—
The aggregate intrinsic value of all restricted stock awards that vested during the years ended December 31, 2021 and 2020 was $1.5 million and
$8.8 million, respectively.
Stock-based Compensation Expense
The total compensation cost recognized in the statements of operations and comprehensive loss associated with all stock-based compensation
awards granted by the Company is as follows (in thousands):
General and administrative
Research and development
Total stock-based compensation expense
Year Ended
December 31,
2021
2020
$
$
6,614 $
4,456
11,070 $
3,970
3,380
7,350
As of December 31, 2021, the Company had an aggregate of $34.6 million of unrecognized stock-based compensation expense, which is expected to
be recognized over a weighted average period of 2.76 years.
2019 Employee Stock Purchase Plan
On July 2, 2019, the Company’s stockholders approved the 2019 Employee Stock Purchase Plan (the “ESPP”), which became effective on July 17,
2019. A total of 252,142 shares of common stock were initially reserved for issuance under the ESPP. In addition, the number of shares of common stock
reserved under the ESPP was annually increased on January 1, 2020, and will be increased on each January 1 thereafter through January 1, 2029, by the
least of (i) 428,571 shares of common stock, (ii) 1% of the number of shares of the Company’s common stock outstanding on the first day of each such
year or (iii) an amount determined by the Company’s board of directors. As of December 31, 2021, there were 706,658 shares available for future issuance
under the ESPP. On January 1, 2022, the number of shares reserved for issuance under the 2019 ESPP was increased by 406,363 shares.
F-19
10. Collaboration and License Agreements
Acceleron Collaboration Agreement
On December 20, 2019, the Company entered into the Acceleron Collaboration Agreement to identify biological targets to modulate specific
pathways associated with a targeted indication within the pulmonary disease space (the “Indication”). Under the terms of the Acceleron Collaboration
Agreement, the Company granted Acceleron an exclusive worldwide license under certain intellectual property rights to make, have made, use, sell, have
sold, import, export, distribute and have distributed, market, have marketed, promote, have promoted, or otherwise exploit molecules and products directed
against or expressing certain biological targets identified by the Company for the treatment, prophylaxis, or diagnosis of the Indication.
Pursuant to a mutually agreed research plan, the Company will perform assay screening and related research activities to identify and validate
potential biological targets for further research, in order to support the development, manufacture and commercialization of product candidates by
Acceleron. Upon completion of the research activities, the Company will deliver a data package to Acceleron with respect to the biological targets
identified by the Company in the conduct of the research activities for the treatment, prophylaxis, or diagnosis of the Indication. As provided for under the
exclusive worldwide license that was conveyed at the inception of the arrangement, Acceleron has the right to designate a specified number of the
biological targets identified by the Company for Acceleron’s research, development, manufacture and commercialization of products or molecules directed
to such targets for the treatment, prophylaxis, or diagnosis of the Indication (the “Targets”). If Acceleron does not designate any Targets during the
designated period, then the Acceleron Collaboration Agreement will automatically terminate. If Acceleron designates one or more Targets, then Acceleron
will be obligated to use commercially reasonable efforts to seek regulatory approval for one product directed to a Target in certain specified countries.
Upon receipt of regulatory approval for any product directed to a Target, Acceleron must use commercially reasonable efforts to commercialize such
product in certain specified countries.
Acceleron may also request that the Company perform medicinal chemistry services related to the generation and optimization of molecules directed
against or expressing biological targets for the treatment, prophylaxis, or diagnosis of the Indication beyond the scope of the research plan. If the Company
agrees to provide such medicinal chemistry services, the Company and Acceleron will negotiate to determine the scope, timeline and budget for such
medicinal chemistry services.
The Company received a non-refundable upfront payment of $10.0 million in December 2019 upon the execution of the Acceleron Collaboration
Agreement. The Company is entitled to research milestone payments of up to $18.5 million in the aggregate upon achievement of specified research
milestones, development milestone payments of up to $202.5 million in the aggregate upon achievement of specified clinical and regulatory milestones,
and sales milestones payments of up to $217.5 million in the aggregate upon the achievement of certain aggregate annual worldwide net sales milestones
for certain products directed to a Target that have achieved such milestones. To date, the Company achieved $2.0 million of specified research milestones.
In addition, the Company is entitled to tiered royalties ranging from a mid single-digit percentage to a low double-digit percentage on Acceleron’s annual
worldwide net sales of products directed to any Target, subject to reduction in specified circumstances. The Company is also entitled to receive
reimbursement from Acceleron for research costs incurred under the research plan, including internal and external costs.
The Acceleron Collaboration Agreement continues on a country-by-country and Target-by-Target basis until the last to expire royalty term for a
product directed to such Target, at which time the Acceleron Collaboration Agreement expires with respect to such Target in such country. Either party has
the right to terminate the Acceleron Collaboration Agreement if the other party has materially breached in the performance of its obligations under the
contract and such breach has not been cured within the applicable cure period. Acceleron also has the right to terminate the Acceleron Collaboration
Agreement for convenience in its entirety or on a Target-by-Target and, if the Company performs medicinal chemistry services, on a molecule-by-molecule
basis with respect to any molecule directed against a Target.
F-20
While the Company is performing the research activities pursuant to the research plan and for a specified period thereafter, the Company may not
research, develop, manufacture, commercialize, use, or otherwise exploit any compound or product for the treatment, prophylaxis, or diagnosis of the
Indication other than for Acceleron. While the Company is performing the research activities pursuant to the research plan and for a specified period
thereafter, other than for Acceleron, the Company may not research, develop, manufacture, commercialize, use, or otherwise exploit any compound or
product for the treatment, prophylaxis, or diagnosis of the Indication that is directed against certain specified biological targets identified by the Company
in the performance of the research activities.
Accounting Analysis
Identification of the Contract
The Company assessed the Acceleron Collaboration Agreement and concluded that it represents a contract with a customer within the scope of ASC
606.
Identification of the Promises and Performance Obligations
The Company determined that the Acceleron Collaboration Agreement contains the following promises: (i) an exclusive worldwide license under
certain intellectual property rights, including rights to a specified number of biological targets identified by the Company for the treatment, prophylaxis, or
diagnosis of a targeted indication within the pulmonary disease space that was conveyed at the inception of the arrangement (the “License”), (ii) research
services to identify and validate potential biological targets (the “Research Services”), and (iii) participation in the joint steering committee (the “JSC”).
The Company assessed the above promises and concluded that the License is not capable of being distinct from the Research Services given that the
License has limited value without the performance of the Research Services and the Research Services can only be performed by the Company due to their
specialized nature. Therefore, the Company has concluded that the License and the Research Services represent a single combined performance obligation.
The Company also assessed the participation on the JSC and concluded that the promise is quantitatively and qualitatively immaterial in the context
of the Acceleron Collaboration Agreement. Accordingly, the Company has disregarded its participation on the JSC as a performance obligation.
The potential medicinal chemistry services were not identified as a promised good or service because the Company is under no obligation to provide
those services.
Determination of the Transaction Price
The Company received a non-refundable upfront payment of $10.0 million upon the execution of the Acceleron Collaboration Agreement, which
the Company included in the transaction price. In December 2020, the Company achieved $2.0 million of specified research milestones associated with the
Acceleron Collaboration Agreement, which were previously constrained due to the significant uncertainty regarding whether such research milestones
would be achieved. The Company included this amount in the transaction price as of December 31, 2020. Based on the continued uncertainty associated
with the achievement of any of the remaining research and development milestone payments that the Company is eligible to receive, the Company has
constrained the variable consideration associated with those remaining milestone payments and excluded them from the transaction price. As part of its
evaluation of constraining the remaining research and development milestones, the Company considered numerous factors, including the fact that the
achievement of the research and development milestones are contingent upon the results of the underlying research and development activities and are thus
outside of the control of the Company.
The Company also included in the transaction price the expected amount of costs to be reimbursed for the Research Services.
The Company reassesses the transaction price at the end of each reporting period and as uncertain events are resolved or other changes in
circumstances occur, and, if necessary, adjusts its estimate of the transaction price.
Any consideration related to sales milestone payments (including royalties) will be recognized when the related sales occur as these amounts have
been determined to relate predominantly to the license granted to Acceleron and therefore are recognized at the later of when the related sales occur or the
performance obligation is satisfied.
F-21
Allocation of the Transaction Price to Performance Obligations
As noted above, the Company has identified a single performance obligation associated with the Acceleron Collaboration Agreement. Therefore, the
Company will allocate the entire amount of the transaction price to the identified single performance obligation.
Recognition of Revenue
The Company recognizes revenue related to the Acceleron Collaboration Agreement over time as the Research Services are rendered. The Company
has concluded that an input method is a representative depiction of the transfer of services under the Acceleron Collaboration Agreement. The method of
measuring progress towards the delivery of the services incorporates actual cumulative internal and external costs incurred relative to total internal and
external costs expected to be incurred to satisfy the performance obligation. The period over which total costs are estimated reflects the Company’s
estimate of the period over which it will perform the Research Services. Changes in estimates of total internal and external costs expected to be incurred are
recognized in the period of change as a cumulative catch-up adjustment.
During the year ended December 31, 2021, the Company recognized $9.6 million of collaboration revenue associated with the Acceleron
Collaboration Agreement, which includes $7.3 million of revenue recognized that was included in deferred revenue as of December 31, 2020. During the
year ended December 31, 2020, the Company recognized $6.3 million of collaboration revenue associated with the Acceleron Collaboration Agreement,
which includes $3.4 million of revenue recognized that was included in deferred revenue as of December 31, 2019 and a cumulative catch-up adjustment of
$0.5 million attributable to the removal of the constraint associated with the $2.0 million of research milestones achieved in December 2020. As of
December 31, 2021 and 2020, the Company recorded deferred revenue associated with the Acceleron Collaboration Agreement of $0.6 million and $7.9
million, respectively, which is classified as either current or net of current portion in the accompanying consolidated balance sheets based on the period
over which the revenue is expected to be recognized. The aggregate deferred revenue balance represents the aggregate amount of the transaction price
allocated to the performance obligations that are unsatisfied as of December 31, 2021 and 2020. As of December 31, 2021, the Company had received $3.9
million of cost reimbursement payments under the Acceleron Collaboration Agreement and $2.0 million associated with the achievement of specified
research milestones. As of December 31, 2020, the Company had received $1.7 million of cost reimbursement payments and no milestone or royalty
payments under the Acceleron Collaboration Agreement. As of December 31, 2021, the Company recorded unbilled accounts receivable of $0.7 million
related to reimbursable research and development costs under the Acceleron Collaboration Agreement for activities performed during the three months
ended December 31, 2021. As of December 31, 2020, the Company recorded unbilled accounts receivable of $0.5 million related to reimbursable research
and development costs under the Acceleron Collaboration Agreement for activities performed during the three months ended December 31, 2020. As of
December 31, 2021, the Company had recorded no accounts receivable under the Acceleron Collaboration Agreement. As of December 31, 2020, the
Company recorded accounts receivable of $2.0 million associated with the achievement of specified research milestones in December 2020.
MyoKardia Collaboration Agreement
On July 20, 2020, the Company entered into the MyoKardia Collaboration Agreement, pursuant to which the Company granted to MyoKardia an
exclusive worldwide license under certain intellectual property rights to research, develop, make, have made, use, have used, sell, have sold, offer for sale,
have offered for sale, import, have imported, export, have exported, distribute, have distributed, market, have marketed, promote, have promoted, or
otherwise exploit products directed against certain biological targets identified by the Company that are capable of modulating up to a certain number of
genes of interest with relevance to certain genetically defined cardiomyopathies.
Pursuant to a mutually agreed research plan, the Company will perform assay screening and related research activities to identify and validate up to
a specified number of potential cardiomyopathy gene targets (“Identified Targets”) for further research, development, manufacture and commercialization
by MyoKardia. The Company and MyoKardia will work together to determine how best to advance at each stage of the research activities under the
research plan and to identify which of the Identified Targets, if any, meet the criteria set forth in the research plan (the “Cardiomyopathy Target
Candidates”). Upon completion of the research plan, the parties will work together to prepare a final data package and MyoKardia may designate certain
Cardiomyopathy Target Candidates for MyoKardia’s further exploitation under the MyoKardia Collaboration Agreement (the “Cardiomyopathy Targets”).
If MyoKardia does not designate any Cardiomyopathy Targets during the designated period, then the MyoKardia Collaboration Agreement will
automatically terminate. If MyoKardia designates one or more Cardiomyopathy Targets, then MyoKardia will be obligated to use commercially reasonable
efforts to seek regulatory approval for and to commercialize one product directed against an Identified Target in certain specified countries.
F-22
During the period in which the Company is performing the research activities pursuant to the research plan (the “Research Term”) and for a
specified period beyond the Research Term if MyoKardia designates a Cardiomyopathy Target, the Company may only use the data generated from such
research activities for MyoKardia in accordance with the MyoKardia Collaboration Agreement. During the Research Term and for a specified period
thereafter, the Company may not research, develop, manufacture, commercialize, use, or otherwise exploit any compound or product (a) that is a
Compound or Product under the MyoKardia Collaboration Agreement that is directed against the Cardiomyopathy Target Candidates for the treatment,
prophylaxis, or diagnosis of any indication or (b) for the treatment of any genetically defined cardiomyopathies shown to be related to certain specified
genes of interest that are modulated by the Cardiomyopathy Targets.
Under the MyoKardia Collaboration Agreement, MyoKardia made a $10.0 million upfront payment and a $2.5 million payment as prepaid research
funding to the Company in July 2020. MyoKardia will also reimburse the Company for the costs of the research activities not covered by the prepaid
research funding, up to a maximum amount of total research funding (including the prepaid research funding). Upon the achievement of specified
preclinical, development and sales milestones, the Company will be entitled to preclinical milestone payments, development milestone payments and sales
milestone payments of up to $298.5 million in the aggregate per target for certain Identified Targets, and of up to $150.0 million in the aggregate per target
for certain other Identified Targets. To date, the Company has achieved a $2.5 million specified preclinical milestone. MyoKardia will also pay the
Company tiered royalties ranging from a mid single-digit percentage to a low double-digit percentage based on MyoKardia’s, and any of its affiliates’ and
sublicensees’, annual worldwide net sales of products under the MyoKardia Collaboration Agreement directed against any Identified Target. The royalties
are payable on a product-by-product basis during a specified royalty term, and may be reduced in specified circumstances.
The MyoKardia Collaboration Agreement continues on a country-by-country and product-by-product basis until the last to expire royalty term for a
product, at which time the MyoKardia Collaboration Agreement expires with respect to such product in such country. Either party has the right to terminate
the MyoKardia Collaboration Agreement if the other party has materially breached in the performance of its obligations under the MyoKardia
Collaboration Agreement and such breach has not been cured within the applicable cure period. MyoKardia also has the right to terminate the MyoKardia
Collaboration Agreement for convenience in its entirety or on a target-by-target, product-by-product or molecule-by-molecule basis.
Accounting Analysis
Identification of the Contract
The Company assessed the MyoKardia Collaboration Agreement and concluded that it represents a contract with a customer within the scope of
ASC 606.
Identification of the Promises and Performance Obligations
The Company determined that the MyoKardia Collaboration Agreement contains the following promises: (i) an exclusive worldwide license under
certain intellectual property rights, including rights to a specified number of potential cardiomyopathy gene targets identified by the Company for further
research, development, manufacture and commercialization for the treatment, prophylaxis, or diagnosis of certain genetically defined cardiomyopathies that
was conveyed at the inception of the arrangement (the “MyoKardia License”), (ii) research services to identify and validate potential biological targets (the
“MyoKardia Research Services”), and (iii) participation in the joint steering committee (the “MyoKardia JSC”).
The Company assessed the above promises and concluded that the MyoKardia License is not capable of being distinct from the MyoKardia
Research Services given that the MyoKardia License has limited value without the performance of the MyoKardia Research Services and the MyoKardia
Research Services can only be performed by the Company due to their specialized nature. Therefore, the Company has concluded that the MyoKardia
License and the MyoKardia Research Services represent a single combined performance obligation.
F-23
The Company also assessed the participation on the MyoKardia JSC and concluded that the promise is quantitatively and qualitatively immaterial in
the context of the MyoKardia Collaboration Agreement. Accordingly, the Company has disregarded its participation on the MyoKardia JSC as a
performance obligation.
Determination of the Transaction Price
The Company received a non-refundable upfront payment of $10.0 million, which the Company included in the transaction price. In December
2021, the Company achieved a $2.5 million specified preclinical milestone associated with the MyoKardia Collaboration Agreement, which was previously
constrained due to the significant uncertainty regarding whether such preclinical milestone would be achieved. Based on the uncertainty associated with the
achievement of any preclinical and development milestone payments that the Company is eligible to receive, the Company has constrained the variable
consideration associated with those milestone payments and excluded them from the transaction price. As part of its evaluation of constraining the
preclinical and development milestones, the Company considered numerous factors, including the fact that the achievement of the preclinical and
development milestones are contingent upon the results of the underlying preclinical and development activities and are thus outside of the control of the
Company.
The Company also included in the transaction price the expected amount of costs to be reimbursed for the MyoKardia Research Services, which
includes the $2.5 million prepaid research funding payment that the Company received in the third quarter of 2020.
The Company reassesses the transaction price at the end of each reporting period and as uncertain events are resolved or other changes in
circumstances occur, and, if necessary, adjusts its estimate of the transaction price.
Any consideration related to sales milestone payments (including royalties) will be recognized when the related sales occur as these amounts have
been determined to relate predominantly to the license granted to MyoKardia and therefore are recognized at the later of when the related sales occur or the
performance obligation is satisfied.
Allocation of the Transaction Price to Performance Obligations
As noted above, the Company has identified a single performance obligation associated with the MyoKardia Collaboration Agreement. Therefore,
the Company will allocate the entire amount of the transaction price to the identified single performance obligation.
Recognition of Revenue
The Company recognizes revenue related to the MyoKardia Collaboration Agreement over time as the MyoKardia Research Services are rendered.
The Company has concluded that an input method is a representative depiction of the transfer of services under the MyoKardia Collaboration Agreement.
The method of measuring progress towards the delivery of the services incorporates actual cumulative internal and external costs incurred relative to total
internal and external costs expected to be incurred to satisfy the performance obligation. The period over which total costs are estimated reflects the
Company’s estimate of the period over which it will perform the MyoKardia Research Services. Changes in estimates of total internal and external costs
expected to be incurred are recognized in the period of change as a cumulative catch-up adjustment.
During the year ended December 31, 2021, the Company recognized $9.6 million of collaboration revenue associated with the MyoKardia
Collaboration Agreement, which includes $6.7 million of revenue recognized that was included in deferred revenue as of December 31, 2020 and a
cumulative catch-up adjustment of $1.7 million attributable to the removal of the constraint associated with the $2.5 million preclinical milestone achieved
in December 2021. During the year ended December 31, 2020, the Company recognized $2.5 million of collaboration revenue associated with the
MyoKardia Collaboration Agreement. As of December 31, 2021 and 2020, the Company recorded deferred revenue of $4.1 million and $10.0 million,
respectively, associated with the MyoKardia Collaboration Agreement, which is classified as either current or net of current portion in the accompanying
consolidated balance sheets based on the period over which the revenue is expected to be recognized. The aggregate deferred revenue balance represents
the aggregate amount of the transaction price allocated to the performance obligations that are unsatisfied as of December 31, 2021 and 2020. As of
December 31, 2021, the Company had received $3.2 million of cost reimbursement payments under the MyoKardia Collaboration Agreement, including
the $2.5 million payment as prepaid research funding in July 2020, and no milestone or royalty payments. As of December 31, 2020, the Company had not
received any milestone, royalty, or cost reimbursement payments under the MyoKardia Collaboration Agreement, other than the $2.5 million payment as
prepaid research funding in July 2020. As of December 31, 2021, the Company recorded unbilled accounts receivable of $0.5 million related to
reimbursable research and development costs under the MyoKardia Collaboration Agreement for activities performed during the three months ended
December 31, 2021. As of December 31, 2021, the Company has recorded accounts receivable of $2.5 million under the MyoKardia Collaboration
Agreement associated with the achievement of a preclinical milestone in December 2021. As of December 31, 2020, the Company had recorded no
accounts receivable under the MyoKardia Collaboration Agreement.
F-24
11. Right of Reference and License Agreement
In February 2019, the Company entered into the right of reference and license agreement, as amended (the “GSK Agreement”), with subsidiaries of
GlaxoSmithKline plc (collectively referred to as “GSK”), pursuant to which the Company has been granted an exclusive worldwide license to develop and
commercialize losmapimod. Under the GSK Agreement, the Company also acquired reference rights to relevant regulatory and manufacturing documents
and GSK’s existing supply of losmapimod drug substance and product. The Company also has the right to sublicense its rights under the license agreement,
subject to certain conditions. The Company is obligated to use commercially reasonable efforts to develop and commercialize losmapimod at its sole cost.
The Company is also responsible for costs related to the filing and maintenance of the licensed patent rights.
Under the GSK Agreement, the Company issued 12,500,000 shares of Series B Preferred Stock to GSK. In addition, the Company may owe GSK
up to $37.5 million in certain specified clinical and regulatory milestones, including $2.5 million previously achieved and paid during 2019, and up to
$60.0 million in certain specified sales milestones. The Company has agreed to pay tiered royalties on annual net sales of losmapimod that range from mid
single-digit percentages to a low double-digit, but less than teens, percentage. The royalties are payable on a product-by-product and country-by-country
basis, and may be reduced in specified circumstances.
The GSK Agreement may be terminated by either party for a material breach by the other, subject to notice and cure provisions. Unless earlier
terminated, the GSK Agreement will continue in effect until the expiration of the Company’s royalty obligations, which expire on a country-by-country
basis on the later of (i) ten years after the first commercial sale in the country or (ii) approval of a generic version of losmapimod by the applicable
regulatory agency.
The Company will recognize clinical and regulatory milestone payments when the underlying contingency is resolved and the consideration is paid
or becomes payable. The milestone payments will be capitalized or expensed depending on the nature of the associated asset as of the date of recognition.
The Company will record sales milestone payments and royalties as additional expense of the related product sales in the period in which the corresponding
sales occur.
12. Commitments and Contingencies
Operating Leases
26 Landsdowne Street
In November 2017, the Company entered into a lease agreement for its current corporate headquarters comprising approximately 28,731 square feet
of office and laboratory space at 26 Landsdowne Street in Cambridge, Massachusetts, commencing December 2017 when the Company gained access to
the leased space for purposes of making leasehold improvements. The Company began recognizing rent expense associated with this lease during
December 2017. The Company began to occupy and use the leased space for its intended purpose in June 2018. The lease ends on June 30, 2028. The
Company has the option to extend the term of the lease for an additional five-year period, at the market rate, by giving the landlord written notice of its
election to exercise the extension at least nine months prior to the original expiration of the lease term. The lease has a total commitment of $25.1 million
over the ten year term, and includes escalating rent payments. The lease provides the Company with an allowance for normal leasehold improvements of
$5.0 million. The Company accounts for leasehold improvement incentives as a reduction to rent expense ratably over the lease term. The balance from the
leasehold improvement incentives is classified as a deferred lease incentive on the balance sheet. The lease agreement requires the Company to either pay a
security deposit or maintain a letter of credit of $1.1 million. The Company maintains a letter of credit for this lease and has recorded the cash held to
secure the letter of credit as restricted cash on the consolidated balance sheet as of December 31, 2021 and 2020. The Company records rent expense for
this lease on a straight-line basis. Rent expense associated with this lease for the years ended December 31, 2021 and 2020 was approximately $1.9 million.
The future minimum lease payments associated with the lease for the Company’s current headquarters as of December 31, 2021 are as follows (in
thousands):
2022
2023
2024
2025
2026
Thereafter
Total minimum lease payments
F-25
2,424
2,497
2,572
2,649
2,729
4,237
17,108
$
125 Sidney Street
In November 2021, the Company entered into a lease agreement comprising approximately 12,196 square feet of office space at 125 Sidney Street
in Cambridge, Massachusetts, commencing November 2021 when the Company gained access to the leased space for purposes of making leasehold
improvements. The Company began recognizing rent expense associated with this lease during November 2021. The lease ends on March 31, 2024. The
Company has the option to extend the term of the lease for two successive one-year periods, at the market rate, by giving the landlord written notice of its
election to exercise the extension at least nine months prior to the original expiration of the lease term. The lease has a total commitment of $1.7 million
over the initial term, and includes escalating rent payments. Rent expense associated with this lease for the year ended December 31, 2021 was $0.1
million.
The future minimum lease payments associated with the 125 Sidney Street lease as of December 31, 2021 are as follows (in thousands):
2022
2023
2024
Total minimum lease payments
613
836
210
1,659
$
Other Agreements
The Company has agreements with third parties in the normal course of business under which it can license certain developed technologies. If the
Company exercises its rights to license the technologies it may be subject to additional fees and milestone payments. As of December 31, 2021, the
Company has not exercised its rights to license such technologies.
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 arising out of the relationship between such parties and the Company. 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 as of December 31, 2021 or 2020.
Legal Proceedings
The Company is not currently a party to any material legal proceedings. At each reporting date, the Company evaluates whether or not a potential
loss amount or a potential range of loss is probable and reasonably estimable under the provisions of the authoritative guidance that addresses accounting
for contingencies. The Company expenses the costs related to its legal proceedings as they are incurred. No such costs have been incurred for the years
ended December 31, 2021 and 2020.
F-26
13. Income Taxes
A reconciliation of the U.S. federal statutory income tax rate to the Company’s effective income tax rate is as follows:
Federal income tax at statutory rate
Permanent differences
Federal and state research and development credits
Federal orphan drug credits
State income tax, net of federal benefit
Other
Change in valuation allowance
Effective income tax rate
Year Ended
December 31,
2021
Year Ended
December 31,
2020
21.00 %
(0.31 )
2.39
4.51
6.12
(0.06 )
(33.65 )
— %
21.00 %
(0.79 )
2.57
4.28
6.14
0.47
(33.67 )
— %
During the years ended December 31, 2021 and 2020, the Company incurred book and tax losses and, because it maintains a full valuation
allowance on its net deferred tax assets, did not recognize federal or state income tax expense or benefit.
The Company’s deferred tax assets and liabilities consist of the following (in thousands):
Deferred tax assets:
Net operating loss carryforwards
Research and development credit carryforwards
Orphan drug credit carryforwards
Intangible assets
Deferred revenue
Accrued expenses and other
Deferred lease incentive
Deferred rent
Gross deferred tax assets
Valuation allowance
Net deferred tax assets
Deferred tax liability
Net deferred tax assets
December 31,
2021
December 31,
2020
$
$
67,043 $
8,774
6,679
6,192
1,061
4,537
832
471
95,589
(94,630 )
959
(959 )
— $
46,603
6,842
3,032
6,722
1,791
2,240
962
450
68,642
(67,427 )
1,215
(1,215 )
—
The Company has evaluated the positive and negative evidence bearing upon its ability to realize the net deferred tax assets. The Company
considered its history of cumulative net losses incurred since inception and its lack of commercialization of any products since inception and has concluded
that it is more likely than not that the Company will not realize the benefits of the net deferred tax assets. Accordingly, a full valuation allowance has been
established against the net deferred tax assets as of December 31, 2021 and 2020. The valuation allowance increased by $27.2 million during the year
ended December 31, 2021, which is primarily attributable to increases in net operating loss carryforwards as a result of current year net losses and the
generation of research and development and orphan drug tax credit carryforwards. The Company reevaluates the positive and negative evidence at each
reporting period.
As of December 31, 2021, the Company had federal net operating loss carryforwards of approximately $245.8 million, a portion of which begin to
expire in 2036. Approximately $214.8 million of the federal net operating losses can be carried forward indefinitely. As of December 31, 2021, the
Company also had state net operating loss carryforwards of approximately $244.0 million, which begin to expire in 2036.
As of December 31, 2021, the Company had federal orphan drug credits of approximately $6.7 million, which begin to expire in 2040. As of
December 31, 2021, the Company had federal research and development tax credit carryforwards of approximately $6.1 million, which begin to expire in
2035. As of December 31, 2021, the Company also had state research and development tax credit carryforwards of approximately $3.3 million, which
begin to expire in 2030.
F-27
Utilization of the net operating loss carryforwards and research and development tax credit carryforwards may be subject to an annual limitation
under Section 382 of the Internal Revenue Code of 1986, as amended (the “Internal Revenue Code”), and corresponding provisions of state law, due to
ownership changes that have occurred previously or that could occur in the future. These ownership changes may limit the amount of carryforwards that
can be utilized annually to offset future taxable income. In general, an ownership change, as defined by Section 382, results from transactions increasing
the ownership of certain shareholders or public groups in the stock of a corporation by more than 50% over a three-year period. The Company has not
conducted a study to assess whether a change of control has occurred or whether there have been multiple changes of control since inception due to the
significant complexity and cost associated with such a study. If the Company has experienced a change of control, as defined by Section 382, at any time
since inception, utilization of the net operating loss carryforwards or research and development tax credit carryforwards would be subject to an annual
limitation under Section 382, which is determined by first multiplying the value of the Company’s stock at the time of the ownership change by the
applicable long-term tax-exempt rate, and then could be subject to additional adjustments, as required. Any limitation may result in expiration of a portion
of the net operating loss carryforwards or research and development tax credit carryforwards before utilization. Further, until a study is completed and any
limitation is known, no amounts are being presented as an uncertain tax position.
The Company files tax returns as prescribed by the tax laws of the jurisdictions in which it operates. In the normal course of business, the Company
is subject to examination by federal and state jurisdictions, where applicable. There are currently no pending tax examinations. As of December 31, 2021,
the Company’s tax years are still open under statute from 2016 to the present.
It is the Company’s policy to include penalties and interest expense related to income taxes as a component of the provision for income taxes. As of
December 31, 2021 and 2020, the Company had no accrued interest or penalties related to uncertain tax positions and no amounts have been recognized in
the Company’s statements of operations. For the year ended December 31, 2021, the Company generated research and development tax credits but has not
conducted a study to document the qualified activities. This study may result in an adjustment to the Company’s research and development tax credit
carryforwards; however, until a study is completed and any adjustment is known, no amounts are being presented as an uncertain tax position. A full
valuation allowance has been provided against the Company’s research and development tax credit carryforwards and, if an adjustment is required, this
adjustment would result in an adjustment to the deferred tax asset established for the research and development tax credit carryforwards and the valuation
allowance.
14. Defined Contribution Plan
The Company has a defined contribution savings plan under Section 401(k) of the Internal Revenue Code (the “401(k) Plan”). The 401(k) Plan
covers all employees who meet defined minimum age and service requirements, and allows participants the option to elect to defer a portion of their annual
compensation on a pretax basis. As currently established, the Company is not required to make and has not made any contributions to the 401(k) Plan as of
December 31, 2021.
15. Net Loss per Share
The following common stock equivalents were excluded from the calculation of diluted net loss per share for the periods indicated because
including them would have had an anti-dilutive effect:
Outstanding stock options
Unvested restricted stock awards
Total
F-28
Year Ended
December 31,
2021
2020
5,188,354
10,174
5,198,528
2,962,347
125,836
3,088,183
Exhibit
Number
3.1
3.2
4.1
4.2
10.1
10.2
10.3#
10.4#
10.5#
10.6#
10.7#
10.8#
10.9#
10.10*#
10.11#
10.12*#
10.13*#
10.14*#
10.15*#
10.16#
10.17#
10.18#
EXHIBIT INDEX
Description
Restated Certificate of Incorporation of the Registrant (incorporated by reference to Exhibit 3.1 to the Registrant’s Current Report on Form
8-K filed with the Securities and Exchange Commission on July 22, 2019).
Amended and Restated Bylaws of the Registrant (incorporated by reference to Exhibit 3.2 to the Registrant’s Current Report on Form 8-K
filed with the Securities and Exchange Commission on July 22, 2019).
Specimen Stock Certificate evidencing shares of common stock (incorporated by reference to Exhibit 4.1 to the Registrant’s Registration
Statement on Form S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on June 21, 2019).
Description of the Registrant’s Securities Registered under Section 12 of the Exchange Act (incorporated by reference to Exhibit 4.2 to the
Registrant’s Annual Report on Form 10-K filed with the Securities and Exchange Commission on March 5, 2020).
Amended and Restated Investors' Rights Agreement, dated as of August 24, 2018, by and among the Registrant and the other parties thereto
(incorporated by reference to Exhibit 10.1 to the Registrant’s Registration Statement on Form S-1 (File No. 333-232260) filed with the
Securities and Exchange Commission on June 21, 2019).
Registration Rights Agreement, dated June 9, 2020, by and among the Registrant and the other parties thereto (incorporated by reference to
Exhibit 10.2 of the Registrant's Current Report on Form 8-K filed with the Securities and Exchange Commission on June 10, 2020).
2016 Stock Incentive Plan, as amended (incorporated by reference to Exhibit 10.2 to the Registrant’s Registration Statement on Form S-1
(File No. 333-232260) filed with the Securities and Exchange Commission on June 21, 2019).
Form of Incentive Stock Option Agreement under the 2016 Stock Incentive Plan (incorporated by reference to Exhibit 10.3 to the
Registrant’s Registration Statement on Form S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on June 21,
2019).
Form of Non-Statutory Stock Option Agreement under the 2016 Stock Incentive Plan (incorporated by reference to Exhibit 10.4 to the
Registrant’s Registration Statement on Form S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on June 21,
2019).
Form of Restricted Stock Agreement under the 2016 Stock Incentive Plan (incorporated by reference to Exhibit 10.5 to the Registrant’s
Registration Statement on Form S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on June 21, 2019).
2019 Stock Incentive Plan (incorporated by reference to Exhibit 10.6 to Amendment No. 1 to Registrant’s Registration Statement on Form
S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on July 8, 2019).
Form of Stock Option Agreement under the 2019 Stock Incentive Plan (incorporated by reference to Exhibit 10.7 to Amendment No. 1 to
Registrant’s Registration Statement on Form S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on July 8,
2019).
Form of Inducement Stock Option Agreement (incorporated by reference to Exhibit 10.1 to the Registrant’s Quarterly Report on Form 10-Q
filed with the Securities and Exchange Commission on November 4, 2021).
Form of Restricted Stock Unit Agreement under the 2019 Stock Incentive Plan.
2019 Employee Stock Purchase Plan (incorporated by reference to Exhibit 10.8 to Amendment No. 1 to Registrant’s Registration Statement
on Form S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on July 8, 2019).
2022 Inducement Stock Incentive Plan.
Form of Non-Statutory Stock Option Agreement under 2022 Inducement Stock Incentive Plan.
Form of Restricted Stock Unit Agreement under 2022 Inducement Stock Incentive Plan.
Summary of Non-Employee Director Compensation Program.
Form of Employment Agreement for Executive Officers (incorporated by reference to Exhibit 10.12 to Amendment No. 1 to Registrant’s
Registration Statement on Form S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on July 8, 2019).
Consulting Agreement, dated March 31, 2021, by and between the Registrant and Robert J. Gould (incorporated by reference to Exhibit 10.3
to the Registrant’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on May 6, 2021).
Employment Agreement, dated March 31, 2021, by and between the Registrant and Bryan Stuart (incorporated by reference to Exhibit 10.4
to the Registrant’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on May 6, 2021).
10.19#
10.20#
10.21#
10.22#
10.23*#
10.24#
10.25†
10.26†
10.27†
10.28†
10.29
10.30
10.31
21.1*
23.1*
31.1*
31.2*
32.1+
32.2+
101.INS
101.SCH
101.CAL
101.DEF
101.LAB
Employment Agreement, dated October 29, 2020, by and between the Registrant and Curtis Oltmans (incorporated by reference to Exhibit
10.16 to the Registrant’s Annual Report on Form 10-K filed with the Securities and Exchange Commission on March 4, 2021).
Employment Agreement, dated February 6, 2021, by and between the Registrant and Christopher Moxham (incorporated by reference to
Exhibit 10.1 to the Registrant’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on May 6, 2021).
Employment Agreement, dated February 6, 2021, by and between the Registrant and Judith Dunn (incorporated by reference to Exhibit 10.2
to the Registrant’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on May 6, 2021).
Employment Agreement, dated May 10, 2021, by and between the Registrant and Christopher Morabito (incorporated by reference to
Exhibit 10.1 to the Registrant’s Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission on August 10, 2021).
Employment Agreement, dated January 3, 2022, by and between the Registrant and Esther Rajavelu.
Form of Indemnification Agreement between the Registrant and each of its Executive Officers and Directors (incorporated by reference to
Exhibit 10.15 to Registrant’s Registration Statement on Form S-1 (File No. 333-232260) filed with the Securities and Exchange
Commission on June 21, 2019).
Right of Reference and License Agreement, dated as of February 8, 2019, by and among the Registrant, GlaxoSmithKline Intellectual
Property (No. 2) Limited, GlaxoSmithKline LLC and Glaxo Group Limited (incorporated by reference to Exhibit 10.10 to the Registrant’s
Registration Statement on Form S-1 (File No. 333-232260) filed with the Securities and Exchange Commission on June 21, 2019).
First Amendment to the Right of Reference and License Agreement, dated as of September 23, 2020, by and among the Registrant,
GlaxoSmithKline Intellectual Property (No. 2) Limited, GlaxoSmithKline LLC and Glaxo Group Limited (incorporated by reference to
Exhibit 10.2 to the Registrant’s Quarterly Report on Form 10-Q (File No. 001-38978) filed with the Securities and Exchange Commission
on November 10, 2020).
Collaboration and License Agreement, dated as of December 20, 2019, by and between the Registrant and Acceleron Pharma Inc, a wholly-
owned subsidiary of Merck & Co., Inc. (incorporated by reference to Exhibit 10.17 to the Registrant’s Annual Report on Form 10-K (File
No. 001-38978) filed with the Securities and Exchange Commission on March 5, 2020).
Collaboration and License Agreement, dated as of July 20, 2020, by and between the Registrant and MyoKardia, Inc, a wholly-owned
subsidiary of Bristol Myers Squibb Company (incorporated by reference to Exhibit 10.1 to the Registrant’s Quarterly Report on Form 10-Q
(File No. 001-38978) filed with the Securities and Exchange Commission on November 10, 2020).
Lease for 26 Landsdowne Street, dated November 22, 2017, by and between the UP 26 Landsdowne, LLC and the Registrant (incorporated
by reference to Exhibit 10.11 to the Registrant’s Registration Statement on Form S-1 (File No. 333-232260) filed with the Securities and
Exchange Commission on June 21, 2019).
Equity Distribution Agreement, dated August 11, 2020, by and between the Registrant and Piper Sandler & Co. (incorporated by reference
to Exhibit 1.2 to the Registrant’s Registration Statement on Form S-3 (File No. 333-244136) filed with the Securities and Exchange
Commission on August 11, 2020).
Amendment No. 1 to the Equity Distribution Agreement, dated November 4, 2021, by and between the Registrant and Piper Sandler & Co.
(incorporated by reference to Exhibit 1.3 to the Registrant’s Registration Statement on Form S-3 (File No. 333-260754) filed with the
Securities and Exchange Commission on November 4, 2021.
Subsidiary of the Registrant.
Consent of Ernst & Young LLP, independent registered public accounting firm.
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.
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.
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.
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.
XBRL Instance Document
XBRL Taxonomy Extension Schema Document
XBRL Taxonomy Extension Calculation Linkbase Document
XBRL Taxonomy Extension Definition Linkbase Document
XBRL Taxonomy Extension Label Linkbase Document
101.PRE
104
XBRL Taxonomy Extension Presentation Linkbase Document
Cover Page Interactive Data File (formatted as Inline XBRL with applicable taxonomy extension information contained in Exhibits 101)
# Indicates a management contract or any compensatory plan, contract or arrangement.
† Certain portions of this exhibit have been omitted because they are not material and would likely cause competitive harm to the Registrant if disclosed.
* Filed herewith.
+ Furnished herewith.
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.
Date: March 3, 2022
By:
/s/ Bryan Stuart
Bryan Stuart
President and Chief Executive Officer
Fulcrum Therapeutics, Inc.
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, this report has been signed below by the following persons on
behalf of the registrant in the capacities and on the dates indicated.
Name
/s/ Bryan Stuart
Bryan Stuart
/s/ Esther Rajavelu
Esther Rajavelu
/s/ Peter Thomson
Peter Thomson
/s/ Kate Haviland
Kate Haviland
/s/ Sonja Banks
Sonja Banks
/s/ James J. Collins
James J. Collins Ph.D.
/s/ Katina Dorton
Katina Dorton
/s/ Alan Ezekowitz
Alan Ezekowitz, MBChB, D. Phil
/s/ James Geraghty
James Geraghty
/s/ Robert J. Gould
Robert J. Gould, Ph.D.
/s/ Mark Levin
Mark Levin
Title
Date
President and Chief Executive Officer, Director
(Principal Executive Officer)
March 3, 2022
Chief Financial Officer (Principal Financial Officer)
March 3 2022
Vice President, Finance & Accounting (Principal
Accounting Officer)
Chair of the Board
Director
Director
Director
Director
Director
Director
Director
March 3, 2022
March 3, 2022
March 3, 2022
March 3, 2022
March 3, 2022
March 3, 2022
March 3, 2022
March 3, 2022
March 3, 2022
Fulcrum Therapeutics, Inc.
RESTRICTED STOCK UNIT AGREEMENT
Exhibit 10.10
Fulcrum Therapeutics, Inc. (the “Company”) hereby grants the following restricted stock units pursuant to its 2019 Stock
Incentive Plan. The terms and conditions attached hereto are also a part hereof.
Notice of Grant
Name of recipient (the “Participant”):
Grant Date:
Number of restricted stock units (“RSUs”)
granted:
Number, if any, of RSUs that vest
immediately on the grant date:
RSUs that are subject to vesting schedule:
Vesting Start Date:
Vesting Schedule:
Vesting Date:
Number of RSUs that Vest:
All vesting is dependent on the Participant remaining an Eligible Participant, as provided herein.
This grant of RSUs satisfies in full all commitments that the Company has to the Participant with respect to the issuance
of stock, stock options or other equity securities.
Signature of Participant
Street Address
City/State/Zip Code
Fulcrum Therapeutics, Inc.
By:
Name of Officer
Title:
IF " DOCVARIABLE "SWDocIDLocation" 1" = "1" " DOCPROPERTY "SWDocID" ActiveUS 191962360v.1" "" ActiveUS 191962360v.1
Fulcrum Therapeutics, Inc.
Restricted Stock Unit Agreement
Incorporated Terms and Conditions
1.
Award of Restricted Stock Units. In consideration of services rendered and to be rendered to the Company, by
the Participant, the Company has granted to the Participant, subject to the terms and conditions set forth in this Restricted Stock
Unit Agreement (this “Agreement”) and in the Company’s 2019 Stock Incentive Plan (the “Plan”), an award with respect to the
number of restricted stock units (the “RSUs”) set forth in the Notice of Grant that forms part of this Agreement (the “Notice of
Grant”). Each RSU represents the right to receive one share of common stock, $0.001 par value per share, of the Company (the
“Common Stock”) upon vesting of the RSU, subject to the terms and conditions set forth herein.
1.
Vesting. The RSUs shall vest in accordance with the Vesting Schedule set forth in the Notice of Grant (the
“Vesting Schedule”). Any fractional shares resulting from the application of any percentages used in the Vesting Schedule shall
be rounded down to the nearest whole number of RSUs. As soon as practicable after the vesting of the RSU, the Company will
deliver to the Participant, for each RSU that becomes vested, one share of Common Stock, subject to the payment of any taxes
pursuant to Section 7. The Common Stock will be delivered to the Participant as soon as practicable following each vesting date,
but in any event within 30 days of such date.
2.
Forfeiture of Unvested RSUs Upon Cessation of Service. In the event that the Participant ceases to be an
Eligible Participant (as defined below) for any reason or no reason, with or without cause, all of the RSUs that are unvested as of
the time of such cessation shall be forfeited immediately and automatically to the Company, without the payment of any
consideration to the Participant, effective as of such cessation. The Participant shall have no further rights with respect to the
unvested RSUs or any Common Stock that may have been issuable with respect thereto. The Participant shall be an “Eligible
Participant” if the individual is an employee, director or officer of the Company or any other entity the employees, officers,
directors are eligible to receive awards of RSUs under the Plan.
3.
Restrictions on Transfer. The Participant shall not sell, assign, transfer, pledge, hypothecate, encumber or
otherwise dispose of, by operation of law or otherwise (collectively “transfer”) any RSUs, or any interest therein. The Company
shall not be required to treat as the owner of any RSUs or issue any Common Stock to any transferee to whom such RSUs have
been transferred in violation of any of the provisions of this Agreement.
4.
Rights as a Stockholder. The Participant shall have no rights as a stockholder of the Company with respect to
any shares of Common Stock that may be issuable with respect to the RSUs until the issuance of the shares of Common Stock to
the Participant following the vesting of the RSUs.
5.
Provisions of the Plan. This Agreement is subject to the provisions of the Plan, a copy of which is furnished to
the Participant with this Agreement.
6.
Tax Matters.
a.
Acknowledgments; No Section 83(b) Election. The Participant acknowledges that he or she is
responsible for obtaining the advice of the Participant’s own tax advisors with respect to the award of RSUs and the Participant is
relying solely on such advisors and not on any statements or representations of the Company or any of its agents with respect to
the tax consequences relating to the RSUs. The Participant understands that the Participant (and not the Company) shall be
responsible for the Participant’s tax liability that may arise in connection with the acquisition, vesting and/or disposition of the
RSUs. The Participant acknowledges that no election under Section 83(b) of the Internal Revenue Code of 1986, as amended,
(the “Code”) is available with respect to RSUs.
a.
Withholding. The Participant acknowledges and agrees that the Company has the right to
deduct from payments of any kind otherwise due to the Participant any federal, state, local or other taxes of any kind required by
law to be withheld with respect to the vesting of the RSUs. At such time as the Participant is not aware of any material nonpublic
information about the Company or the Common Stock and the Participant is not subject to any restriction on trading activities
with respect to the Common Stock pursuant to any Company insider trading or other policy, the Participant shall execute the
instructions set forth in Schedule A attached hereto (the “Automatic Sale Instructions”) as the means of satisfying such tax
obligation. If the Participant does not execute the Automatic Sale Instructions prior to an applicable vesting date, then the
Participant agrees that if under applicable law the Participant will owe taxes at such vesting date on the portion of the award then
vested the Company shall be entitled to immediate payment from the Participant of the amount of any tax required to be withheld
by the Company. The Company shall not deliver any shares of Common Stock to the Participant until it is satisfied that all
required withholdings have been made.
7.
Miscellaneous.
a.
Section 409A. The RSUs awarded pursuant to this Agreement are intended to be exempt from
or comply with the requirements of Section 409A of the Code and the Treasury Regulations issued thereunder (“Section 409A”).
The delivery of shares of Common Stock on the vesting of the RSUs may not be accelerated or deferred unless permitted or
required by Section 409A.
b.
Participant’s Acknowledgements. The Participant acknowledges that he or she: (i) has read
this Agreement; (ii) has been represented in the preparation, negotiation and execution of this Agreement by legal counsel of the
Participant’s own choice or has voluntarily declined to seek such counsel; (iii) understands the terms and consequences of this
Agreement; (iv) is fully aware of the legal and binding effect of this Agreement; and (v) agrees that in accepting this award, the
Participant will be bound by any clawback policy that the Company may adopt in the future.
Schedule A
Automatic Sale Instructions
The undersigned hereby consents and agrees that any taxes due on a vesting date as a result of the vesting of RSUs on such date
shall be paid through an automatic sale of shares as follows:
(a) Upon any vesting of RSUs pursuant to Section 2 hereof, the Company shall arrange for the sale of such number of
shares of Common Stock issuable with respect to the RSUs that vest pursuant to Section 2 as is sufficient to generate net
proceeds in the amount necessary to satisfy the Company’s minimum statutory withholding obligations with respect to the
income recognized by the Participant upon the vesting of the RSUs (based on minimum statutory withholding rates for all tax
purposes, including payroll and social security taxes, that are applicable to such income), and the net proceeds of such sale shall
be delivered to the Company in satisfaction of such tax withholding obligations.
(b) The Participant hereby appoints the Chief Executive Officer, the Chief Financial Officer and the Chief Legal
Officer (or a person holding a similar title), and any of them acting alone and with full power of substitution, to serve as his or her
attorneys in fact to arrange for the sale of the Participant’s Common Stock in accordance with this Schedule A. The Participant
agrees to execute and deliver such documents, instruments and certificates as may reasonably be required in connection with the
sale of the shares pursuant to this Schedule A.
(c) The Participant represents to the Company that, as of the date hereof, he or she is not aware of any material
nonpublic information about the Company or the Common Stock and is not subject to any restriction on trading activities with
respect to the Common Stock pursuant to any Company insider trading policy or other policy. The Participant and the Company
have structured this Agreement, including this Schedule A, to constitute a “binding contract” relating to the sale of Common
Stock, consistent with the affirmative defense to liability under Section 10(b) of the Securities Exchange Act of 1934 under Rule
10b5-1(c) promulgated under such Act.
The Company shall not deliver any shares of Common Stock to the Participant until it is satisfied that all required
withholdings have been made.
_______________________________
Participant Name: ________________
Date: __________________________
FULCRUM THERAPEUTICS, INC.
2022 INDUCEMENT STOCK INCENTIVE PLAN
Exhibit 10.12
1. Purpose
The purpose of this 2022 Inducement Stock Incentive Plan (the “Plan”) of Fulcrum Therapeutics, Inc., a Delaware corporation (the “Company”),
is to advance the interests of the Company’s stockholders by enhancing the Company’s ability to attract, retain and motivate persons who are expected to
make important contributions to the Company with an inducement material for such persons to enter into employment with the Company and by providing
such persons with equity ownership opportunities and performance-based incentives that are intended to better align the interests of such persons with those
of the Company’s stockholders. Except where the context otherwise requires, the term “Company” shall include any of the Company’s present or future
parent or subsidiary corporations as defined in Sections 424(e) or (f) of the Internal Revenue Code of 1986, as amended, and any regulations thereunder
(the “Code”) and any other business venture (including, without limitation, joint venture or limited liability company) in which the Company has a
controlling interest, as determined by the Board of Directors of the Company (the “Board”).
2. Eligibility
Awards under the Plan may only be granted to persons who (a) were not previously an employee or director of the Company or (b) are
commencing employment with the Company following a bona fide period of non-employment, in either case as an inducement material to the individual’s
entering into employment with the Company and in accordance with the requirements of Nasdaq Stock Market Rule 5635(c)(4). For the avoidance of
doubt, neither consultants nor advisors shall be eligible to participate in the Plan. Each person who is granted an Award under the Plan is deemed a
“Participant.” “Award” means Options (as defined in Section 5), SARs (as defined in Section 6), Restricted Stock (as defined in Section 7), Restricted
Stock Units (as defined in Section 7) and Other Stock-Based Awards (as defined in Section 8).
3. Administration and Delegation
(a) Administration by Board of Directors. The Plan will be administered by the Board. The Board shall have authority to grant Awards and
to adopt, amend and repeal such administrative rules, guidelines and practices relating to the Plan as it shall deem advisable; provided that the grant of any
Award under the Plan must be approved by the Company’s independent compensation committee or a majority of the Company’s independent directors (as
defined in Nasdaq Stock Market Rule 5605(a)(2)) (the “Independent Directors”) in order to comply with the exemption from the stockholder approval
requirement for “inducement grants” provided for under Nasdaq Stock Market Rule 5635(c)(4). The Board may construe and interpret the terms of the
Plan and any Award agreements entered into under the Plan. The Board may correct any defect, supply any omission or reconcile any inconsistency in the
Plan or any Award in the manner and to the extent it shall deem expedient and it shall be the sole and final judge of such expediency. All decisions by the
Board shall be made in the Board’s sole discretion and shall be final and binding on all persons having or claiming any interest in the Plan or in any Award.
(b) Appointment of Committees. To the extent permitted by applicable law and the Nasdaq Stock Market rules, the Board (including acting
with a majority of the Independent Directors) may delegate any or all of its powers under the Plan to one or more committees or subcommittees of the
Board (a “Committee”). All references in the Plan to the “Board” shall mean the Board or a Committee of the Board or the officers referred to in Section
3(c) to the extent that the Board’s powers or authority under the Plan have been delegated to such Committee or officers.
(c) Delegation to Officers. Subject to any requirements of applicable law (including as applicable Sections 152 and 157(c) of the General
Corporation Law of the State of Delaware) and the Nasdaq Stock Market rules, the Board (acting with a majority of the Independent Directors) or the
Company’s independent compensation committee may delegate to one or more officers of the Company the power to grant Awards (subject to any
limitations under the Plan) to employees or officers of the Company and to exercise such other powers under the
Plan as the Board may determine, provided that the Board shall fix the terms of Awards to be granted by such officers, the maximum number of shares
subject to Awards that the officers may grant, and the time period in which such Awards may be granted; and provided further, that no officer shall be
authorized to grant Awards to any “executive officer” of the Company (as defined by Rule 3b-7 under the Securities Exchange Act of 1934, as amended
(the “Exchange Act”)) or to any “officer” of the Company (as defined by Rule 16a-1(f) under the Exchange Act).
4. Stock Available for Awards
(a) Authorized Number of Shares. Subject to adjustment under Section 9, Awards may be made under the Plan for up to 1,750,000 shares
of common stock, $0.001 par value per share, of the Company (the “Common Stock”). Shares issued under the Plan may consist in whole or in part of
authorized but unissued shares or treasury shares.
(b) Share Counting. For purposes of counting the number of shares available for the grant of Awards under the Plan:
(1)
all shares of Common Stock covered by SARs shall be counted against the number of shares available for the grant of Awards
under the Plan; provided, however, that (i) SARs that may be settled only in cash shall not be so counted and (ii) if the Company grants an SAR
in tandem with an Option for the same number of shares of Common Stock and provides that only one such Award may be exercised (a “Tandem
SAR”), only the shares covered by the Option, and not the shares covered by the Tandem SAR, shall be so counted, and the expiration of one in
connection with the other’s exercise will not restore shares to the Plan;
(2)
if any Award (i) expires or is terminated, surrendered or canceled without having been fully exercised or is forfeited in whole or
in part (including as the result of shares of Common Stock subject to such Award being repurchased by the Company at the original issuance
price pursuant to a contractual repurchase right) or (ii) results in any Common Stock not being issued (including as a result of an SAR that was
settleable either in cash or in stock actually being settled in cash), the unused Common Stock covered by such Award shall again be available for
the grant of Awards; provided, however, that (1) in the case of the exercise of an SAR, the number of shares counted against the shares available
under the Plan shall be the full number of shares subject to the SAR multiplied by the percentage of the SAR actually exercised, regardless of the
number of shares actually used to settle such SAR upon exercise and (2) the shares covered by a Tandem SAR shall not again become available
for grant upon the expiration or termination of such Tandem SAR; and
(3) shares of Common Stock delivered (by actual delivery, attestation, or net exercise) to the Company by a Participant to (i)
purchase shares of Common Stock upon the exercise of an Award or (ii) satisfy tax withholding obligations with respect to Awards (including
shares retained from the Award creating the tax obligation) shall be added back to the number of shares available for the future grant of Awards.
5. Stock Options
(a) General. The Board may grant options to purchase Common Stock (each, an “Option”) and determine the number of shares of
Common Stock to be covered by each Option, the exercise price of each Option and the conditions and limitations applicable to the exercise of each
Option, including conditions relating to applicable federal or state securities laws, as it considers necessary or advisable. All Options under the Plan shall
be Nonstatutory Stock Options. A “Nonstatutory Stock Option” is an Option which is not intended to be an “incentive stock option” within the meaning of
Section 422 of the Code.
(b) Exercise Price. The Board shall establish the exercise price of each Option or the formula by which such exercise price will be
determined. The exercise price shall be specified in the applicable Option agreement. The exercise price shall be not less than 100% of the Grant Date Fair
Market Value (as defined below) of the Common Stock on the date the Option is granted; provided that if the Board approves the grant of an Option with
an exercise price to be determined on a future date, the exercise price shall be not less than 100% of the Grant
Date Fair Market Value on such future date. “Grant Date Fair Market Value” of a share of Common Stock for purposes of the Plan will be determined as
follows:
date of grant; or
(1) if the Common Stock trades on a national securities exchange, the closing sale price (for the primary trading session) on the
grant as reported by an over-the-counter marketplace designated by the Board; or
(2) if the Common Stock does not trade on any such exchange, the average of the closing bid and asked prices on the date of
(3) if the Common Stock is not publicly traded, the Board will determine the Grant Date Fair Market Value for purposes of the
Plan using any measure of value it determines to be appropriate (including, as it considers appropriate, relying on appraisals) in a manner consistent with
the valuation principles under Code Section 409A, except as the Board may expressly determine otherwise.
For any date that is not a trading day, the Grant Date Fair Market Value of a share of Common Stock for such date will be determined by using
the closing sale price or average of the bid and asked prices, as appropriate, for the immediately preceding trading day and with the timing in the formulas
above adjusted accordingly. The Board can substitute a particular time of day or other measure of “closing sale price” or “bid and asked prices” if
appropriate because of exchange or market procedures or can, in its sole discretion, use weighted averages either on a daily basis or such longer period as
complies with Code Section 409A.
The Board has sole discretion to determine the Grant Date Fair Market Value for purposes of the Plan, and all Awards are conditioned on the
Participants’ agreement that the Board’s determination is conclusive and binding even though others might make a different determination.
(d) Duration of Options. Each Option shall be exercisable at such times and subject to such terms and conditions as the Board may specify
in the applicable option agreement; provided, however, that no Option will be granted with a term in excess of 10 years.
(e) Exercise of Options. Options may be exercised by delivery to the Company of a notice of exercise in a form (which may be electronic)
approved by the Company, together with payment in full (in the manner specified in Section 5(f)) of the exercise price for the number of shares for which
the Option is exercised. Shares of Common Stock subject to the Option will be delivered by the Company as soon as practicable following exercise.
(f) Payment Upon Exercise. Common Stock purchased upon the exercise of an Option granted under the Plan shall be paid for as follows:
(1) in cash or by check, payable to the order of the Company;
(2) except as may otherwise be provided in the applicable Option agreement or approved by the Board, by (i) delivery of an
irrevocable and unconditional undertaking by a creditworthy broker to deliver promptly to the Company sufficient funds to pay the exercise price and any
required tax withholding or (ii) delivery by the Participant to the Company of a copy of irrevocable and unconditional instructions to a creditworthy broker
to deliver promptly to the Company cash or a check sufficient to pay the exercise price and any required tax withholding;
(3) to the extent provided for in the applicable Option agreement or approved by the Board, by delivery (either by actual delivery
or attestation) of shares of Common Stock owned by the Participant valued at their fair market value (valued in the manner determined by (or in a manner
approved by) the Board), provided (i) such method of payment is then permitted under applicable law, (ii) such Common Stock, if acquired directly from
the Company, was owned by the Participant for such minimum period of time, if any, as may be established by the Board and (iii) such Common Stock is
not subject to any repurchase, forfeiture, unfulfilled vesting or other similar requirements;
(4) to the extent provided for in the applicable Nonstatutory Stock Option agreement or approved by the Board, by delivery of a
notice of “net exercise” to the Company, as a result of which the Participant would receive (i) the number of shares underlying the portion of the Option
being exercised, less (ii) such number of shares as is equal to (A) the aggregate exercise price for the portion of the Option being exercised divided by (B)
the fair market value of the Common Stock (valued in the manner determined by (or in a manner approved by) the Board) on the date of exercise;
payment of such other lawful consideration as the Board may determine; or
(5) to the extent permitted by applicable law and provided for in the applicable Option agreement or approved by the Board by
(6) by any combination of the above permitted forms of payment.
(g) Limitation on Repricing. Unless such action is approved by the Company’s stockholders, the Company may not (except as provided for
under Section 9): (1) amend any outstanding Option granted under the Plan to provide an exercise price per share that is lower than the then-current
exercise price per share of such outstanding Option, (2) cancel any outstanding option (whether or not granted under the Plan) and grant in substitution
therefor new Awards under the Plan covering the same or a different number of shares of Common Stock and having an exercise price per share lower than
the then-current exercise price per share of the cancelled option, (3) cancel in exchange for a cash payment any outstanding Option with an exercise price
per share above the then-current fair market value of the Common Stock (valued in the manner determined by (or in the manner approved by) the Board) or
(4) take any other action under the Plan that constitutes a “repricing” within the meaning of the rules of the Nasdaq Global Market or any other exchange or
marketplace on which the Company stock is listed or traded (the “Exchange”).
6. Stock Appreciation Rights
(a) General. The Board may grant Awards consisting of stock appreciation rights (“SARs”) entitling the holder, upon exercise, to receive
an amount of Common Stock or cash or a combination thereof (such form to be determined by the Board) determined by reference to appreciation, from
and after the date of grant, in the fair market value of a share of Common Stock (valued in the manner determined by (or in the manner approved by) the
Board) over the measurement price established pursuant to Section 6(b). The date as of which such appreciation is determined shall be the exercise date.
(b) Measurement Price. The Board shall establish the measurement price of each SAR and specify it in the applicable SAR agreement.
The measurement price shall not be less than 100% of the Grant Date Fair Market Value of the Common Stock on the date the SAR is granted; provided
that if the Board approves the grant of an SAR effective as of a future date, the measurement price shall be not less than 100% of the Grant Date Fair
Market Value on such future date.
(c) Duration of SARs. Each SAR shall be exercisable at such times and subject to such terms and conditions as the Board may specify in
the applicable SAR agreement; provided, however, that no SAR will be granted with a term in excess of 10 years.
(d) Exercise of SARs. SARs may be exercised by delivery to the Company of a notice of exercise in a form (which may be electronic)
approved by the Company, together with any other documents required by the Board.
(e) Limitation on Repricing. Unless such action is approved by the Company’s stockholders, the Company may not (except as provided for
under Section 9): (1) amend any outstanding SAR granted under the Plan to provide a measurement price per share that is lower than the then-current
measurement price per share of such outstanding SAR, (2) cancel any outstanding SAR (whether or not granted under the Plan) and grant in substitution
therefor new Awards under the Plan covering the same or a different number of shares of Common Stock and having an exercise or measurement price per
share lower than the then-current measurement price per share of the cancelled SAR, (3) cancel in exchange for a cash payment any outstanding SAR with
a measurement price per share above the then-current fair market value of the Common Stock (valued in the manner determined by (or in a manner
approved by) the Board) or (4) take any other action under the Plan that constitutes a “repricing” within the meaning of the rules of the Exchange.
7. Restricted Stock; Restricted Stock Units
(a) General. The Board may grant Awards entitling recipients to acquire shares of Common Stock (“Restricted Stock”), subject to the right
of the Company to repurchase all or part of such shares at their issue price or other stated or formula price (or to require forfeiture of such shares if issued at
no cost) from the recipient in the event that conditions specified by the Board in the applicable Award are not satisfied prior to the end of the applicable
restriction period or periods established by the Board for such Award. The Board may also grant Awards entitling the recipient to receive shares of
Common Stock or cash to be delivered at the time such Award vests or is settled (“Restricted Stock Units”) (Restricted Stock and Restricted Stock Units
are each referred to herein as a “Restricted Stock Award”).
(b) Terms and Conditions for All Restricted Stock Awards. The Board shall determine the terms and conditions of a Restricted Stock
Award, including the conditions for vesting and repurchase (or forfeiture) and the issue price, if any.
(c) Additional Provisions Relating to Restricted Stock.
(1) Dividends. Unless otherwise provided in the applicable Award agreement, any dividends (whether paid in cash, stock or
property) declared and paid by the Company with respect to shares of Restricted Stock (“Accrued Dividends”) shall be paid to the Participant only if and
when such shares become free from the restrictions on transferability and forfeitability that apply to such shares. Each payment of Accrued Dividends will
be made no later than the end of the calendar year in which the dividends are paid to stockholders of that class of stock or, if later, the 15th day of the third
month following the lapsing of the restrictions on transferability and the forfeitability provisions applicable to the underlying shares of Restricted Stock.
(2) Stock Certificates. The Company may require that any stock certificates issued in respect of shares of Restricted Stock, as
well as dividends or distributions paid on such Restricted Stock, shall be deposited in escrow by the Participant, together with a stock power endorsed in
blank, with the Company (or its designee). At the expiration of the applicable restriction periods, the Company (or such designee) shall deliver the
certificates no longer subject to such restrictions to the Participant or if the Participant has died, to his or her Designated Beneficiary. “Designated
Beneficiary” means (i) the beneficiary designated, in a manner determined by the Board, by a Participant to receive amounts due or exercise rights of the
Participant in the event of the Participant’s death or (ii) in the absence of an effective designation by a Participant, the Participant’s estate.
(d) Additional Provisions Relating to Restricted Stock Units.
(1) Settlement. Upon the vesting of and/or lapsing of any other restrictions (i.e., settlement) with respect to each Restricted Stock
Unit, the Participant shall be entitled to receive from the Company such number of shares of Common Stock or (if so provided in the applicable Award
agreement) an amount of cash equal to the fair market value (valued in the manner determined by (or in a manner approved by) the Board) of such number
of shares of Common Stock as are set forth in the applicable Restricted Stock Unit agreement. The Board may provide that settlement of Restricted Stock
Units shall be deferred, on a mandatory basis or at the election of the Participant in a manner that complies with Section 409A of the Code.
(2) Voting Rights. A Participant shall have no voting rights with respect to any Restricted Stock Units.
(3) Dividend Equivalents. The Award agreement for Restricted Stock Units may provide Participants with the right to receive an
amount equal to any dividends or other distributions declared and paid on an equal number of outstanding shares of Common Stock (“Dividend
Equivalents”). Dividend Equivalents may be settled in cash and/or shares of Common Stock and shall be subject to the same restrictions on transfer and
forfeitability as the Restricted Stock Units with respect to which paid, in each case to the extent provided in the Award agreement.
8. Other Stock-Based Awards
(a) General. The Board may grant other Awards of shares of Common Stock, and other Awards that are valued in whole or in part by
reference to, or are otherwise based on, shares of Common Stock or other property (“Other Stock-Based Awards”). Such Other Stock-Based Awards shall
also be available as a form of payment in the settlement of other Awards granted under the Plan or as payment in lieu of compensation to which a
Participant is otherwise entitled. Other Stock-Based Awards may be paid in shares of Common Stock or cash, as the Board shall determine.
(b) Terms and Conditions. Subject to the provisions of the Plan, the Board shall determine the terms and conditions of each Other Stock-
Based Award, including any purchase price applicable thereto.
9. Adjustments for Changes in Common Stock and Certain Other Events
(a) Changes in Capitalization. In the event of any stock split, reverse stock split, stock dividend, recapitalization, combination of shares,
reclassification of shares, spin-off or other similar change in capitalization or event, or any dividend or distribution to holders of Common Stock other than
an ordinary cash dividend, (i) the number and class of securities available under the Plan, (ii) the share counting rules set forth in Section 4, (iii) the
number and class of securities and exercise price per share of each outstanding Option, (iv) the share and per-share provisions and the measurement price
of each outstanding SAR, (v) the number of shares subject to and the repurchase price per share subject to each outstanding award of Restricted Stock and
(vi) the share and per-share-related provisions and the purchase price, if any, of each outstanding Restricted Stock Unit award and each outstanding Other
Stock-Based Award, shall be equitably adjusted by the Company (or substituted Awards may be made, if applicable) in the manner determined by the
Board. Without limiting the generality of the foregoing, in the event the Company effects a split of the Common Stock by means of a stock dividend and
the exercise price of and the number of shares subject to an outstanding Option are adjusted as of the date of the distribution of the dividend (rather than as
of the record date for such dividend), then an optionee who exercises an Option between the record date and the distribution date for such stock dividend
shall be entitled to receive, on the distribution date, the stock dividend with respect to the shares of Common Stock acquired upon such Option exercise,
notwithstanding the fact that such shares were not outstanding as of the close of business on the record date for such stock dividend.
(b) Reorganization Events.
(1) Definition. A “Reorganization Event” shall mean: (a) any merger or consolidation of the Company with or into another
entity as a result of which all of the Common Stock of the Company is converted into or exchanged for the right to receive cash, securities or other property
or is cancelled, (b) any transfer or disposition of all of the Common Stock of the Company for cash, securities or other property pursuant to a share
exchange or other transaction or (c) any liquidation or dissolution of the Company.
(2) Consequences of a Reorganization Event on Awards Other than Restricted Stock.
(A) In connection with a Reorganization Event, the Board may take any one or more of the following actions as to all
or any (or any portion of) outstanding Awards other than Restricted Stock on such terms as the Board determines (except to the extent specifically provided
otherwise in an applicable Award agreement or another agreement between the Company and the Participant): (i) provide that such Awards shall be
assumed, or substantially equivalent Awards shall be substituted, by the acquiring or succeeding corporation (or an affiliate thereof), (ii) upon written
notice to a Participant, provide that all of the Participant’s unvested Awards will be forfeited immediately prior to the consummation of such
Reorganization Event and/or unexercised Awards will terminate immediately prior to the consummation of such Reorganization Event unless exercised by
the Participant (to the extent then exercisable) within a specified period following the date of such notice, (iii) provide that outstanding Awards shall
become exercisable, realizable or deliverable, or restrictions applicable to an Award shall lapse, in whole or in part prior to or upon such Reorganization
Event, (iv) in the event of a Reorganization Event under the terms of which holders of Common Stock will receive upon consummation thereof a cash
payment for each share surrendered in the Reorganization Event (the “Acquisition Price”), make or provide for a cash payment to Participants with respect
to each Award held by a Participant equal to (A) the number of shares of Common Stock
subject to the vested portion of the Award (after giving effect to any acceleration of vesting that occurs upon or immediately prior to such Reorganization
Event) multiplied by (B) the excess, if any, of (I) the Acquisition Price over (II) the exercise, measurement or purchase price of such Award and any
applicable tax withholdings, in exchange for the termination of such Award, (v) provide that, in connection with a liquidation or dissolution of the
Company, Awards shall convert into the right to receive liquidation proceeds (if applicable, net of the exercise, measurement or purchase price thereof and
any applicable tax withholdings) and (vi) any combination of the foregoing. In taking any of the actions permitted under this Section 9(b)(2), the Board
shall not be obligated by the Plan to treat all Awards, all Awards held by a Participant, or all Awards of the same type, identically.
(B) Notwithstanding the terms of Section 9(b)(2)(A), in the case of outstanding Restricted Stock Units that are subject
to Section 409A of the Code: (i) if the applicable Restricted Stock Unit agreement provides that the Restricted Stock Units shall be settled upon a “change
in control event” within the meaning of Treasury Regulation Section 1.409A-3(i)(5)(i), and the Reorganization Event constitutes such a “change in control
event”, then no assumption or substitution shall be permitted pursuant to Section 9(b)(2)(A)(i) and the Restricted Stock Units shall instead be settled in
accordance with the terms of the applicable Restricted Stock Unit agreement; and (ii) the Board may only undertake the actions set forth in clauses (iii), (iv)
or (v) of Section 9(b)(2)(A) if the Reorganization Event constitutes a “change in control event” as defined under Treasury Regulation Section 1.409A-3(i)
(5)(i) and such action is permitted or required by Section 409A of the Code; if the Reorganization Event is not a “change in control event” as so defined or
such action is not permitted or required by Section 409A of the Code, and the acquiring or succeeding corporation does not assume or substitute the
Restricted Stock Units pursuant to clause (i) of Section 9(b)(2)(A), then the unvested Restricted Stock Units shall terminate immediately prior to the
consummation of the Reorganization Event without any payment in exchange therefor.
(C) For purposes of Section 9(b)(2)(A)(i), an Award (other than Restricted Stock) shall be considered assumed if,
following consummation of the Reorganization Event, such Award confers the right to purchase or receive pursuant to the terms of such Award, for each
share of Common Stock subject to the Award immediately prior to the consummation of the Reorganization Event, the consideration (whether cash,
securities or other property) received as a result of the Reorganization Event by holders of Common Stock for each share of Common Stock held
immediately prior to the consummation of the Reorganization Event (and if holders were offered a choice of consideration, the type of consideration chosen
by the holders of a majority of the outstanding shares of Common Stock); provided, however, that if the consideration received as a result of the
Reorganization Event is not solely common stock of the acquiring or succeeding corporation (or an affiliate thereof), the Company may, with the consent of
the acquiring or succeeding corporation, provide for the consideration to be received upon the exercise or settlement of the Award to consist solely of such
number of shares of common stock of the acquiring or succeeding corporation (or an affiliate thereof) that the Board determines to be equivalent in value
(as of the date of such determination or another date specified by the Board) to the per share consideration received by holders of outstanding shares of
Common Stock as a result of the Reorganization Event.
(3) Consequences of a Reorganization Event on Restricted Stock. Upon the occurrence of a Reorganization Event other than a
liquidation or dissolution of the Company, the repurchase and other rights of the Company with respect to outstanding Restricted Stock shall inure to the
benefit of the Company’s successor and shall, unless the Board determines otherwise, apply to the cash, securities or other property which the Common
Stock was converted into or exchanged for pursuant to such Reorganization Event in the same manner and to the same extent as they applied to such
Restricted Stock; provided, however, that the Board may provide for termination or deemed satisfaction of such repurchase or other rights under the
instrument evidencing any Restricted Stock or any other agreement between a Participant and the Company, either initially or by amendment. Upon the
occurrence of a Reorganization Event involving the liquidation or dissolution of the Company, except to the extent specifically provided to the contrary in
the instrument evidencing any Restricted Stock or any other agreement between a Participant and the Company, all restrictions and conditions on all
Restricted Stock then outstanding shall automatically be deemed terminated or satisfied.
10. General Provisions Applicable to Awards
(a) Transferability of Awards. Awards shall not be sold, assigned, transferred, pledged or otherwise encumbered by the Participant, either
voluntarily or by operation of law, except by will or the laws of descent and distribution or pursuant to a qualified domestic relations order, and, during the
life of the Participant, shall be
exercisable only by the Participant; provided, however, that, except with respect to Awards subject to Section 409A of the Code, the Board may permit or
provide in an Award for the gratuitous transfer of the Award by the Participant to or for the benefit of any immediate family member, family trust or other
entity established for the benefit of the Participant and/or an immediate family member thereof if the Company would be eligible to use a Form S-8 under
the Securities Act of 1933, as amended, for the registration of the sale of the Common Stock subject to such Award to such proposed transferee; provided
further, that the Company shall not be required to recognize any such permitted transfer until such time as such permitted transferee shall, as a condition to
such transfer, deliver to the Company a written instrument in form and substance satisfactory to the Company confirming that such transferee shall be
bound by all of the terms and conditions of the Award. References to a Participant, to the extent relevant in the context, shall include references to
authorized transferees. For the avoidance of doubt, nothing contained in this Section 10(a) shall be deemed to restrict a transfer to the Company.
(b) Documentation; Press Release. Each Award shall be evidenced in such form (written, electronic or otherwise) as the Board shall
determine. Each Award may contain terms and conditions in addition to those set forth in the Plan. Promptly following the grant of an Award hereunder,
the Company must disclose in a press release the material terms of the grant, the number of shares involved, and, if required by law or the rules of the
Exchange, the identity of the Participant and each Participant, by accepting the Award, consents to the foregoing.
(c) Board Discretion. Except as otherwise provided by the Plan, each Award may be made alone or in addition or in relation to any other
Award. The terms of each Award need not be identical, and the Board need not treat Participants uniformly.
(d) Termination of Status. The Board shall determine the effect on an Award of the disability, death, termination or other cessation of
employment, authorized leave of absence or other change in the employment or other status of a Participant and the extent to which, and the period during
which, the Participant, or the Participant’s legal representative, conservator, guardian or Designated Beneficiary, may exercise rights under the Award.
(e) Withholding. The Participant must satisfy all applicable federal, state, and local or other income and employment tax withholding
obligations before the Company will deliver stock certificates or otherwise recognize ownership of Common Stock under an Award. The Company may
elect to satisfy the withholding obligations through additional withholding on salary or wages. If the Company elects not to or cannot withhold from other
compensation, the Participant must pay the Company the full amount, if any, required for withholding or have a broker tender to the Company cash equal to
the withholding obligations. Payment of withholding obligations is due before the Company will issue any shares on exercise, vesting or release from
forfeiture of an Award or at the same time as payment of the exercise or purchase price, unless the Company determines otherwise. If provided for in an
Award or approved by the Committee, a Participant may satisfy the tax obligations in whole or in part by delivery (either by actual delivery or attestation)
of shares of Common Stock, including shares retained from the Award creating the tax obligation, valued at their fair market value (valued in the manner
determined by (or in a manner approved by) the Company); provided, however, except as otherwise provided by the Committee, that the total tax
withholding where stock is being used to satisfy such tax obligations cannot exceed the Company’s minimum statutory withholding obligations (based on
minimum statutory withholding rates for federal, state and local tax purposes, including payroll taxes, that are applicable to such supplemental taxable
income), except that, to the extent that the Company is able to retain shares of Common Stock having a fair market value (determined by, or in a manner
approved by, the Company) that exceeds the statutory minimum applicable withholding tax without financial accounting implications or the Company is
withholding in a jurisdiction that does not have a statutory minimum withholding tax, the Company may retain such number of shares of Common Stock
(up to the number of shares having a fair market value equal to the maximum individual statutory rate of tax (determined by, or in a manner approved by,
the Company)) as the Company shall determine in its sole discretion to satisfy the tax liability associated with any Award. Shares used to satisfy tax
withholding requirements cannot be subject to any repurchase, forfeiture, unfulfilled vesting or other similar requirements.
(f) Amendment of Award. Except as otherwise provided in Sections 5(g) and 6(e) with respect to repricings, the Board may amend,
modify or terminate any outstanding Award, including but not limited to, substituting therefor another Award of the same or a different type and changing
the date of exercise or realization provided that no amendment that would require stockholder approval under the rules of the Exchange may be made
effective unless and until the Company’s stockholders approve such amendment. The Participant’s consent to such
action shall be required unless (i) the Board determines that the action, taking into account any related action, does not materially and adversely affect the
Participant’s rights under the Plan or (ii) the change is permitted under Section 9.
(g) Conditions on Delivery of Stock. The Company will not be obligated to deliver any shares of Common Stock pursuant to the Plan or to
remove restrictions from shares previously issued or delivered under the Plan until (i) all conditions of the Award have been met or removed to the
satisfaction of the Company, (ii) in the opinion of the Company’s counsel, all other legal matters in connection with the issuance and delivery of such
shares have been satisfied, including any applicable securities laws and regulations and any applicable stock exchange or stock market rules and regulations
and (iii) the Participant has executed and delivered to the Company such representations or agreements as the Company may consider appropriate to satisfy
the requirements of any applicable laws, rules or regulations.
(h) Acceleration. The Board may at any time provide that any Award shall become immediately exercisable in whole or in part, free from
some or all restrictions or conditions, or otherwise realizable in whole or in part, as the case may be.
11. Miscellaneous
(a) No Right To Employment or Other Status. No person shall have any claim or right to be granted an Award by virtue of the adoption of
the Plan, and the grant of an Award shall not be construed as giving a Participant the right to continued employment or any other relationship with the
Company. The Company expressly reserves the right at any time to dismiss or otherwise terminate its relationship with a Participant free from any liability
or claim under the Plan, except as expressly provided in the applicable Award.
(b) No Rights As Stockholder; Clawback Policy. Subject to the provisions of the applicable Award, no Participant or Designated
Beneficiary shall have any rights as a stockholder with respect to any shares of Common Stock to be issued with respect to an Award until becoming the
record holder of such shares. In accepting an Award under the Plan, a Participant agrees to be bound by any clawback policy the Company has in effect or
may adopt in the future.
(c) Effective Date. The Plan shall become effective on the date on which it is adopted by the Board (the “Effective Date”). It is expressly
intended that approval of the Company’s stockholders not be required as a condition to the effectiveness of the Plan, and the Plan’s provisions shall be
interpreted in a manner consistent with such intent for all purposes.
(d) Amendment of Plan. The Board may amend, suspend or terminate the Plan or any portion thereof at any time provided that no
amendment that would require stockholder approval under the rules of the Exchange may be made effective unless and until the Company’s stockholders
approve such amendment. Unless otherwise specified in the amendment, any amendment to the Plan adopted in accordance with this Section 11(d) shall
apply to, and be binding on the holders of, all Awards outstanding under the Plan at the time the amendment is adopted, provided the Board determines that
such amendment, taking into account any related action, does not materially and adversely affect the rights of Participants under the Plan.
(e) Authorization of Sub-Plans (including for Grants to non-U.S. Employees). The Board may from time to time establish one or more sub-
plans under the Plan for purposes of satisfying applicable securities, tax or other laws of various jurisdictions. The Board shall establish such sub-plans by
adopting supplements to the Plan containing (i) such limitations on the Board’s discretion under the Plan as the Board deems necessary or desirable or (ii)
such additional terms and conditions not otherwise inconsistent with the Plan as the Board shall deem necessary or desirable. All supplements adopted by
the Board shall be deemed to be part of the Plan, but each supplement shall apply only to Participants within the affected jurisdiction and the Company
shall not be required to provide copies of any supplement to Participants in any jurisdiction which is not the subject of such supplement.
(f) Compliance with Section 409A of the Code. If and to the extent (i) any portion of any payment, compensation or other benefit provided
to a Participant pursuant to the Plan in connection with his or her employment termination constitutes “nonqualified deferred compensation” within the
meaning of Section 409A of
the Code and (ii) the Participant is a specified employee as defined in Section 409A(a)(2)(B)(i) of the Code, in each case as determined by the Company in
accordance with its procedures, by which determinations the Participant (through accepting the Award) agrees that he or she is bound, such portion of the
payment, compensation or other benefit shall not be paid before the day that is six months plus one day after the date of “separation from service” (as
determined under Section 409A of the Code) (the “New Payment Date”), except as Section 409A of the Code may then permit. The aggregate of any
payments that otherwise would have been paid to the Participant during the period between the date of separation from service and the New Payment Date
shall be paid to the Participant in a lump sum on such New Payment Date, and any remaining payments will be paid on their original schedule.
The Company makes no representations or warranty and shall have no liability to the Participant or any other person if any provisions of or payments,
compensation or other benefits under the Plan are determined to constitute nonqualified deferred compensation subject to Section 409A of the Code but do
not to satisfy the conditions of that section.
(g) Limitations on Liability. Notwithstanding any other provisions of the Plan, no individual acting as a director, officer, employee or
agent of the Company will be liable to any Participant, former Participant, spouse, beneficiary, or any other person for any claim, loss, liability, or expense
incurred in connection with the Plan, nor will such individual be personally liable with respect to the Plan because of any contract or other instrument he or
she executes in his or her capacity as a director, officer, employee or agent of the Company. The Company will indemnify and hold harmless each director,
officer, employee or agent of the Company to whom any duty or power relating to the administration or interpretation of the Plan has been or will be
delegated, against any cost or expense (including attorneys’ fees) or liability (including any sum paid in settlement of a claim with the Board’s approval)
arising out of any act or omission to act concerning the Plan unless arising out of such person’s own fraud or bad faith.
(h) Governing Law. The provisions of the Plan and all Awards made hereunder shall be governed by and interpreted in accordance with the
laws of the State of Delaware, excluding choice-of-law principles of the law of such state that would require the application of the laws of a jurisdiction
other than the State of Delaware.
FULCRUM THERAPEUTICS, INC.
NONSTATUTORY STOCK OPTION AGREEMENT
Granted Under 2022 Inducement Stock Incentive Plan
Exhibit 10.13
Fulcrum Therapeutics, Inc. (the “Company”) hereby grants the following stock option pursuant to its 2022 Inducement Stock Incentive Plan (the
“Plan”). The terms and conditions attached hereto are also a part hereof.
Notice of Grant
Name of optionee (the “Participant”):
Grant Date:
Number of shares of the Company’s Common Stock subject to this option
(“Shares”):
Option exercise price per Share (1):
Number, if any, of Shares that vest immediately on the grant date:
Shares that are subject to vesting schedule:
Vesting Start Date:
Final Exercise Date (2):
Vesting Schedule:
Vesting Date:
Number of Options that Vest:
All vesting is dependent on the Participant remaining an Eligible Participant, as provided herein.
This option satisfies in full all commitments that the Company has to the Participant with respect to the issuance of stock, stock options or other
equity securities.
Signature of Participant
Street Address
City/State/Zip Code
Fulcrum Therapeutics, Inc.
By:
Name of Officer
Title:
(1) This must be at least 100% of the Grant Date Fair Market Value (as defined in the Plan) of the Common Stock on the date of grant.
(2) The Final Exercise Date must be no more than 10 years from the date of grant. The correct approach to calculate the final exercise date is to use the day
immediately prior to the date ten years out from the date of the stock option award grant.
Fulcrum Therapeutics, Inc.
Stock Option Agreement
Granted Under 2022 Inducement Stock Incentive Plan
Incorporated Terms and Conditions
1. Grant of Option.
This agreement evidences the grant by the Company, on the grant date (the “Grant Date”) set forth in the Notice of Grant that forms part of this
agreement (the “Notice of Grant”), to the Participant of an option to purchase, in whole or in part, on the terms provided herein and in the Company’s 2022
Inducement Stock Incentive Plan (the “Plan”), the number of Shares set forth in the Notice of Grant of common stock, $0.001 par value per share, of the
Company (“Common Stock”), at the exercise price per Share set forth in the Notice of Grant. Unless earlier terminated, this option shall expire at 5:00
p.m., Eastern time, on the Final Exercise Date set forth in the Notice of Grant (the “Final Exercise Date”).
The option evidenced by this agreement was granted to the Participant pursuant to the inducement grant exception under Nasdaq Stock Market
Rule 5635(c)(4) as an inducement that is material to the Participant’s employment with the Company.
It is intended that the option evidenced by this agreement shall not be an incentive stock option as defined in Section 422 of the Internal Revenue
Code of 1986, as amended, and any regulations promulgated thereunder (the “Code”). Except as otherwise indicated by the context, the term
“Participant”, as used in this option, shall be deemed to include any person who acquires the right to exercise this option validly under its terms.
2. Vesting Schedule.
This option will become exercisable (“vest”) in accordance with the vesting schedule set forth in the Notice of Grant.
The right of exercise shall be cumulative so that to the extent the option is not exercised in any period to the maximum extent permissible it shall
continue to be exercisable, in whole or in part, with respect to all Shares for which it is vested until the earlier of the Final Exercise Date or the termination
of this option under Section 3 hereof or the Plan.
3. Exercise of Option.
(a) Form of Exercise. Each election to exercise this option shall be in writing, in the form of the Stock Option Exercise Notice attached as
Annex A, signed by the Participant, and received by the Company at its principal office, accompanied by this agreement, or in such other form (which may
be electronic) as is approved by the Company, together with payment in full in the manner provided in the Plan. The Participant may purchase less than the
number of shares covered hereby, provided that no partial exercise of this option may be for any fractional share.
(b) Continuous Relationship with the Company Required. Except as otherwise provided in this Section 3, this option may not be exercised
unless the Participant, at the time he or she exercises this option, is, and has been at all times since the Grant Date, an employee, director or officer of, or
consultant or advisor to, the Company or any other entity the employees, officers, directors, consultants, or advisors of which are eligible to receive option
grants under the Plan (an “Eligible Participant”).
(c) Termination of Relationship with the Company. If the Participant ceases to be an Eligible Participant for any reason, then, except as
provided in paragraphs (d) and (e) below, the right to exercise this option shall terminate three months after such cessation (but in no event after the Final
Exercise Date), provided that this option shall be exercisable only to the extent that the Participant was entitled to exercise this option on the date of such
cessation. Notwithstanding the foregoing, if the Participant, prior to the Final Exercise Date, violates the restrictive covenants (including, without
limitation, the non-competition, non-solicitation, or confidentiality provisions) of any employment contract, any non-competition, non-solicitation,
confidentiality or assignment agreement to which the Participant is a party, or any other agreement between the Participant and the Company, the right to
exercise this option shall terminate immediately upon such violation.
(d) Exercise Period Upon Death or Disability. If the Participant dies or becomes disabled (within the meaning of Section 22(e)(3) of the
Code) prior to the Final Exercise Date while he or she is an Eligible Participant and the Company has not terminated such relationship for “cause” as
specified in paragraph (e) below, this option shall be exercisable, within the period of one year following the date of death or disability of the Participant,
by the Participant (or in the case of death by an authorized transferee), provided that this option shall be exercisable only to the extent that this option was
exercisable by the Participant on the date of his or her death or disability, and further provided that this option shall not be exercisable after the Final
Exercise Date.
(e) Termination for Cause. If, prior to the Final Exercise Date, the Participant’s employment is terminated by the Company for Cause (as
defined in below), the right to exercise this option shall terminate immediately upon the effective date of such termination of employment. If, prior to the
Final Exercise Date, the Participant is given notice by the Company of the termination of his or her employment by the Company for Cause, and the
effective date of such employment termination is subsequent to the date of delivery of such notice, the right to exercise this option shall be suspended from
the time of the delivery of such notice until the earlier of (i) such time as it is determined or otherwise agreed that the Participant’s employment shall not be
terminated for Cause as provided in such notice or (ii) the effective date of such termination of employment (in which case the right to exercise this option
shall, pursuant to the preceding sentence, terminate upon the effective date of such termination of employment). If the Participant is subject to an
individual employment agreement with the Company or eligible to participate in a Company severance plan or arrangement, in any case which agreement,
plan or arrangement contains a definition of “cause” for termination of employment, “Cause” shall have the meaning ascribed to such term in such
agreement, plan or arrangement. Otherwise, “Cause” shall mean willful misconduct by the Participant or willful failure by the Participant to perform his
or her responsibilities to the Company (including, without limitation, breach by the Participant of any provision of any employment, consulting, advisory,
nondisclosure, non-competition or other similar agreement between the Participant and the Company), as determined by the Company, which determination
shall be conclusive. The Participant’s employment shall be considered to have been terminated for Cause if the Company determines, within 30 days after
the Participant’s resignation, that termination for Cause was warranted.
4. Withholding.
No Shares will be issued pursuant to the exercise of this option unless and until the Participant pays to the Company, or makes provision
satisfactory to the Company for payment of, any federal, state or local withholding taxes required by law to be withheld in respect of this option.
5. Transfer Restrictions; Clawback.
(a) This option may not be sold, assigned, transferred, pledged or otherwise encumbered by the Participant, either voluntarily or by
operation of law, except by will or the laws of descent and distribution, and, during the lifetime of the Participant, this option shall be exercisable only by
the Participant.
(b) In accepting this option, the Participant agrees to be bound by any clawback policy that the Company has in place or may adopt in the
future.
6. Provisions of the Plan.
This option is subject to the provisions of the Plan (including the provisions relating to amendments to the Plan), a copy of which is furnished to
the Participant with this option.
ANNEX A
Fulcrum Therapeutics, Inc.
Stock Option Exercise Notice
Fulcrum Therapeutics, Inc.
26 Landsdowne Street
Cambridge, MA 02139
Dear Sir or Madam:
I, (the “Participant”), hereby irrevocably exercise the right to purchase shares of the Common Stock, $0.001 par value per
share (the “Shares”), of Fulcrum Therapeutics, Inc. (the “Company”) at $ per share pursuant to the Company’s 2022 Inducement Stock Incentive
Plan and a stock option agreement with the Company dated (the “Option Agreement”). Enclosed herewith is a payment of $ ,
the aggregate purchase price for the Shares. The certificate for the Shares should be registered in my name as it appears below or, if so indicated below,
jointly in my name and the name of the person designated below, with right of survivorship.
Dated:
Signature
Print Name:
Address:
Name and address of persons in whose name the Shares are to be jointly registered (if applicable):
Fulcrum Therapeutics, Inc.
RESTRICTED STOCK UNIT AGREEMENT
Granted under 2022 Inducement Stock Incentive Plan
Exhibit 10.14
Fulcrum Therapeutics, Inc. (the “Company”) hereby grants the following restricted stock units pursuant to its 2022
Inducement Stock Incentive Plan. The terms and conditions attached hereto are also a part hereof.
Notice of Grant
Name of recipient (the “Participant”):
Grant Date:
Number of restricted stock units (“RSUs”)
granted:
Number, if any, of RSUs that vest
immediately on the grant date:
RSUs that are subject to vesting schedule:
Vesting Start Date:
Vesting Schedule:
Vesting Date:
Number of RSUs that Vest:
All vesting is dependent on the Participant remaining an Eligible Participant, as provided herein.
This grant of RSUs satisfies in full all commitments that the Company has to the Participant with respect to the issuance
of stock, stock options or other equity securities.
Signature of Participant
Street Address
City/State/Zip Code
Fulcrum Therapeutics, Inc.
By:
Name of Officer
Title:
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Fulcrum Therapeutics, Inc.
Restricted Stock Unit Agreement
Granted under 2022 Inducement Stock Incentive Plan
Incorporated Terms and Conditions
1.
Award of Restricted Stock Units. In consideration of services rendered and to be rendered to the Company, by
the Participant, the Company has granted to the Participant, subject to the terms and conditions set forth in this Restricted Stock
Unit Agreement (this “Agreement”) and in the Company’s 2022 Inducement Stock Incentive Plan (the “Plan”), an award with
respect to the number of restricted stock units (the “RSUs”) set forth in the Notice of Grant that forms part of this Agreement (the
“Notice of Grant”). Each RSU represents the right to receive one share of common stock, $0.001 par value per share, of the
Company (the “Common Stock”) upon vesting of the RSU, subject to the terms and conditions set forth herein.
The RSUs evidenced by this Agreement were granted to the Participant pursuant to the inducement grant exception
under Nasdaq Stock Market Rule 5635(c)(4), as an inducement that is material to the Participant’s employment with the
Company.
1.
Vesting. The RSUs shall vest in accordance with the Vesting Schedule set forth in the Notice of Grant (the
“Vesting Schedule”). Any fractional shares resulting from the application of any percentages used in the Vesting Schedule shall
be rounded down to the nearest whole number of RSUs. As soon as practicable after the vesting of the RSU, the Company will
deliver to the Participant, for each RSU that becomes vested, one share of Common Stock, subject to the payment of any taxes
pursuant to Section 7. The Common Stock will be delivered to the Participant as soon as practicable following each vesting date,
but in any event within 30 days of such date.
2.
Forfeiture of Unvested RSUs Upon Cessation of Service. In the event that the Participant ceases to be an
Eligible Participant (as defined below) for any reason or no reason, with or without cause, all of the RSUs that are unvested as of
the time of such cessation shall be forfeited immediately and automatically to the Company, without the payment of any
consideration to the Participant, effective as of such cessation. The Participant shall have no further rights with respect to the
unvested RSUs or any Common Stock that may have been issuable with respect thereto. The Participant shall be an “Eligible
Participant” if the individual is an employee, director or officer of, or consultant or advisor to, the Company or any other entity
the employees, officers, directors, consultants or advisors of which are eligible to receive awards of RSUs under the Plan.
3.
Restrictions on Transfer. The Participant shall not sell, assign, transfer, pledge, hypothecate, encumber or
otherwise dispose of, by operation of law or otherwise (collectively “transfer”) any RSUs, or any interest therein. The Company
shall not be required to treat as the owner of any RSUs or issue any Common Stock to any transferee to whom such RSUs have
been transferred in violation of any of the provisions of this Agreement.
4.
Rights as a Stockholder. The Participant shall have no rights as a stockholder of the Company with respect to
any shares of Common Stock that may be issuable with respect to the
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RSUs until the issuance of the shares of Common Stock to the Participant following the vesting of the RSUs.
5.
Provisions of the Plan. This Agreement is subject to the provisions of the Plan, a copy of which is furnished to
the Participant with this Agreement.
6.
Tax Matters.
a.
Acknowledgments; No Section 83(b) Election. The Participant acknowledges that he or she is
responsible for obtaining the advice of the Participant’s own tax advisors with respect to the award of RSUs and the Participant is
relying solely on such advisors and not on any statements or representations of the Company or any of its agents with respect to
the tax consequences relating to the RSUs. The Participant understands that the Participant (and not the Company) shall be
responsible for the Participant’s tax liability that may arise in connection with the acquisition, vesting and/or disposition of the
RSUs. The Participant acknowledges that no election under Section 83(b) of the Internal Revenue Code of 1986, as amended,
(the “Code”) is available with respect to RSUs.
a.
Withholding. The Participant acknowledges and agrees that the Company has the right to
deduct from payments of any kind otherwise due to the Participant any federal, state, local or other taxes of any kind required by
law to be withheld with respect to the vesting of the RSUs. At such time as the Participant is not aware of any material nonpublic
information about the Company or the Common Stock and the Participant is not subject to any restriction on trading activities
with respect to the Common Stock pursuant to any Company insider trading or other policy, the Participant shall execute the
instructions set forth in Schedule A attached hereto (the “Automatic Sale Instructions”) as the means of satisfying such tax
obligation. If the Participant does not execute the Automatic Sale Instructions prior to an applicable vesting date, then the
Participant agrees that if under applicable law the Participant will owe taxes at such vesting date on the portion of the award then
vested the Company shall be entitled to immediate payment from the Participant of the amount of any tax required to be withheld
by the Company. The Company shall not deliver any shares of Common Stock to the Participant until it is satisfied that all
required withholdings have been made.
7.
Miscellaneous.
a.
Section 409A. The RSUs awarded pursuant to this Agreement are intended to be exempt from
or comply with the requirements of Section 409A of the Code and the Treasury Regulations issued thereunder (“Section 409A”).
The delivery of shares of Common Stock on the vesting of the RSUs may not be accelerated or deferred unless permitted or
required by Section 409A.
b.
Participant’s Acknowledgements. The Participant acknowledges that he or she: (i) has read
this Agreement; (ii) has been represented in the preparation, negotiation and execution of this Agreement by legal counsel of the
Participant’s own choice or has voluntarily declined to seek such counsel; (iii) understands the terms and consequences of this
Agreement; (iv) is fully aware of the legal and binding effect of this Agreement; and (v) agrees that in
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accepting this award, the Participant will be bound by any clawback policy that the Company may adopt in the future.
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Schedule A
Automatic Sale Instructions
The undersigned hereby consents and agrees that any taxes due on a vesting date as a result of the vesting of RSUs on such date
shall be paid through an automatic sale of shares as follows:
(a) Upon any vesting of RSUs pursuant to Section 2 hereof, the Company shall arrange for the sale of such number of
shares of Common Stock issuable with respect to the RSUs that vest pursuant to Section 2 as is sufficient to generate net
proceeds in the amount necessary to satisfy the Company’s minimum statutory withholding obligations with respect to the
income recognized by the Participant upon the vesting of the RSUs (based on minimum statutory withholding rates for all tax
purposes, including payroll and social security taxes, that are applicable to such income), and the net proceeds of such sale shall
be delivered to the Company in satisfaction of such tax withholding obligations.
(b) The Participant hereby appoints the Chief Executive Officer, the Chief Financial Officer and the Chief Legal
Officer (or a person holding a similar title), and any of them acting alone and with full power of substitution, to serve as his or her
attorneys in fact to arrange for the sale of the Participant’s Common Stock in accordance with this Schedule A. The Participant
agrees to execute and deliver such documents, instruments and certificates as may reasonably be required in connection with the
sale of the shares pursuant to this Schedule A.
(c) The Participant represents to the Company that, as of the date hereof, he or she is not aware of any material
nonpublic information about the Company or the Common Stock and is not subject to any restriction on trading activities with
respect to the Common Stock pursuant to any Company insider trading policy or other policy. The Participant and the Company
have structured this Agreement, including this Schedule A, to constitute a “binding contract” relating to the sale of Common
Stock, consistent with the affirmative defense to liability under Section 10(b) of the Securities Exchange Act of 1934 under Rule
10b5-1(c) promulgated under such Act.
The Company shall not deliver any shares of Common Stock to the Participant until it is satisfied that all required
withholdings have been made.
_______________________________
Participant Name: ________________
Date: __________________________
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FULCRUM THERAPEUTICS, INC.
NON-EMPLOYEE DIRECTOR COMPENSATION POLICY
Effective January 19, 2022
Exhibit 10.15
The Company’s non-employee directors shall receive the following compensation for their service as members of the Board of Directors (the
“Board”) of the Company.
Director Compensation
Our goal is to provide compensation for our non-employee directors in a manner that enables us to attract and retain outstanding director
candidates and reflects the substantial time commitment necessary to oversee the Company’s affairs. We also seek to align the interests of our directors and
our stockholders and we have chosen to do so by compensating our non-employee directors with a mix of cash and equity-based compensation.
Cash Compensation
The fees that will be paid to our non-employee directors for service on the Board, and for service on each committee of the Board on which the
director is then a member, and the fees that will be paid to the chairperson of the Board, if one is then appointed, and the chairperson of each committee of
the Board will be as follows:
Board of Directors
Audit Committee
Compensation Committee
Nominating and Corporate Governance Committee
Science and Technology Committee
Member Annual Fee
40,000
7,500
5,000
4,000
5,000
$
$
$
$
$
Chairman Incremental Annual Fee
30,000
$
7,500
$
5,000
$
4,000
$
5,000
$
The foregoing fees will be payable in arrears in four equal quarterly installments on the last day of each quarter, provided that the amount of such
payment will be prorated for any portion of such quarter that the director is not serving on the Board, on such committee or in such position.
Equity Compensation
Initial Grants . Upon initial election to the Board, each non-employee director will be granted, automatically and without the need for any further
action by the Board, an initial equity award of an option to purchase 30,000 shares of our common stock. The initial award shall have a term of ten years
from the date of the award, and shall vest and become exercisable as to 1/36 of the shares underlying such award at the end of each successive one-month
period following the grant date until the third anniversary of the grant date, subject to the director’s continued service to the Company through each
applicable vesting date. The vesting shall accelerate as to 100% of the shares upon a change in control of the Company. The exercise price shall be the
closing price of our common stock on the date of grant.
Annual Grants . Each non-employee director who has served as a member of the Board for at least six months prior to the date of our annual
meeting of stockholders for a particular year will be granted, automatically and without the need for any further action by the Board, an equity award on the
date of the first Board meeting held after our annual meeting of stockholders for such year of an option to purchase 19,000 shares of our common stock.
The annual award shall have a term of ten years from the date of the award, and shall vest and become exercisable in full on the one-year anniversary of the
grant date (or, if earlier, immediately prior to the first annual meeting of stockholders occurring after the grant date), subject to the director’s continued
service to the Company through each
applicable vesting date. The vesting shall accelerate as to 100% of the shares upon a change in control of the Company. The exercise price shall be the
closing price of our common stock on the date of grant.
The foregoing share amounts shall be automatically adjusted in the event of any stock split, reverse stock split, stock dividend, recapitalization,
combination of shares, reclassification of shares, spin-off or other similar change in capitalization or event effecting our common stock, or any distribution
to holders of our common stock other than an ordinary cash dividend.
The initial awards and the annual awards shall be subject to the terms and conditions of our 2019 Stock Incentive Plan, or any successor plan,
and the terms of the option agreements entered into with each director in connection with such awards.
Expenses
Upon presentation of documentation of such expenses reasonably satisfactory to the Company, each non-employee director shall be reimbursed
for his or her reasonable out-of-pocket business expenses incurred in connection with attending meetings of the Board and committees thereof or in
connection with other business related to the Board, and each non-employee director shall also be reimbursed for his or her reasonable out-of-pocket
business expenses authorized by the Board or a committee of the Board that are incurred in connection with attendance at various conferences or meetings
with management of the Company, in accordance with the Company’s travel policy, as it may be in effect from time to time.
2
EMPLOYMENT AGREEMENT
Exhibit 10.23
THIS EMPLOYMENT AGREEMENT (the “Agreement”), is made as of January 3rd, 2022, ( Executive’s first day of
employment, after all eligibility criteria have been met) by and between Fulcrum Therapeutics, Inc. (the “Company”), and Esther
Rajavelu (the “Executive”) (together, the “Parties”).
RECITALS
WHEREAS, the Company desires to employ the Executive as its Chief Financial Officer; and
WHEREAS, the Executive has agreed to accept such employment on the terms and conditions set forth in this
Agreement;
NOW, THEREFORE, in consideration of the foregoing and of the respective covenants and agreements of the Parties
herein contained, the Parties hereto agree as follows:
1. Agreement. This Agreement shall be effective as of the Effective Date (“Date of Hire”). Following the Effective Date, the
Executive shall continue to be an employee of the Company until such employment relationship is terminated in accordance with
Section 7 hereof (the “Term of Employment”).
2. Position. During the Term of Employment, the Executive shall serve as the Chief Financial Officer of the Company, working
out of the Company’s office in Cambridge, Massachusetts, and travelling as reasonably required by the Executive’s job duties.
3. Scope of Employment. During the Term of Employment, the Executive shall be responsible for the performance of those duties
consistent with the Executive’s position as Chief Financial Officer. The Executive shall report to the President, Chief Executive
Officer and shall perform and discharge faithfully, diligently, and to the best of the Executive’s ability, the Executive’s duties and
responsibilities hereunder. The Executive shall devote substantially all of the Executive’s business time, loyalty, attention and
efforts to the business and affairs of the Company and its affiliates. Membership on boards of directors of any other companies
will be permitted only with the express approval of the Company’s board of directors (the “Board”); provided, however, that the
Executive may engage in community and charitable activities or participate in industry associations and serve on the boards of up
to two (2) community, charitable or industry organizations, without the approval of the Board, provided such activities do not
create a conflict of interest or otherwise interfere with the Executive’s performance of the Executive’s duties hereunder. The
Executive agrees to abide by the rules, regulations, instructions, personnel practices and policies of the Company and any
changes therein that may be adopted from time to time by the Company.
4. Compensation. As full compensation for all services rendered by the Executive to the Company and any affiliate thereof,
during the Term of Employment, the Company will provide to the Executive the following:
(a) Base Salary. Effective as of the Effective Date, the Executive shall receive a base salary at the annualized rate of
$435,000 (the “Base Salary). The Executive’s Base Salary shall be paid in equal installments in accordance with the Company’s
regularly established payroll procedures. The Executive’s Base Salary will be reviewed on an annual or more frequent basis by
the Board and is subject to change in the discretion of the Board.
(b) Annual Discretionary Bonus. Effective as of the Effective Date, the Executive will be eligible to earn an annual
performance bonus of up to 40% of the Executive’s Base Salary (the “Target Bonus”), based upon the Board’s assessment of the
Executive’s performance and the Company’s attainment of targeted goals as set by the Board in its sole discretion. To the extent
the Executive’s Base Salary and/or target bonus percentage of Base Salary is changed during the year to which the performance
bonus relates, the Target Bonus shall be calculated based on base salary actually paid during such year (and not solely on the
Executive’s Base Salary at the end of such year) and shall apply the initial target bonus percentage of Base Salary and the revised
target bonus percentage of Base Salary based on the portion of the year during which each was in effect. The Board may
determine to provide the bonus in the form of cash, equity award(s), or a combination of cash and equity. Following the close of
each calendar year, the Board will determine whether the Executive has earned a performance bonus, and the amount of any
performance bonus, based on the set criteria. No amount of the annual bonus is guaranteed, and the Executive must be an
employee in good standing on the date of payment in order to be eligible for any annual bonus, except as specifically set forth
below. The annual performance bonus, if earned, will be paid by no later than March 15 of the calendar year after the year to
which it relates. The Executive’s bonus eligibility will be reviewed on an annual or more frequent basis by the Board and is
subject to change in the discretion of the Board.
(c) Equity Award. The Executive will be eligible to receive equity awards, if any, at such times and on such terms and
conditions as the Board shall, in its sole discretion, determine. As part of your initial offer and subject to the approval of the
Company’s Board of Directors, and as a material inducement to you entering into employment with the Company, you will
receive a one- time grant of options to purchase 200,000 shares of the Company’s Common Stock (“Option”). The exercise price
per share of the Option shall be equal to the closing price per share of the Common Stock on the Nasdaq Select Market on the
effective date of the Option. The Option is subject to adjustment for stock splits, combinations or other recapitalizations. The
Option shall be issued outside the Company’s 2019 Stock Incentive Plan, as an “inducement grant” within the meaning of Nasdaq
Listing Rule 5635(c)(4), will be a non-qualified stock option for United States tax purposes and will be subject to all of the terms
set forth in a written agreement covering the Option. Subject to the terms of the stock option agreement evidencing the Option
and your continued employment, the Option shall vest over four years at the rate of 25% on the first anniversary of the Start Date
and an additional 6.25% per quarter for the next twelve successive quarters of employment when, after four full years of
employment, the Option will be fully vested.
(d) Paid Time Off. The Executive shall be entitled to paid time off, vacation time plus sick time, consistent with the
Company’s policies.
(e) Benefits. Subject to eligibility requirements and the Company’s polices, you shall have the right, on the same basis as
other similarly situated employees of the Company, to participate in, and to receive benefits under, any medical, vision and dental
insurance policy maintained by the Company and the Company shall pay a portion of the cost of the premiums for such medical,
vision and dental insurance that is consistent with the Company’s then current employee benefit policy if you elect to participate
in such plans.
(f) Withholdings. All compensation payable to the Executive shall be subject to applicable taxes and withholdings.
5. Expenses. The Executive will be reimbursed for his actual, necessary and reasonable business expense pursuant to Company
policy, subject to the provisions of Section 3 of Exhibit A attached hereto.
6. Restrictive Covenants Agreement. The Executive hereby acknowledges that in connection with entering into this Agreement,
the Executive shall be required to enter into an Employee Confidentiality and Assignment Agreement with the Company.
7. Employment Termination. This Agreement and the employment of the Executive shall terminate upon the occurrence of any of
the following:
(a) Upon the death or “Disability” of the Executive. As used in this Agreement, the term “Disability” shall mean a
physical or mental illness or disability that prevents the Executive from performing the duties of the Executive’s position for a
period of more than any three consecutive months or for periods aggregating more than twenty-six weeks. The Company shall
determine in good faith and in its sole discretion whether the Executive is unable to perform the services provided for herein.
(b) At the election of the Company, with or without “Cause” (as defined below), immediately upon written notice by the
Company to the Executive. As used in this Agreement, “Cause” shall mean:
(i)
(ii)
(iii)
Executive’s dishonest statements or acts with respect to the Company or any affiliate of the Company, or any
current or prospective customers, suppliers, vendors or other third parties with which such entity does business
that results in or is reasonably anticipated to result in material harm to the Company;
Executive’s conviction of (A) a felony or (B) any misdemeanor involving moral turpitude, deceit, dishonesty or
fraud;
Executive’s gross negligence, willful misconduct or insubordination with respect to the Company that results in
or is reasonably anticipated to result in material harm to the Company, provided, however, that the Executive
shall have a period of not less than ten(10) days to cure any curable act or omission constituting Cause
described in this Section 7(b)(iii) following the Company’s delivery to the Executive of written notice of such
act or omission; or
(iv)
Executive’s material violation of any provision of any agreement(s) between the Executive and the Company
relating to non-solicitation, nondisclosure and/or assignment of inventions.
(c) At the election of the Executive, with or without “Good Reason” (as defined below), immediately upon written notice
by the Executive to the Company (subject, if it is with Good Reason, to the timing provisions set forth in the definition of Good
Reason). As used in this Agreement, “Good Reason” shall mean (without the Executive’s consent):
(i)
(ii)
(iii)
(iv)
a material diminution of the Executive’s base compensation, other than in connection with, and substantially
proportionate to, reductions by the Company of the base compensation of all or substantially all senior
executives of the Company;
a material diminution in the Executive’s duties, authority or responsibilities;
the Company’s requiring Executive to relocate Executive’s primary office more than fifty (50) miles from
the Executive’s then-current primary office; or
any material breach of this Agreement, or any other agreement between the Company and the Executive, by
the Company not otherwise covered by this
paragraph;
provided, however, that in each case, the Company shall have a period of not less than thirty (30) days to cure any act constituting
Good Reason following Executive’s delivery to the Company of written notice within sixty (60) days of the action or omission
constituting Good Reason and that the Executive actually terminates employment within thirty (30) days following the expiration
of the Company’s cure period.
8. Effect of Termination.
(a) All Terminations Other Than by the Company Without Cause or by the Executive With Good Reason. If the
Executive’s employment is terminated under any circumstances other than a Qualifying Termination (as defined below)
(including a voluntary termination by the Executive without Good Reason pursuant to Section 7(c), a termination by the
Company for Cause pursuant to Section 7(b) or due to the Executive’s death or Disability pursuant to Section 7(a)), the
Company’s obligations under this Agreement shall immediately cease and the Executive shall only be entitled to receive (i) the
Base Salary that has accrued and to which the Executive is entitled as of the effective date of such termination and to the extent
consistent with general Company policy, to be paid in accordance with the Company’s established payroll procedure and
applicable law but no later than the next regularly scheduled pay period, (ii) unreimbursed business expenses for which expenses
the Executive has timely submitted appropriate documentation in accordance with Section 5 hereof, and (iii) any amounts or
benefits to which the Executive is then entitled under the terms of the benefit plans then-sponsored by the Company in
accordance with their terms (and not accelerated to the extent acceleration does not satisfy Section 409A of the Internal Revenue
Code of 1986, as amended, (the “Code”)) (the payments described in this sentence, the “Accrued Obligations”).
(b) Termination by the Company Without Cause or by the Executive With Good Reason Prior to or More Than Twelve
Months Following a Change in Control. If the Executive’s employment is terminated by the Company without Cause pursuant to
Section 7(b) or by the Executive with Good Reason pursuant to Section 7(c) (in either case, a “Qualifying Termination”) prior to
or more than twelve (12) months following a Change in Control (as defined below), the Executive shall be entitled to the Accrued
Obligations. In addition, and subject to Exhibit A and the conditions of Section 8(d), the Company shall: (i) continue to pay to the
Executive, in accordance with the Company’s regularly established payroll procedures, the Executive’s Base Salary for a period
of nine (9) months and (ii) provided the Executive is eligible for and timely elects to continue receiving group medical insurance
pursuant to the “COBRA” law, continue to pay (but in no event longer than nine (9) months following the Executive’s
termination date) the share of the premium for health coverage that is paid by the Company for active and similarly-situated
employees who receive the same type of coverage, unless the Company’s provision of such COBRA payments will violate the
nondiscrimination requirements of applicable law, in which case this benefit will not apply (collectively, the “Severance
Benefits”).
(c) Termination by the Company Without Cause or by the Executive With Good Reason Within Twelve Months Following
a Change in Control. If a Qualifying Termination occurs within twelve (12) months following a Change in Control, then the
Executive shall be entitled to the Accrued Obligations. In addition, and subject to Exhibit A and the conditions of Section 8(d),
the Company shall: (i) continue to pay to the Executive, in accordance with the Company’s regularly established payroll
procedures, the Executive’s Base Salary (or, if higher, the Executive’s Base Salary in effect immediately prior to the Change in
Control) for a period of twelve (12) months; (ii) pay to the Executive, in a single lump sum on the Payment Date (as defined
below) an amount equal to 100% of the Executive’s Target Bonus for the year in which termination occurs or, if
higher, the Executive’s Target Bonus immediately prior to the Change in Control, (iii) provided the Executive is eligible for and
timely elects to continue receiving group medical insurance pursuant to the “COBRA” law, continue to pay (but in no event
longer than twelve(12) months following the Executive’s termination date) the share of the premium for health coverage that is
paid by the Company for active and similarly-situated employees who receive the same type of coverage, unless the Company’s
provision of such COBRA payments will violate the nondiscrimination requirements of applicable law, in which case this benefit
will not apply, and (iv) provide that the vesting of the Executive’s then-unvested equity awards that vest based solely on the
passage of time shall be accelerated, such that all then-unvested equity awards that vest based solely on the passage of time vest
and become fully exercisable or non- forfeitable as of the termination date (collectively, the “Change in Control Severance
Benefits”).
(d) Release. As a condition of the Executive’s receipt of the Severance Benefits or the Change in Control Severance
Benefits, as applicable, the Executive must execute and deliver to the Company a severance and release of claims agreement in a
form to be provided by the Company (the “Severance Agreement”), which Severance Agreement must become irrevocable
within 60 days following the date of the Executive’s termination of employment (or such shorter period as may be directed by the
Company). The Severance Benefits or the Change in Control Severance Benefits, as applicable, will be paid or commence to be
paid in the first regular payroll beginning after the Severance Agreement becomes effective, provided that if the foregoing 60 day
period would end in a calendar year subsequent to the year in which the Executive’s employment ends, the Severance Benefits or
Change in Control Severance Benefits, as applicable, will not be paid or begin to be paid before the first payroll of the subsequent
calendar year (the date the Severance Benefits or Change in Control Severance Benefits, as applicable, commence pursuant to
this sentence, the “Payment Date”). The Executive must continue to comply with the Employee Confidentiality and Assignment
Agreement and any similar agreement with the Company in order to be eligible to continue receiving the Severance Benefits or
Change in Control Severance Benefits, as applicable.
(e) Change in Control Definition. For purposes of this Agreement, “Change in Control” shall mean the occurrence of any
of the following events, provided that such event or occurrence constitutes a change in the ownership or effective control of the
Company, or a change in the ownership of a substantial portion of the assets of the Company, as defined in Treasury Regulation
§§ 1.409A-3(i)(5)(v), (vi) and (vii): (i) the acquisition by an individual, entity or group (within the meaning of Section 13(d)(3)
or 14(d)(2) of the Securities Exchange Act of 1934 (the “Exchange Act”)) (a “Person”) of beneficial ownership of any capital
stock of the Company if, after such acquisition, such Person beneficially owns (within the meaning of Rule 13d-3 under the
Exchange Act) fifty percent (50%) or more of either (x) the then-outstanding shares of common stock of the Company (the
“Outstanding Company Common Stock”) or (y) the combined voting power of the then-outstanding securities of the Company
entitled to vote generally in the election of directors (the “Outstanding Company Voting Securities”); provided, however, that for
purposes of this subsection (i), the following acquisitions shall not constitute a Change in Control: (1) any acquisition directly
from the Company or (2) any acquisition by any entity pursuant to a Business Combination (as defined below) which complies
with clauses (x) and (y) of subsection (iii) of this definition; or (ii) a change in the composition of the Board that results in the
Continuing Directors (as defined below) no longer constituting a majority of the Board (or, if applicable, the Board of Directors
of a successor corporation to the Company), where the term “Continuing Director” means at any date a member of the Board (x)
who was a member of the Board on the Effective Date or (y) who was nominated or elected subsequent to such date by at least a
majority of the directors who were Continuing Directors at the time of such nomination or election or whose election to the
Board was recommended or endorsed by at least a majority of the directors who
were Continuing Directors at the time of such nomination or election; provided, however, that there shall be excluded from this
clause (y) any individual whose initial assumption of office occurred as a result of an actual or threatened election contest with
respect to the election or removal of directors or other actual or threatened solicitation of proxies or consents, by or on behalf of a
person other than the Board; or (iii) the consummation of a merger, consolidation, reorganization, recapitalization or share
exchange involving the Company, or a sale or other disposition of all or substantially all of the assets of the Company (a
“Business Combination”), unless, immediately following such Business Combination, each of the following two (2) conditions is
satisfied: (x) all or substantially all of the individuals and entities who were the beneficial owners of the Outstanding Company
Common Stock and Outstanding Company Voting Securities immediately prior to such Business Combination beneficially own,
directly or indirectly, more than fifty percent (50%) of the then-outstanding shares of common stock and the combined voting
power of the then-outstanding securities entitled to vote generally in the election of directors, respectively, of the resulting or
acquiring corporation in such Business Combination (which shall include, without limitation, a corporation which as a result of
such transaction owns the Company or substantially all of the Company’s assets either directly or through one (1) or more
subsidiaries) (such resulting or acquiring corporation is referred to herein as the “Acquiring Corporation”) in substantially the
same proportions as their ownership of the Outstanding Company Common Stock and Outstanding Company Voting Securities,
respectively, immediately prior to such Business Combination and (y) no Person (excluding any employee benefit plan (or related
trust) maintained or sponsored by the Company or by the Acquiring Corporation) beneficially owns, directly or indirectly, fifty
percent (50%) or more of the then-outstanding shares of common stock of the Acquiring Corporation, or of the combined voting
power of the then-outstanding securities of such corporation entitled to vote generally in the election of directors (except to the
extent that such ownership existed prior to the Business Combination); or (iv) the liquidation or dissolution of the Company.
9. Absence of Restrictions. The Executive represents and warrants that the Executive is not bound by any employment contracts,
restrictive covenants or other restrictions that prevent the Executive from entering into employment with, or carrying out the
Executive’s responsibilities for, the Company, or which are in any way inconsistent with any of the terms of this Agreement.
10. Notice. Any notice delivered under this Agreement shall be deemed duly delivered three (3) business days after it is sent by
registered or certified mail, return receipt requested, postage prepaid, one (1) business day after it is sent for next-business day
delivery via a reputable nationwide overnight courier service, or immediately upon hand delivery, in each case to the address of
the recipient set forth below.
To Executive:
At the address set forth in the Executive’s personnel file
To Company:
Fulcrum Therapeutics, Inc.
26 Landsdowne Street, 5th Floor
Cambridge, MA 02139
Either Party may change the address to which notices are to be delivered by giving notice of such change to the other Party in the
manner set forth in this Section 10.
11. Applicable Law; Jury Trial Waiver. This Agreement shall be governed by and construed in accordance with the laws of the
Commonwealth of Massachusetts (without reference to the conflict of laws provisions thereof). Any action, suit or other legal
proceeding arising under or relating to any provision of this Agreement shall be commenced only in a court of the
Commonwealth of Massachusetts (or, if appropriate, a federal court located within the Commonwealth of Massachusetts), and the
Company and the Executive each consents to the jurisdiction of such a court. The Company and the Executive each hereby
irrevocably waives any right to a trial by jury in any action, suit or other legal proceeding arising under or relating to any
provision of this Agreement.
12. Successors and Assigns. This Agreement shall be binding upon and inure to the benefit of both Parties and their respective
successors and assigns, including any corporation with which or into which the Company may be merged or which may succeed
to its assets or business; provided, however, that the obligations of the Executive are personal and shall not be assigned by the
Executive.
13. At-Will Employment. During the Term of Employment, the Executive will continue to be an at-will employee of the Company,
which means that, notwithstanding any other provision set forth herein, the employment relationship can be terminated by either
Party for any reason, at any time, with or without prior notice and with or without Cause.
14. Acknowledgment. The Executive states and represents that the Executive has had an opportunity to fully discuss and review
the terms of this Agreement with an attorney. The Executive further states and represents that the Executive has carefully read
this Agreement, understands the contents herein, freely and voluntarily assents to all of the terms and conditions hereof, and signs
the Executive’s name of the Executive’s own free act.
15. No Oral Modification, Waiver, Cancellation or Discharge. This Agreement may be amended or modified only by a written
instrument executed by both the Company and the Executive. No delay or omission by the Company in exercising any right
under this Agreement shall operate as a waiver of that or any other right. A waiver or consent given by the Company on any one
occasion shall be effective only in that instance and shall not be construed as a bar to or waiver of any right on any other
occasion.
16. Captions and Pronouns. The captions of the sections of this Agreement are for convenience of reference only and in no way
define, limit or affect the scope or substance of any section of this Agreement. Whenever the context may require, any pronouns
used in this Agreement shall include the corresponding masculine, feminine or neuter forms, and the singular forms of nouns and
pronouns shall include the plural, and vice versa.
17. Interpretation. The Parties agree that this Agreement will be construed without regard to any presumption or rule requiring
construction or interpretation against the drafting Party. References in this Agreement to “include” or “including” should be read
as though they said “without limitation” or equivalent forms. References in this Agreement to the “Board” shall include any
authorized committee thereof.
S8verability. Each provision of this Agreement must be interpreted in such manner as to be effective and valid under applicable
law, but if any provision of this Agreement is held to be prohibited by or invalid under applicable law, such provision will be
ineffective only to the extent of such prohibition or invalidity, without invalidating the remainder of such provision or the
remaining provisions of this Agreement. Moreover, if a court of competent jurisdiction determines any of the provisions
contained in this Agreement to be unenforceable because the provision is
excessively broad in scope, whether as to duration, activity, geographic application, subject or otherwise, it will be construed, by
limiting or reducing it to the extent legally permitted, so as to be enforceable to the extent compatible with then applicable law to
achieve the intent of the Parties.
19. Entire Agreement. This Agreement constitutes the entire agreement between the Parties and supersedes all prior agreements
and understandings, whether written or oral, relating to the subject matter of this Agreement, including, without limitation, the
Existing Agreement.
[Signatures on Page Following]
IN WITNESS WHEREOF, the Parties hereto have executed this Agreement as of the day and year set forth above.
FULCRUM THERAPEUTICS, INC.
By:
/s/ Kim Hazen
Name:
Kim Hazen
Title:
SVP, Human Resources
EXECUTIVE:
/s/ Esther Rajavelu
Esther Rajavelu
EXHIBIT A
Payments Subject to Section 409A
1. Subject to this Exhibit A, any severance payments that may be due under the Agreement shall begin only upon the
date of the Executive’s “separation from service” (determined as set forth below) which occurs on or after the termination of the
Executive’s employment. The following rules shall apply with respect to distribution of the severance payments, if any, to be
provided to the Executive under the Agreement, as applicable:
(a) It is intended that each installment of the severance payments provided under the Agreement shall
be treated as a separate “payment” for purposes of Section 409A of the Internal Revenue Code (“Section 409A”).
Neither the Company nor the Executive shall have the right to accelerate or defer the delivery of any such payments
except to the extent specifically permitted or required by Section 409A.
(b) If, as of the date of the Executive’s “separation from service” from the Company, the Executive is
not a “specified employee” (within the meaning of Section 409A), then each installment of the severance payments shall
be made on the dates and terms set forth in the letter agreement.
“specified employee” (within the meaning of Section 409A), then:
(c) If, as of the date of the Executive’s “separation from service” from the Company, the Executive is a
(i)
(ii)
Each installment of the severance payments due under the Agreement that, in accordance with the dates
and terms set forth herein, will in all circumstances, regardless of when the Executive’s separation from
service occurs, be paid within the short-term deferral period (as defined under Section 409A) shall be
treated as a short-term deferral within the meaning of Treasury Regulation Section 1.409A-1(b)(4) to
the maximum extent permissible under Section 409A and shall be paid on the dates and terms set forth
in the Agreement; and
Each installment of the severance payments due under the Agreement that is not described in this
Exhibit A, Section 1(c)(i) and that would, absent this subsection, be paid within the six-month period
following the Executive’s “separation from service” from the Company shall not be paid until the date
that is six months and one day after such separation from service (or, if earlier, your death), with any
such installments that are required to be delayed being accumulated during the six-month period and
paid in a lump sum on the date that is six months and one day following the Executive’s separation
from service and any subsequent installments, if any, being paid in accordance with the dates and
terms set forth herein; provided, however, that the preceding provisions of this sentence shall not
apply to any installment of payments if and to the maximum extent that that such installment is
deemed to be paid under a separation pay plan that does not provide for a deferral of compensation by
reason of the application of Treasury Regulation 1.409A- 1(b)(9)(iii) (relating to separation pay upon
an involuntary separation from service). Any installments that qualify for the exception under
Treasury Regulation Section 1.409A-1(b)(9)(iii) must be paid no later than the last day of the
Executive’s second taxable year
following the taxable year in which the separation from service occurs.
2. The determination of whether and when the Executive’s separation from service from the Company has occurred shall
be made and in a manner consistent with, and based on the presumptions set forth in, Treasury Regulation Section 1.409A-1(h).
Solely for purposes of Section 2 of this Exhibit A, “Company” shall include all persons with whom the Company would be
considered a single employer under Section 414(b) and 414(c) of the Code.
3. All reimbursements and in-kind benefits provided under the Agreement shall be made or provided in accordance with
the requirements of Section 409A to the extent that such reimbursements or in-kind benefits are subject to Section 409A,
including, where applicable, the requirements that (i) any reimbursement is for expenses incurred during the Executive’s lifetime
(or during a shorter period of time specified in the Agreement), (ii) the amount of expenses eligible for reimbursement during a
calendar year may not affect the expenses eligible for reimbursement in any other calendar year, (iii) the reimbursement of an
eligible expense will be made on or before the last day of the calendar year following the year in which the expense is incurred
and (iv) the right to reimbursement is not subject to set off or liquidation or exchange for any other benefit.
4. The Company makes no representation or warranty and shall have no liability to the Executive or to any other person
if any of the provisions of the Agreement (including this Exhibit A) are determined to constitute deferred compensation subject to
Section 409A but that do not satisfy an exemption from, or the conditions of, that section.
5. The Agreement is intended to comply with, or be exempt from, Section 409A and shall be interpreted accordingly.
[Remainder of page intentionally left blank.]
Fulcrum Therapeutics Securities Corp.
Massachusetts
Jurisdiction of Incorporation
List of Subsidiaries
Exhibit 21.1
Exhibit 23.1
Consent of Independent Registered Public Accounting Firm
We consent to the incorporation by reference in the following Registration Statements:
1. Registration Statement (Form S-8 No. 333-233452) pertaining to the 2016 Stock Incentive Plan, as amended, 2019 Stock
Incentive Plan, and 2019 Employee Stock Purchase Plan of Fulcrum Therapeutics, Inc.;
2. Registration Statement (Form S-8 No. 333-236910) pertaining to the 2019 Stock Incentive Plan and 2019 Employee
Stock Purchase Plan of Fulcrum Therapeutics, Inc.,
3. Registration Statement (Form S-1 No. 333-239353) and related Prospectus of Fulcrum Therapeutics, Inc. (as amended
by Form S-3/A No. 333-239353);
4. Registration Statement (Form S-8 No. 333-253862) pertaining to the 2019 Stock Incentive Plan and 2019 Employee
Stock Purchase Plan of Fulcrum Therapeutics, Inc.,
5. Registration Statement (Form S-3 No. 333-260754) and related Prospectus of Fulcrum Therapeutics, Inc. (as amended
by Form S-3/A No. 333-260754); and
6. Registration Statement (Form S-8 No. 333-262356) pertaining to the 2019 Stock Incentive Plan, 2019 Employee Stock
Purchase Plan, and Inducement Stock Option Awards (September 2021 – January 2022) of Fulcrum Therapeutics, Inc.,
of our report dated March 3, 2022, with respect to the consolidated financial statements of Fulcrum Therapeutics, Inc. included in
this Annual Report (Form 10-K) of Fulcrum Therapeutics, Inc. for the year ended December 31, 2021.
/s/ Ernst & Young LLP
Boston, Massachusetts
March 3, 2022
Exhibit 31.1
CERTIFICATION 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
I, Bryan Stuart, certify that:
1. I have reviewed this Annual Report on Form 10-K of Fulcrum Therapeutics, Inc.;
2. Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the
statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this report;
3. Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the
financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;
4. The registrant’s other certifying officer(s) and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in
Exchange Act Rules 13a-15(e) and 15d-15(e)) for the registrant and have:
(a) Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our
supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by others
within those entities, particularly during the period in which this report is being prepared;
(b) (Paragraph omitted pursuant to SEC Release Nos. 33-8238/34-47986 and 33-8392/34-49313);
(c) Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the
effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and
(d) Disclosed in this report any change in the registrant’s internal control over financial reporting that occurred during the registrant’s most
recent fiscal quarter (the registrant’s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to
materially affect, the registrant’s internal control over financial reporting; and
5. The registrant’s other certifying officer(s) and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to
the registrant’s auditors and the audit committee of the registrant’s board of directors (or persons performing the equivalent functions):
(a) All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are
reasonably likely to adversely affect the registrant’s ability to record, process, summarize and report financial information; and
(b) Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant’s internal
control over financial reporting.
Date: March 3, 2022
By: /s/ Bryan Stuart
Bryan Stuart
President and Chief Executive Officer
(Principal Executive Officer)
Exhibit 31.2
CERTIFICATION 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
I, Esther Rajavelu, certify that:
1. I have reviewed this Annual Report on Form 10-K of Fulcrum Therapeutics, Inc.;
2. Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the
statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered by this report;
3. Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the
financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;
4. The registrant’s other certifying officer(s) and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in
Exchange Act Rules 13a-15(e) and 15d-15(e)) for the registrant and have:
(a) Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our
supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us by others
within those entities, particularly during the period in which this report is being prepared;
(b) (Paragraph omitted pursuant to SEC Release Nos. 33-8238/34-47986 and 33-8392/34-49313);
(c) Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the
effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and
(d) Disclosed in this report any change in the registrant’s internal control over financial reporting that occurred during the registrant’s most
recent fiscal quarter (the registrant’s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to
materially affect, the registrant’s internal control over financial reporting; and
5. The registrant’s other certifying officer(s) and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to
the registrant’s auditors and the audit committee of the registrant’s board of directors (or persons performing the equivalent functions):
(a) All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are
reasonably likely to adversely affect the registrant’s ability to record, process, summarize and report financial information; and
(b) Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant’s internal
control over financial reporting.
Date: March 3, 2022
By: /s/ Esther Rajavelu
Esther Rajavelu
Chief Financial Officer
(Principal Financial Officer)
CERTIFICATION PURSUANT TO 18 U.S.C. SECTION 1350,
AS ADOPTED PURSUANT TO
SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002
Exhibit 32.1
In connection with the Annual Report on Form 10-K of Fulcrum Therapeutics, Inc. (the “Company”) for the year ended December 31, 2021, as filed
with the Securities and Exchange Commission on the date hereof (the “Report”), the undersigned, Bryan Stuart, President and Chief Executive Officer of
the Company, hereby certifies, pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002, that to his
knowledge:
(1) the Report fully complies with the requirements of Section 13(a) or 15(d) of the Securities Exchange Act of 1934; and
(2) the information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.
Date: March 3, 2022
By:
/s/ Bryan Stuart
Bryan Stuart
President and Chief Executive Officer
(Principal Executive Officer)
CERTIFICATION PURSUANT TO 18 U.S.C. SECTION 1350,
AS ADOPTED PURSUANT TO
SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002
Exhibit 32.2
In connection with the Annual Report on Form 10-K of Fulcrum Therapeutics, Inc. (the “Company”) for the year ended December 31, 2021, as filed
with the Securities and Exchange Commission on the date hereof (the “Report”), the undersigned, Esther Rajavelu, Chief Financial Officer of the
Company, hereby certifies, pursuant to 18 U.S.C. Section 1350, as adopted pursuant to Section 906 of the Sarbanes-Oxley Act of 2002, that to his
knowledge:
(1) the Report fully complies with the requirements of Section 13(a) or 15(d) of the Securities Exchange Act of 1934; and
(2) the information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.
Date: March 3, 2022
By:
/s/ Esther Rajavelu
Esther Rajavelu
Chief Financial Officer
(Principal Financial Officer)