Ionis Pharmaceuticals

2024
ANNUAL
REPORT

 
UNITED STATES 
SECURITIES AND EXCHANGE COMMISSION 
Washington, DC 20549 
  
 
 
 
  
FORM 10-K  
  
☒ 
ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 
 
For the fiscal year ended December 31, 2024 
 
☐ 
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 000-19125 
 
 
 
 
Ionis Pharmaceuticals, Inc. 
(Exact name of Registrant as specified in its charter) 
  
Delaware 
 
33-0336973 
(State or other jurisdiction of incorporation or organization) 
 
(IRS Employer Identification No.) 
  
2855 Gazelle Court, Carlsbad, CA 
92010 
(Address of Principal Executive Offices) 
 
(Zip Code) 
  
760-931-9200 
(Registrant’s telephone number, including area code) 
 
Securities registered pursuant to Section 12(b) of the Act: 
Title of each class 
 
Trading symbol 
 
Name of each exchange on which registered 
Common Stock, $.001 Par Value  
 
“IONS” 
 
The Nasdaq Stock Market LLC 
  
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 if the Registrant is not required to file reports pursuant to Section 13 or Section 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, a 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 assessment of the effectiveness 
of its internal controls over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered 

 
public accounting firm that prepared or issued its audit report ☒ 
 
If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the 
registrant included in the filing reflect the correction of an error to previously issued financial statements.  ☐ 
 
Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based 
compensation received by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b).  ☐ 
 
Indicate by check mark whether the Registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes ☐  No ☒ 
 
The approximate aggregate market value of the voting common stock held by non-affiliates of the Registrant, based upon the last sale 
price of the common stock reported on The Nasdaq Global Select Market was $5,738,934,243 as of June 30, 2024.* 
 
The number of shares of voting common stock outstanding as of February 13, 2025 was 158,964,772. 
 
DOCUMENTS INCORPORATED BY REFERENCE 
 
Portions of the Registrant’s definitive Proxy Statement to be filed on or about April 25, 2025 with the Securities and Exchange 
Commission in connection with the Registrant’s annual meeting of stockholders to be held on June 5, 2025 are incorporated by 
reference into Part III of this Report.  
 
________________ 
* 
Excludes 25,611,183 shares of common stock held by directors and officers and by stockholders whose beneficial ownership is 
known by the Registrant to exceed 10 percent of the common stock outstanding at June 30, 2024. Exclusion of shares held by any 
person should not be construed to indicate that such person possesses the power, direct or indirect, to direct or cause the direction 
of the management or policies of the Registrant, or that such person is controlled by or under common control with the Registrant. 
 
 
 

 
FORWARD-LOOKING STATEMENTS 
 
This report on Form 10-K and the information incorporated herein by reference includes forward-looking statements 
regarding our business and the therapeutic and commercial potential of our commercial medicines, additional medicines in 
development and technologies. Any statement describing our goals, expectations, financial or other projections, intentions or 
beliefs, is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain 
risks and uncertainties and particularly those inherent in the process of discovering, developing and commercializing 
medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such 
medicines. Our forward-looking statements also involve assumptions that, if they never materialize or prove correct, could 
cause our results to differ materially from those expressed or implied by such forward-looking statements. Factors that could 
cause or contribute to such differences include, but are not limited to, those discussed in this report on Form 10-K, including 
those identified in Item 1A, Risk Factors. Although our forward-looking statements reflect the good faith judgment of our 
management, these statements are based only on facts and factors currently known by us. Except as required by law, we 
undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on 
these forward-looking statements. 
 
In this report, unless the context requires otherwise, “Ionis,” the “Company,” “we,” “our,” and “us” refers to Ionis 
Pharmaceuticals, Inc. and its subsidiaries. 
 
Summary of Risk Factors 
 
There are a number of risks related to our business and our securities. Below is a summary of material factors that make an 
investment in our securities speculative or risky. Importantly, this summary does not address all of the risks that we face. Additional 
discussion of the risks summarized in this risk factor summary, as well as other risks that we face, can be found in this report on Form 
10-K in Item 1A, Risk Factors: 
  
● 
Our ability to generate substantial revenue from the sale of our medicines; 
● 
The availability of adequate coverage and payment rates for our medicines; 
● 
Our and our partners’ ability to compete effectively; 
● 
Our ability to successfully manufacture our medicines; 
● 
Our ability to successfully develop and obtain marketing approvals for our medicines; 
● 
Our ability to secure and maintain effective corporate partnerships; 
● 
Our ability to sustain cash flows and achieve consistent profitability; 
● 
Our ability to protect our intellectual property; 
● 
Our ability to maintain the effectiveness of our personnel; 
● 
The impacts of health epidemics, climate change, war and other global events; and 
● 
Our dependence upon our own and third-party information technology systems. 
 
TRADEMARKS  
 
“Ionis,” the Ionis logo, and other trademarks or service marks of Ionis Pharmaceuticals, Inc. appearing in this report are the 
property of Ionis Pharmaceuticals, Inc. “Akcea,” the Akcea logo, and other trademarks or service marks of Akcea Therapeutics, Inc. 
appearing in this report are the property of Akcea Therapeutics, Inc., Ionis’ wholly owned subsidiary. This report contains additional 
trade names, trademarks and service marks of others, which are the property of their respective owners. Solely for convenience, 
trademarks and trade names referred to in this report may appear without the ® or TM symbols.  
 
CORPORATE INFORMATION 
 
We incorporated in California in 1989 and in January 1991 we changed our state of incorporation to Delaware. In December 
2015, we changed our name to Ionis Pharmaceuticals, Inc. from Isis Pharmaceuticals, Inc. Our principal offices are in Carlsbad, 
California.  
 
We make available, free of charge, on our website, www.ionis.com, our reports on Forms 10-K, 10-Q, 8-K and amendments 
thereto, as soon as reasonably practicable after we file such materials with, or furnish such materials to, the Securities and Exchange 
Commission, or SEC. Periodically, we provide updates about the company in the Newsroom section of the Investors & Media page of 
our website. Any information that we include on or link to our website is not a part of this report or any registration statement that 
incorporates this report by reference. The SEC maintains an internet site, www.sec.gov, that contains reports, proxy and information 
statements, and other information that we file electronically with the SEC. 
 
 

 
IONIS PHARMACEUTICALS, INC. 
FORM 10-K  
For the Fiscal Year Ended December 31, 2024 
Table of Contents 
 
PART I 
 
 
 
 
Page 
Item 1.  
Business 
4 
Item 1A. 
Risk Factors 
40 
Item 1B. 
Unresolved Staff Comments 
57 
Item 1C. 
Cybersecurity 
57 
Item 2. 
Properties 
59 
Item 3.  
Legal Proceedings 
59 
Item 4.  
Mine Safety Disclosures 
59 
 
 
 
PART II 
 
 
 
 
 
Item 5.  
Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity 
Securities 
59 
Item 6.  
Reserved 
61 
Item 7.  
Management’s Discussion and Analysis of Financial Condition and Results of Operations 
61 
Item 7A.  
Quantitative and Qualitative Disclosures About Market Risk 
71 
Item 8. 
Financial Statements and Supplementary Data 
71 
Item 9. 
Changes in and Disagreements With Accountants on Accounting and Financial Disclosure 
72 
Item 9A. 
Controls and Procedures 
72 
Item 9B. 
Other Information 
74 
Item 9C. 
Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 
74 
 
 
 
PART III 
 
 
 
 
 
Item 10. 
Directors, Executive Officers and Corporate Governance 
74 
Item 11. 
Executive Compensation 
75 
Item 12. 
Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters 
75 
Item 13. 
Certain Relationships and Related Transactions, and Director Independence 
75 
Item 14. 
Principal Accountant Fees and Services 
75 
 
 
 
PART IV 
 
 
 
 
 
Item 15. 
Exhibits, Financial Statement Schedules 
75 
 
 
 
Signatures 
 
83 
 
 

PART I 
 
Item 1. Business 
 
Overview 
 
For three decades, we have invented medicines that bring better futures to people with serious diseases. As a pioneer in RNA-
targeted medicines with a deep understanding of disease biology and an industry-leading drug discovery technology, we are driven to 
deliver innovative, life-changing advances for patients.    
 
In the last year, we delivered on our strategy to create accelerating value for all our stakeholders. With our commercial 
launch of TRYNGOLZA (olezarsen) in the United States, or U.S., following its approval by the U.S. Food and Drug Administration, 
or FDA, we began a new chapter as a fully integrated commercial-stage biotechnology company. We currently have six marketed 
medicines to treat serious diseases: TRYNGOLZA, WAINUA (eplontersen), SPINRAZA (nusinersen), QALSODY (tofersen), 
TEGSEDI (inotersen) and WAYLIVRA (volanesorsen).  
 
Marketed Medicines 
 
• 
TRYNGOLZA is approved in the U.S. as an adjunct to diet to reduce triglycerides in adults with familial 
chylomicronemia syndrome, or FCS. TRYNGOLZA is the first-ever FDA-approved treatment that significantly and 
substantially reduces triglyceride levels in adults with FCS and provides clinically meaningful reduction in acute 
pancreatitis, or AP, events when used with an appropriate diet (≤20 grams of fat per day). TRYNGOLZA is the first 
medicine we are commercializing independently in the U.S. 
• 
WAINUA is approved in numerous countries, including the U.S. and United Kingdom, or UK, for the treatment of 
the polyneuropathy of hereditary transthyretin-medicated amyloidosis, or ATTRv-PN, in adults. WAINUA is the 
only approved medicine for the treatment of ATTRv-PN that can be self-administered via an auto-injector. We and 
AstraZeneca are co-developing WAINUA globally and co-commercializing WAINUA in the U.S. AstraZeneca has 
exclusive rights to commercialize WAINUA outside of the U.S.  
• 
SPINRAZA is a global market leader for the treatment of pediatric and adult patients with spinal muscular atrophy, 
or SMA. Our partner, Biogen, is responsible for commercializing SPINRAZA worldwide. 
• 
QALSODY is approved in the U.S., European Union, or EU, China and Japan for the treatment of Amyotrophic 
Lateral Sclerosis, or ALS, in adults who have a mutation in the superoxide dismutase 1, or SOD1, gene, or SOD1-
ALS. QALSODY received accelerated approval from the FDA and marketing authorization under exceptional 
circumstances from the European Medicines Agency, or EMA. QALSODY was the first treatment approved to 
target a genetic cause of ALS. Our partner, Biogen, is responsible for commercializing QALSODY worldwide. 
• 
TEGSEDI is approved in the EU, Canada and Brazil for the treatment of ATTRv-PN in adults. We currently sell 
TEGSEDI in Europe through our distribution agreement with Swedish Orphan Biovitrum AB, or Sobi. We and Sobi 
terminated our agreement for TEGSEDI in North America, after which we discontinued TEGSEDI in North 
America. In Latin America, PTC Therapeutics International Limited, or PTC, is commercializing TEGSEDI in 
Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us. 
• 
WAYLIVRA is approved in the EU and Brazil as an adjunct to diet in adult patients with genetically confirmed FCS 
and at high risk for acute, potentially fatal pancreatitis, in whom response to diet and triglyceride lowering therapy 
has been inadequate. We sell WAYLIVRA in Europe through our distribution agreement with Sobi. In Latin 
America, PTC is commercializing WAYLIVRA in Brazil for two indications, FCS and familial partial 
lipodystrophy, or FPL, and is pursuing access in additional Latin American countries through its exclusive license 
agreement with us.  
 
In addition to our currently marketed medicines, we are also positioned to deliver multiple products to the market 
independently in the next three years. Donidalorsen for the treatment of hereditary angioedema, or HAE, is currently under regulatory 
review in the U.S., positioning us for our second independent commercial launch in 2025. We also have a rich innovative late- and 
mid-stage pipeline across our focus areas of neurology, cardiology and select areas of high patient needs. We currently have nine 
medicines in Phase 3 development and multiple additional medicines in early and mid-stage development. We delivered eight positive 
data readouts in the last year from our late- and mid-stage pipeline, including positive data for TRYNGOLZA, donidalorsen and 
ION582, our medicine for people with Angelman syndrome, or AS. And we further advanced our next-generation technologies for 
RNA-targeted medicines, including advancing our first program using our mesyl phosphoramidate, or MsPA, backbone into clinical 
development. 
 
 
 
4

We earned revenues of $705 million in 2024 and ended 2024 with a cash and short-term investment balance of $2.3 billion 
that enables our continued investments to support ongoing and upcoming planned launches and to advance our wholly owned 
medicines in development. Our key recent achievements, combined with our independent and partnered product launches anticipated 
over the next three years, position us well to help millions of patients with serious diseases and deliver increasing product and royalty 
revenue.  
 
Our Marketed Medicines – Bringing Value to Patients Today 
 
TRYNGOLZA (apoC-III) – TRYNGOLZA (olezarsen), injection is an APOC-III-directed antisense medicine indicated as 
an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome, or FCS. TRYNGOLZA lowers the body’s 
production of apolipoprotein C-III, or apoC-III, a protein produced in the liver that is a key regulator of triglyceride metabolism. 
TRYNGOLZA was approved by the FDA in December 2024 and is the first-ever FDA-approved treatment that significantly and 
substantially reduces triglyceride levels in adults with FCS and provides clinically meaningful reduction in AP events when used with 
an appropriate diet (≤20 grams of fat per day). TRYNGOLZA is currently under regulatory review in the EU. 
 
FCS is a rare, genetic, potentially life-threatening form of sHTG that prevents the body from breaking down fats and severely 
impairs the body’s ability to remove triglycerides from the bloodstream due to an impaired function of the enzyme lipoprotein lipase, 
or LPL. While healthy levels for adults are below 150 mg/dL, people with FCS often have triglyceride levels of more than 880 mg/dL 
and often have a history of pancreatitis. Those living with FCS have a high risk of potentially fatal AP, which is a painful 
inflammation of the pancreas, and chronic health issues such as fatigue and severe, recurrent abdominal pain. People living with FCS 
can also experience psychological and financial stress, which can significantly impact their quality of life. FCS is estimated to impact 
up to approximately 3,000 people in the U.S., the vast majority of whom remain undiagnosed.  
 
We are also developing olezarsen to treat severe hypertriglyceridemia, or sHTG. See the “olezarsen” description under the 
section titled, Our Innovative Late-Stage Pipeline of Ionis-Owned Investigational Medicines, below for further information on our 
development program for sHTG. 
 
FDA approval was based on positive data from the placebo-controlled Phase 3 Balance study in adult patients with 
genetically identified FCS and fasting triglyceride levels ≥880 mg/dL. In the Balance study, TRYNGOLZA demonstrated a 
statistically significant reduction in triglyceride levels. TRYNGOLZA also demonstrated a substantial, clinically meaningful reduction 
in AP events. In addition, TRYNGOLZA demonstrated a favorable safety and tolerability profile in the Balance study.  
 
TRYNGOLZA was reviewed by the FDA under Priority Review and had previously been granted Fast Track, Orphan Drug 
and Breakthrough Therapy designations for the treatment of FCS. 
 
WAINUA (TTR) – WAINUA (eplontersen) injection is a transthyretin-directed antisense oligonucleotide indicated for the 
treatment of the polyneuropathy of hereditary transthyretin-medicated amyloidosis, or ATTRv-PN, in adults. WAINUA causes 
degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR 
protein and TTR protein deposits in tissues. WAINUA was approved in the U.S. in December 2023 and was recommended for 
approval by the CHMP in the EU in October 2024. WAINUA is also approved in other markets, including the UK and Canada, with 
additional regulatory reviews underway. We and AstraZeneca are co-commercializing WAINUA in the U.S. and AstraZeneca has 
exclusive rest of world commercialization rights.  
 
ATTRv-PN is a debilitating disease that leads to peripheral nerve damage with motor disability within five years of diagnosis 
and, without treatment, is generally fatal within a decade. ATTR is caused by the accumulation of liver-derived misfolded TTR 
protein in tissues, such as the heart and the peripheral nerves, causing organ damage and failure. ATTR then causes complications, 
leading to cardiovascular, neurological and renal diseases such as heart failure and chronic kidney disease. There are both hereditary 
(ATTRv) and non-hereditary (wild-type) forms of ATTR. ATTR has several phenotypes including ATTR-cardiomyopathy, or ATTR-
CM, which predominantly impacts the heart, potentially leading to heart failure, and ATTR-polyneuropathy, which predominantly 
affects the peripheral nervous system and mixed phenotype, where patients experience symptoms of both. Worldwide, there are an 
estimated 10,000 – 40,000 patients with ATTRv-PN. See the “Eplontersen” description under the section titled, Our Innovative Late-
Stage Pipeline of Partnered Investigational Medicines, below for further information on our development program for ATTR-CM.  
 
FDA approval was based on the interim analysis of the open-label Phase 3 NEURO-TTRansform study in patients with 
ATTRv-PN. The study compared WAINUA to the historical placebo arm from the TEGSEDI (inotersen) NEURO-TTR Phase 3 
study. In the interim analysis, WAINUA demonstrated a statistically significant and clinically meaningful change from baseline for 
the co-primary endpoints of serum TTR concentration and Neuropathy Impairment Score +7, or mNIS+7. Additionally, WAINUA 
demonstrated a favorable safety and tolerability profile in the NEURO-TTRansform study. 
 
 
 
5

The FDA granted Orphan Drug designation to WAINUA for the treatment of ATTR.  
 
SPINRAZA (SMN) – SPINRAZA (nusinersen) injection for intrathecal use is a survival motor neuron-2, or SMN2, directed 
antisense medicine indicated for the treatment of SMA in pediatric and adult patients. SPINRAZA targets the root cause of SMA by 
increasing the production of functional survival motor neuron, or SMN, protein. SPINRAZA is a global market leader for the 
treatment of patients with SMA. Our partner, Biogen, is responsible for commercializing SPINRAZA worldwide. 
 
SMA is characterized by loss of motor neurons in the spinal cord and lower brain stem. People with SMA have a deletion or 
defect in their SMN1 gene and rely on their SMN2 gene to produce functional SMN protein, which motor neurons need to maintain 
motor function and muscle strength. However, in untreated people the SMN2 gene can only produce approximately 10% of the SMN 
protein critical for motor neurons, resulting in severe and progressive loss of motor function and strength. The rate and severity of 
degeneration varies depending on the amount of functional SMN protein a patient can produce. Type 1, or infantile-onset, SMA is the 
most severe form of the disease. Type 1 SMA patients produce very little SMN protein and often progress to death or permanent 
ventilation by the age of 2. Patients with Type 2 or Type 3, or later-onset, SMA produce more SMN protein, but also suffer from a 
progressive loss of muscle strength and function and a reduced life expectancy. 
 
The approval of SPINRAZA was based on efficacy and safety data from multiple clinical studies, including two randomized, 
placebo-controlled Phase 3 studies, ENDEAR, in patients with infantile-onset SMA, and CHERISH, in patients with later-onset SMA 
as well as from SHINE, an OLE study for patients with SMA who participated in prior SPINRAZA studies. Additionally, Biogen 
conducted the Phase 2 NURTURE study, an open-label study investigating the benefit of SPINRAZA when administered before 
symptom onset in patients genetically diagnosed with SMA which showed that early and sustained treatment with SPINRAZA helped 
participants to maintain and/or make progressive gains in motor function with most children achieving motor milestones within age-
appropriate timelines and no major motor milestones were lost. SPINRAZA demonstrated a favorable safety and tolerability profile in 
the studies. 
 
Biogen continues to expand the body of evidence supporting SPINRAZA’s durable efficacy and well-established safety 
profile to address the remaining needs of SMA patients of all ages through additional studies. These include the Phase 2/3 DEVOTE 
study, which evaluated a higher dose of SPINRAZA compared to the currently approved dose, the Phase 4 RESPOND study, 
evaluating the benefit of SPINRAZA in infants and children with a suboptimal clinical response to the gene therapy, onasemnogene 
abeparvovec and the Phase 3b ASCEND study evaluating the clinical outcomes and assessing the safety of a higher dose of 
SPINRAZA in children, teens and adults with later-onset SMA following treatment with risdiplam. The positive data generated from 
the DEVOTE study were the basis of the recent U.S. and EU regulatory submissions that were accepted for review for higher dose 
nusinersen. 
 
QALSODY (SOD1) – QALSODY (tofersen) injection for intrathecal use is an antisense medicine indicated for the treatment 
of Amyotrophic Lateral Sclerosis, or ALS, in adults who have a mutation in the superoxide dismutase 1, or SOD1, gene, or SOD1-
ALS. QALSODY inhibits the production of SOD1. QALSODY was granted accelerated approval in April 2023 based on reduction in 
plasma neurofilament light chain, or NfL, observed in patients treated with QALSODY. Continued approval for this indication may be 
contingent upon verification of clinical benefit in confirmatory trial(s). In May 2024, QALSODY was also approved in the EU under 
exceptional circumstances. Additionally, QALSODY was recently approved in China and Japan. Our partner, Biogen, is responsible 
for commercializing QALSODY worldwide. 
 
SOD1-ALS is a rare, fatal, neurodegenerative disorder caused by a mutation in the SOD1 gene leading to a progressive loss 
of motor neurons. As a result, people with SOD1-ALS experience increasing muscle weakness, loss of movement, difficulty breathing 
and swallowing and eventually succumb to the disease. Mutations in the SOD1 gene are responsible for approximately 2% of the 
estimated 168,000 people who have ALS globally (SOD1-ALS). More than 15% of people with ALS are thought to have a genetic 
form of the disease; however, they may not have a known family history of the disease.  
 
Biogen is also evaluating tofersen for treatment of presymptomatic individuals who have a SOD1 genetic mutation.  
 
The QALSODY regulatory submissions included results from a Phase 1 study in healthy volunteers, a Phase 1/2 study 
evaluating ascending dose levels, the Phase 3 VALOR study, and the Phase 3 OLE study, as well as 12-month integrated results from 
the Phase 3 VALOR study and the Phase 3 open-label extension, or OLE, study. The 12-month integrated data show that earlier 
initiation of QALSODY, compared to delayed initiation, slowed declines in clinical function, respiratory function, muscle strength and 
quality of life and build on the results previously observed in the initial readout. The 12-month data compare patients with early 
initiation of QALSODY (at the start of VALOR) to those who had a delayed initiation of QALSODY (six months later, in the OLE). 
Additionally, QALSODY demonstrated a favorable safety and tolerability profile in the VALOR study. 
 
 
 
6

The FDA and EMA granted QALSODY Orphan Drug designation for the treatment of ALS. 
 
TEGSEDI (TTR) – TEGSEDI (inotersen) injection is a transthyretin-directed antisense oligonucleotide medicine indicated 
for the treatment of ATTRv-PN in adults. TEGSEDI prevents the production of TTR protein, reducing the amount of amyloid buildup 
that damages organs and tissues. We currently sell TEGSEDI in Europe through our distribution agreement with Sobi. In Latin 
America, PTC is commercializing TEGSEDI in Brazil and is pursuing access in additional Latin American countries through its 
exclusive license agreement with us.  
 
The approvals of TEGSEDI were based on efficacy and safety data from the Phase 3 NEURO-TTR study in patients with 
ATTRv-PN.  
 
WAYLIVRA (apoC-III) – WAYLIVRA (volanesorsen) injection is an antisense oligonucleotide medicine indicated as an 
adjunct to diet in adult patients with genetically confirmed FCS and at high risk for acute, potentially fatal pancreatitis, in whom 
response to diet and triglyceride lowering therapy has been inadequate. WAYLIVRA reduces triglyceride levels by inhibiting the 
production of apoC-III, a protein that is a key regulator of triglyceride levels. WAYLIVRA received conditional marketing 
authorization in May 2019 from the European Commission, or EC. We sell WAYLIVRA in Europe through our distribution 
agreement with Sobi. In Latin America, WAYLIVRA is approved for two indications, FCS and FPL. PTC is commercializing 
WAYLIVRA in Brazil and is pursuing access in additional Latin American countries through its exclusive license agreement with us.  
 
WAYLIVRA’s conditional marketing authorization in the EU for FCS and approval in Brazil for FCS were based on efficacy 
and safety data from the Phase 3 APPROACH study and supported by results from the Phase 3 COMPASS study. WAYLIVRA’s 
approval in Brazil for FPL was based on efficacy and safety data from the Phase 3 BROADEN study in patients with FPL.  
 
Our Innovative Late-Stage Pipeline of Ionis-Owned Investigational Medicines  
 
As a pioneer in RNA-targeted therapeutics, we continue to drive innovation with a leading pipeline in neurology, cardiology 
and select diseases of high unmet need. The table below lists Ionis-owned medicines currently in late-stage development, which Ionis 
plans to commercialize in the U.S. independently.  
 
 
 
1 
Ionis is commercializing TRYNGOLZA (olezarsen) for the treatment of FCS in the U.S.  
2 
Granted Otsuka exclusive rights to commercialize donidalorsen in Europe and Asia-Pacific regions. 
3 
Granted Theratechnologies exclusive rights to commercialize olezarsen and donidalorsen in Canada. 
 
Olezarsen (apoC-III) – Olezarsen is an investigational RNA-targeted medicine that we are evaluating for people with 
sHTG. Olezarsen is designed to lower the body’s production of apoC-III, a protein produced in the liver that regulates triglyceride 
metabolism in the blood. sHTG is a disease categorized by triglyceride levels of 500 mg/dL and above. It develops due to primary 
(genetic) and secondary causes including diet and lifestyle, other medical conditions and certain medications. More than three million 
people are currently estimated to live with sHTG in the U.S. People living with sHTG are at high risk of pancreatitis (a painful 
inflammation of the pancreas) and damage to the pancreas. As such, reducing the risk of pancreatitis is a critically important reason to 
treat sHTG. People with sHTG are also at risk of heart, brain and blood vessel damage. 
 
 
 
7

We are currently conducting a broad development program for olezarsen that includes three fully enrolled Phase 3 studies 
supporting development for the treatment of sHTG: CORE, CORE2 and ESSENCE. Data from the ESSENCE study is expected in 
mid-2025 and data from the CORE and CORE2 studies are expected in the second half of 2025.  
 
We advanced olezarsen into Phase 3 development based on the positive results from a Phase 2 clinical study in patients with 
hypertriglyceridemia and at high risk of or with established cardiovascular disease, or CVD. In the Phase 2 study, olezarsen achieved 
statistically significant, dose-dependent reductions in fasting triglycerides compared to placebo at all dose levels. Olezarsen also 
achieved statistical significance in numerous key secondary endpoints, including significant reductions in apoC-III. Olezarsen 
demonstrated a favorable safety and tolerability profile in the Phase 2 study supportive of continued development. As discussed above 
under “TRYNGOLZA” in the section titled, Our Marketed Medicines – Bringing Value to Patients Today, olezarsen was recently 
approved in the U.S. for the treatment of FCS. 
 
Donidalorsen (PKK) – Donidalorsen is an investigational RNA-targeted medicine we designed to target the production of 
prekallikrein, or PKK, which plays an important role in the activation of inflammatory mediators associated with acute attacks of 
HAE. By reducing the production of PKK, donidalorsen could be an effective prophylactic approach to preventing HAE attacks. HAE 
is a rare and potentially life-threatening genetic condition that involves recurrent attacks of severe swelling (angioedema) in various 
parts of the body, including the hands, feet, genitals, stomach, face and/or throat. HAE is estimated to affect approximately 20,000 
people in the U.S. and Europe. Donidalorsen is currently under review in the U.S. and the FDA has set an action date of August 21, 
2025 under the Prescription Drug User Fee Act, or PDUFA. Donidalorsen is also under regulatory review in the EU. Otsuka has 
exclusive rights to commercialize donidalorsen in Europe and Asia and Theratechnologies has exclusive rights to commercialize 
donidalorsen in Canada. 
 
Our regulatory submissions are based on the positive data from the placebo-controlled Phase 3 OASIS-HAE study, the Phase 
3 OASISplus study and the Phase 2 OLE study in patients with HAE. The OASIS-HAE study met its primary endpoint with a 
statistically significant reduction in the rate of HAE attacks and demonstrated clinically significant improvement in quality of life as 
measured by the Angioedema Quality of Life Questionnaire, or AE-QoL in patients treated every four weeks and patients treated 
every eight weeks. The OASISplus study includes an OLE cohort and a prospective cohort to assess patients switching from currently 
available long-term prophylactic treatments to donidalorsen. Positive results from a February 2024 data cut from the ongoing OLE 
cohort showed that HAE attack rates continued to improve over time and extended treatment resulted in further improved quality of 
life measures and high levels of disease control. In the OASISplus switch cohort, patients followed a pre-defined specific protocol to 
transition from their prior therapy to donidalorsen. Results showed that patients were able to switch to donidalorsen from prior 
prophylactic treatment without an increase in breakthrough attacks. Donidalorsen treatment also led to a further improvement in mean 
monthly HAE attack rates and continued improvements in measures of quality of life. A majority of patients surveyed reported a 
preference for donidalorsen over their previous treatment. In all of these studies, donidalorsen demonstrated a favorable safety and 
tolerability profile. 
 
The FDA and EMA granted Orphan Drug designation to donidalorsen. 
 
Zilganersen (GFAP) – Zilganersen (formerly ION373) is an investigational RNA-targeted medicine we designed to inhibit 
the production of glial fibrillary acidic protein, or GFAP, that accumulates because of disease-causing variants in the GFAP gene. We 
are developing zilganersen as a potential treatment for people with genetically confirmed Alexander disease, or AxD. AxD is an ultra-
rare, progressive and ultimately fatal type of leukodystrophy, which are a group of genetic disorders that affect the brain’s white 
matter. AxD is estimated to occur in approximately one in one million to one in three million people worldwide and usually leads to 
death within 14 - 25 years after symptom onset. AxD can present throughout life as loss of independence and lack of ability to control 
muscles for swallowing, airway protection and purposeful movements. The impact of AxD can vary depending on factors like age of 
onset. Diagnosing AxD is based on a combination of clinical presentation, brain magnetic resonance imaging, or MRI, findings and 
genetic testing. There are no medicines approved for people with AxD, and current treatments focus on managing their symptoms.  
 
We are conducting a single clinical study of zilganersen in patients with AxD designed to assess the efficacy, safety and 
tolerability of zilganersen. In September 2023, we advanced zilganersen into the Phase 3 portion of the study.  
 
The FDA and EMA granted Orphan Drug designation to zilganersen. Additionally, the FDA granted Fast Track and Rare 
Pediatric designations to zilganersen. 
 
ION582 (UBE3A) (BIIB121) – ION582 is an investigational RNA-targeted medicine we designed to inhibit the expression 
of the UBE3A antisense transcript, or UBE3A-ATS, and increase production of UBE3A protein, for the potential treatment of AS. AS 
is a rare, genetic neurological disease caused by the loss of function of the maternally inherited UBE3A gene. AS typically presents in 
infancy and is characterized by intellectual disability, balance issues, motor impairment, and debilitating seizures. Some patients are 
unable to walk or speak. Some symptoms can be managed with existing drugs; however, there are no approved disease modifying 
therapies. 
 
8

We are conducting the ongoing open label Phase 1/2 study, HALOS, of ION582 in patients with AS designed to assess the 
safety, tolerability and activity of multiple ascending doses of ION582 administered intrathecally. In 2024, we presented positive 
results from the completed multiple ascending dose, or MAD, portion of the study in people with AS demonstrating consistent and 
encouraging clinical improvement on measures assessing all functional domains including communication, cognition and motor 
function. ION582 showed favorable safety and tolerability at all dose levels in the study. 
 
Based on the positive results from the HALOS study and alignment with the FDA, we plan to advance ION582 into Phase 3 
development in the first half of 2025. The planned placebo-controlled Phase 3 study will enroll children and adults with AS who have 
a maternal UBE3A gene deletion or mutation to assess the efficacy, safety and tolerability of ION582.  
 
The FDA and EMA granted Orphan Drug designation to ION582. Additionally, the FDA granted Fast Track and Rare 
Pediatric designations to ION582.  
 
Our Innovative Late-Stage Pipeline of Partnered Investigational Medicines  
 
In addition to our Ionis-owned investigational medicines, we also have numerous potentially transformational partnered 
medicines in clinical development. The table below lists our partnered medicines in late-stage development. For further information 
on our collaboration agreements, refer to the section titled, Collaborative Arrangements.  
 
 
 
Eplontersen (TTR) – Eplontersen is an investigational RNA-targeted medicine designed to degrade mutant and wild-type 
TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in 
tissues. Eplontersen is currently being evaluated in patients with hereditary or wild-type transthyretin-mediated amyloid 
cardiomyopathy, or ATTR-CM. ATTR-CM is a progressive and fatal disease caused by the accumulation of misfolded TTR protein in 
the cardiac muscle. Patients experience ongoing debilitating heart damage resulting in progressive heart failure, which results in death 
within two to six years from disease onset. Worldwide, there are an estimated 300,000 – 500,000 patients with ATTR-CM. We and 
AstraZeneca are co-developing eplontersen globally and co-commercializing eplontersen in the U.S. AstraZeneca has exclusive rest-
of-world commercialization rights. 
 
We are conducting the ongoing placebo-controlled CARDIO-TTRansform Phase 3 cardiovascular outcome study of 
eplontersen in patients with ATTR-CM. We designed the study to evaluate the efficacy, safety and tolerability of eplontersen in 
patients with ATTR-CM. 
 
As discussed above under “WAINUA” in the section titled, Our Marketed Medicines – Bringing Value to Patients Today, 
eplontersen is approved in numerous countries, including the U.S. and UK, for the treatment of the ATTRv-PN.  
 
The FDA granted Orphan Drug designation to WAINUA for the treatment of ATTR. The FDA also granted Fast Track 
designation to eplontersen for ATTR-CM.  
 
 
 
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Pelacarsen (Apo(a)) (TQJ230) – Pelacarsen is an investigational RNA-targeted medicine we designed to inhibit the 
production of apolipoprotein(a), or Apo(a), in the liver to offer a direct approach for reducing lipoprotein(a), or Lp(a). Elevated Lp(a) 
is recognized as an independent, genetic cause of CVD. Lp(a) levels are determined at birth and lifestyle modification, including diet 
and exercise, do not impact Lp(a) levels. Inhibiting the production of Apo(a) in the liver reduces the level of Lp(a) in blood, 
potentially slowing down or reversing CVD in people with hyperlipoproteinemia(a), a condition in which individuals have levels of 
Lp(a) greater than 50 mg/dL, the recognized threshold for risk of CVD. We believe antisense technology is well suited to address 
hyperlipoproteinemia(a) because it specifically targets the RNA that codes for all forms of the Apo(a) molecule. It is estimated that 
there are more than eight million people living with CVD and elevated levels of Lp(a). Our partner, Novartis, is responsible for 
ongoing development and commercialization of pelacarsen worldwide. 
 
Novartis is conducting the placebo-controlled Phase 3 cardiovascular outcome study of pelacarsen, Lp(a)HORIZON, to 
assess the efficacy, safety and tolerability of pelacarsen in patients with elevated Lp(a) levels and established or at risk for CVD.  
 
In November 2018, at the American Heart Association annual meeting, we reported results of the Phase 2 study of pelacarsen 
in patients with hyperlipoproteinemia(a). In the Phase 2 study, we observed statistically significant and dose dependent reductions 
from baseline in Lp(a) levels. Additionally, pelacarsen demonstrated a favorable safety and tolerability profile in the study. 
 
The FDA and Center for Drug Evaluation of China National Medical Products Administration granted pelacarsen Fast Track 
designation and Breakthrough Therapy, respectively, for the treatment of patients with elevated Lp(a) and established CVD.  
 
Bepirovirsen (HBV) (GSK3228836) – Bepirovirsen is an investigational RNA-targeted medicine we designed to inhibit the 
production of viral proteins associated with hepatitis B virus, or HBV. These include proteins associated with infection and 
replication, including the hepatitis B surface antigen, or HBsAg, which is present in both acute and chronic infections and is 
associated with a poor prognosis in people with chronic HBV infection. HBV infection is a serious health problem that can lead to 
significant and potentially fatal health conditions, including cirrhosis, liver failure and liver cancer. Chronic HBV infection is one of 
the most common persistent viral infections in the world, affecting more than 250 million people and resulting in more than 1 million 
deaths annually. Currently available therapies, although effective in reducing circulating HBV in the blood, do not effectively inhibit 
HBV antigen production and secretion, which are associated with poor prognosis and increased risk of liver cancer. Our partner, GSK, 
is responsible for ongoing development and commercialization of bepirovirsen worldwide. 
 
GSK is conducting the placebo-controlled Phase 3 program of bepirovirsen, B-Well, in patients with chronic HBV designed 
to assess the efficacy, safety and tolerability of bepirovirsen.  
 
In June 2022, GSK presented positive results from the Phase 2b B-Clear study of bepirovirsen in patients with chronic HBV 
infection. The end of study results showed that treatment with bepirovirsen in some patients resulted in sustained clearance of HBsAg 
and HBV DNA for 24 weeks after end of bepirovirsen treatment in people with chronic HBV infection. Additionally in June 2023, 
GSK presented durable response data from the Phase 2 B-Sure long-term follow-up study of bepirovirsen in complete responder 
patients from the Phase 2b B-Clear study of patients with HBV. And in October 2023, GSK reported positive data from the B-
Together Phase 2b study of bepirovirsen in patients with chronic HBV infection following sequential treatment with pegylated 
interferon. Bepirovirsen demonstrated a favorable safety and tolerability profile in these studies.  
 
The FDA and Japanese Ministry of Health, Labour and Welfare, or MHLW, granted bepirovirsen Fast Track designation and 
SENKU (formerly known as SAKIGAKE) designation, respectively, for the treatment of patients with chronic HBV infection.  
 
Sefaxersen (IgAN) (RO7434656) – Sefaxersen (formerly IONIS-FB-LRx) is an investigational RNA-targeted medicine we 
designed to reduce the production of complement factor B, or FB, and to lower activation of the alternative complement pathway. 
Genetic association studies have shown that overaction of the alternative complement pathway has been associated with the 
development of several complement-mediated diseases, including immunoglobulin A nephropathy, or IgAN. IgAN is one of the most 
common causes of inflammation that impairs the filtering ability of kidneys and is an important cause of chronic kidney disease and 
kidney failure. Also known as Berger’s disease, IgAN is characterized by deposits of IgA in the kidneys, resulting in inflammation 
and tissue damage. Our partner, Roche, is responsible for ongoing development and commercialization of sefaxersen worldwide. 
 
In April 2023, Roche initiated a placebo-controlled Phase 3 study of sefaxersen, called IMAGINATION, in patients with 
IgAN designed to assess the efficacy, safety and tolerability of sefaxersen. 
 
We reported positive results from a Phase 2 open-label study of sefaxersen in patients with IgAN, demonstrating robust and 
sustained reductions in complement FB and other key measures of the alternative complement pathway. Sefaxersen treatment also 
resulted in sustained reductions in proteinuria with patients maintaining kidney function, as measured by estimated glomerular 
filtration rate, or eGFR, during six months of treatment. Sefaxersen demonstrated a favorable safety and tolerability profile in the 
study. 
 
 
 
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Ulefnersen (FUS) – Ulefnersen is an investigational RNA-targeted medicine we designed to reduce the production of the 
fused in sarcoma, or FUS, protein to treat people with Amyotrophic lateral sclerosis, or ALS, caused by mutations in the FUS gene. 
Because antisense-mediated reduction of mutant FUS protein in a FUS-ALS mouse model demonstrated the ability to prevent motor 
neuron loss, it is hypothesized that reduction of FUS protein will reverse or prevent disease progression in FUS-ALS patients. FUS-
ALS is a rare, fatal, neurodegenerative disorder characterized by muscle weakness, loss of movement, and difficulty breathing and 
swallowing, resulting in a severely declining quality of life and eventually death. Current treatment options are extremely limited, with 
no medicines that significantly slow disease progression. Our partner, Otsuka, is responsible for global regulatory and 
commercialization activities, and costs for ulefnersen. 
  
In April 2021, we initiated a Phase 3 study of ulefnersen in patients with FUS-ALS designed to assess the efficacy, safety and 
tolerability of ulefnersen. 
  
The FDA and EMA granted Orphan Drug designation to ulefnersen. 
 
Our Innovative Mid-Stage Pipeline of Investigational Medicines  
 
We also have a rich mid-stage pipeline with numerous potentially transformational investigational medicines, including both 
Ionis-owned and partnered therapies. The table below lists our medicines in mid-stage development. For further information on our 
collaboration agreements, refer to the section titled, Collaborative Arrangements. 
 
 
 
Our Technology 
 
For three decades through our innovations in science and technology, we have enhanced the profiles of RNA-targeted 
medicines in addition to advancing new approaches in genetic medicine. Our recent technology advancements have enabled us to 
advance programs with the potential for extended dosing and delivery to new tissues, such as muscle. We have also added capabilities 
to utilize small interfering RNA, or siRNA, and potentially gene editing in addition to our novel antisense technology, which gives us 
the potential to deliver medicines to a greater number of people living with serious diseases.  
 
 
 
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Overview of Ionis’ Technology 
  
All of the medicines currently in our clinical pipeline use our antisense technology — an innovative platform for discovering 
first-in-class and/or best-in-class medicines. Antisense medicines target RNA, the intermediary that conveys genetic information from 
a gene to the protein synthesis machinery in the cell. By targeting RNA instead of proteins, we can use antisense technology to 
increase, decrease or alter the production of specific proteins. Most of our antisense medicines are designed to bind to mRNAs and 
inhibit the production of disease-causing proteins. Examples of these include WAINUA, TRYNGOLZA and donidalorsen. 
SPINRAZA is an example of an antisense medicine that modulates RNA splicing to increase protein production of the SMN protein, 
which is critical to the health and survival of nerve cells in the spinal cord that are responsible for neuro-muscular function. The SMN 
protein is deficient in people with SMA. Our antisense technology is also broadly applicable additional antisense mechanisms 
including decreasing toxic RNAs.  
 
We also now use siRNA technology, in addition to antisense technology to develop new medicines. Like antisense, siRNA 
medicines target RNA, and can decrease the production of specific proteins involved in disease. For each program we work on, we 
choose the approach that demonstrates the best potential product profile for the indication we are pursuing. 
 
Our advanced LIgand-Conjugated Antisense, or LICA, technology is a chemical technology we developed that involves 
attaching a molecule called a ligand that binds with receptors on the surface of cells in a highly specific manner. Because these 
receptors are often found only on certain cell types, LICA allows us to increase effective delivery of our antisense medicines with 
higher specificity to certain cell types that express these receptors relative to non-conjugated antisense medicines. We currently have 
an integrated assessment of data from multiple LICA medicines and clinical programs that demonstrates that our LICA technology for 
liver targets can increase potency by 20-30-fold over our non-LICA antisense medicines. Our LICA medicines have also demonstrated 
consistently favorable safety and tolerability in clinical trials, including in our Phase 3 studies of WAINUA (for ATTRv-PN), 
TRYNGOLZA (for FCS patients) and donidalorsen (for HAE). 
 
Emerging Technology Advancements 
 
Our recent technology advancements have enabled us to create even more potent medicines amenable to new potential targets 
and tissue types. We have also diversified the approaches we can use in designing our medicines to reach more patients with severe 
diseases. Today our medicines and those entering our pipeline utilize our key technology advances, including Bicycle technology, 
siRNA technology and MsPA backbone chemistry. And through our Metagenomi collaboration, we added the potential to use gene 
editing, which modifies DNA.  
 
Mesyl phosphoramidate Backbone Chemistry 
 
We designed our MsPA backbone chemistry to improve both therapeutic index and durability. It does this by increasing 
metabolic stability relative to the other backbone chemistries we utilize. We have also shown it can improve potency in certain 
circumstances and reduce non-specific interactions with proteins that can cause undesirable effects, such as proinflammatory effects. 
We currently have multiple new programs using our MsPA backbone in preclinical development.  
 
Bicycle Collaboration  
 
In 2021, we entered into a collaboration with Bicycle Therapeutics that we expect can expand our LICA platform to target 
both skeletal and cardiac muscle, and potentially deliver medicines across the blood brain barrier. Bicycles are small, bicyclic peptides 
that have high affinity and selectivity for protein targets. Our collaboration with Bicycle allows us to utilize Bicycles that bind 
transferrin receptor 1 to facilitate the tissue specific delivery of oligonucleotide drugs (both antisense and siRNAs). We advanced our 
first program that utilizes Bicycle technology into preclinical development in 2023. 
 
Gene Editing and Metagenomi Collaboration  
 
In 2022, we entered into a collaboration with Metagenomi that leverages our extensive expertise in RNA-targeted 
therapeutics and Metagenomi’s next-generation gene editing systems to pursue a mix of validated and novel genetic targets with the 
goal of discovering and developing new drugs. These targets have the potential to expand therapeutic options for patients.  
 
Gene editing utilizes specific RNA-guided nucleases known as Cas enzymes to precisely and permanently modify a DNA 
sequence. Because of this, gene editing holds the promise of treatments that could provide long-term, potentially permanent, 
therapeutic benefits.  
 
 
 
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Gene editing is highly complementary and synergistic with RNA-targeted therapeutics. Both platforms rely on the same 
nucleic acid hybridization principals to precisely target nucleases to either RNA, in the case of RNase H and siRNA drugs, or to DNA 
in the case of Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR-Cas systems. This enables us to leverage our 
expertise in nucleic acids and modified nucleic acid chemistry with the goal to enhance gene editing’s ability to treat diseases for 
which there are limited treatment options. 
 
Collaborative Arrangements 
 
We have established alliances with a number of leading global pharmaceutical companies. Our partners include the following 
companies, among others: AstraZeneca, Biogen, GSK, Novartis, Otsuka and Roche. Through our partnerships, we have earned both 
commercial revenue and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments and milestone 
payments. We are also eligible to receive royalties and additional milestones under our partnerships. Below, we include the significant 
terms of our collaboration agreements. For additional details, including other financial information, refer to Part IV, Item 15, Note 4, 
Collaborative Arrangements and Licensing Agreements, in the Notes to the Consolidated Financial Statements.  
 
AstraZeneca 
 
WAINUA (Eplontersen) Collaboration 
 
In 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and 
commercialize eplontersen for the treatment of ATTR. The FDA and Health Canada approved eplontersen with the brand name, 
WAINUA, for ATTRv-PN, while the Medicines and Healthcare products Regulatory Agency, or MHRA, approved WAINUA for 
ATTRv-PN in the UK as WAINZUA. Under the agreement, we are jointly developing WAINUA with AstraZeneca worldwide for 
ATTRv-PN and ATTR cardiomyopathy, or ATTR-CM. We are jointly commercializing WAINUA with AstraZeneca in the U.S. We 
granted AstraZeneca exclusive rights to commercialize WAINUA outside the U.S.  
 
The collaboration includes territory-specific development, commercial and medical affairs cost-sharing provisions. 
AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. 
AstraZeneca is responsible for the vast majority of the commercial and medical affairs costs in the U.S. and all costs associated with 
bringing WAINUA to market outside the U.S. 
 
Over the term of the collaboration, we are eligible to receive an upfront payment, development and approval milestone 
payments and sales milestone payments. In addition, we are eligible to receive up to mid-20 percent royalties for sales in the U.S. and 
tiered royalties up to the high teens for sales outside the U.S.  
 
In January 2024, we and AstraZeneca launched WAINUA in the U.S. for the treatment of adults with ATTRv-PN. As a 
result, we began earning royalties from WAINUA sales, which we recognize as commercial revenue in our consolidated statements of 
operations. 
 
From inception through December 31, 2024, we have generated more than $520 million in payments under this collaboration, 
including milestone payments for the approval of WAINUA in the U.S. and UK, revenue we earned from cost sharing provisions and 
royalties. 
 
Cardiovascular, Renal and Metabolic Collaboration 
 
We also have a collaboration with AstraZeneca focused on discovering and developing treatments for cardiovascular, renal 
and metabolic diseases, which we formed in 2015. Under our collaboration, AstraZeneca has licensed multiple medicines from us. 
AstraZeneca is responsible for global development, regulatory and commercialization activities and costs for each of the medicines it 
has licensed from us. 
 
Over the term of the collaboration, we are eligible to receive an upfront payment, license fees, development milestone 
payments, regulatory milestone payments and sales milestone payments. In addition, we are eligible to receive tiered royalties up to 10 
percent on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From 
inception through December 31, 2024, we have generated more than $370 million in payments under this collaboration. 
 
 
 
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Biogen 
 
Marketed Medicines 
 
SPINRAZA 
 
In 2012, we entered into a collaboration agreement with Biogen to develop and commercialize SPINRAZA. We are receiving 
tiered royalties ranging from 11 percent to 15 percent on sales of SPINRAZA. Under our agreement, Biogen is responsible for global 
development, regulatory and commercialization activities and costs for SPINRAZA. From inception through December 31, 2024, we 
recognized more than $2.3 billion in total revenue under this collaboration, including approximately $1.9 billion in revenue from 
SPINRAZA royalties and more than $425 million in R&D revenue. 
 
We have exclusively in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of 
Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of 
SPINRAZA.  
 
QALSODY 
 
In 2018, Biogen exercised its option to license QALSODY from us. We are receiving tiered royalties ranging from 11 
percent to 15 percent on net sales of QALSODY. Under our agreement, Biogen is responsible for global development, regulatory and 
commercialization activities and costs for QALSODY. Biogen is also evaluating QALSODY as a potential treatment for 
presymptomatic SOD1-ALS patients in the ongoing ATLAS study. From inception through December 31, 2024, we recognized more 
than $110 million in total revenue under this collaboration, including approximately $4 million in revenue from QALSODY royalties 
and $108 million in R&D revenue. 
 
New antisense medicines for the treatment of SMA 
 
In 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of 
SMA. In 2021, Biogen exercised its option to license ION306. Biogen is solely responsible for the costs and expenses related to the 
development, manufacturing and potential future commercialization of ION306 following the option exercise. We will receive 
development and regulatory milestone payments from Biogen if new medicines, including ION306, advance towards marketing 
approval.  
 
Over the term of this collaboration, we are eligible to receive development, regulatory and sales milestone payments. In 
addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent range on net sales from any product that 
Biogen successfully commercializes under this collaboration. From inception through December 31, 2024, we have generated $85 
million in payments under this collaboration. 
 
Neurology Collaborations 
 
We have multiple collaborations with Biogen focused on using antisense technology to advance the treatment of neurological 
disorders, including our 2018 and 2012 neurology collaborations. Under these collaborations, Biogen gained exclusive rights to the 
use of our antisense technology to develop therapies for certain neurological diseases and the option to license certain medicines 
resulting from these collaborations. If Biogen exercises its option to license a medicine, it will assume global development, regulatory 
and commercialization responsibilities and costs for that medicine.  
 
For each medicine under these collaborations, we are eligible to receive a license fee, development milestone payments and 
regulatory milestone payments. In addition, we are eligible to receive tiered royalties up to the 20 percent range on net sales from any 
products that Biogen successfully commercializes under these collaborations. We are currently advancing multiple programs under 
this collaboration. From inception through December 31, 2024, we have generated more than $1.3 billion in payments under these 
collaborations.  
 
GSK 
 
In 2010, we entered into a collaboration with GSK using our antisense drug discovery platform to discover and develop new 
medicines against targets for serious and rare diseases, including infectious diseases. Under our collaboration, GSK is developing 
bepirovirsen for the treatment of chronic HBV infection. In 2019, following positive Phase 2 results, GSK licensed our HBV program. 
GSK is responsible for all global development, regulatory and commercialization activities and costs for the HBV program.  
 
 
 
14

Over the term of the collaboration, we are eligible to receive an upfront payment, a license fee, development milestone 
payments, regulatory milestone payments and sales milestone payments if GSK successfully develops and commercializes 
bepirovirsen. In addition, we are eligible to receive tiered royalties up to the low-teens on net sales of bepirovirsen. From inception 
through December 31, 2024, we have generated more than $105 million in payments under the HBV program collaboration. 
 
Novartis  
 
Pelacarsen Collaboration 
 
In 2017, we initiated a collaboration with Novartis to develop and commercialize pelacarsen for patients with elevated Lp(a) 
and CVD. Novartis is responsible for conducting and funding development and regulatory activities for pelacarsen, including a global 
Phase 3 cardiovascular outcomes study that Novartis initiated in 2019.  
 
Over the term of the collaboration, we are eligible to receive an upfront payment, a license fee, a development milestone 
payment, regulatory milestone payments and sales milestone payments. We are also eligible to receive tiered royalties in the mid-teens 
to low 20 percent range on net sales of pelacarsen. From inception through December 31, 2024, we have generated more than $275 
million in payments under this collaboration.  
 
New Medicine for the Treatment of Lp(a)-Driven Cardiovascular Disease 
 
In 2023, we entered into a collaboration and license agreement with Novartis for the discovery, development and 
commercialization of a novel medicine for patients with Lp(a)-driven cardiovascular disease, or CVD. Novartis is solely responsible 
for the development, manufacturing and potential commercialization of the next generation Lp(a) medicine.  
 
Over the term of the collaboration, we are eligible to receive an upfront payment, development milestone payments, 
regulatory milestone payments and sales milestone payments. In addition, we are eligible to receive tiered royalties ranging from 10 
percent to 20 percent on net sales. From inception through December 31, 2024, we have generated more than $65 million in payments 
under this collaboration. 
 
Roche 
 
Sefaxersen for Complement-Mediated Diseases 
 
In 2018, we entered into an agreement with Roche to develop sefaxersen for the treatment of complement-mediated diseases, 
including IgAN, and geographic atrophy, or GA. In April 2023, Roche initiated a Phase 3 study of sefaxersen in patients with IgAN.  
 
After positive data from a Phase 2 clinical study in patients with IgAN, Roche licensed sefaxersen in 2022. As a result, Roche 
is responsible for global development, regulatory and commercialization activities, and costs for sefaxersen. 
 
In July 2024, Roche discontinued development of sefaxersen for the treatment of GA, the advanced stage of dry age-related 
macular degeneration, following the completion of the Phase 2 study, which showed a favorable safety profile and target engagement, 
but insufficient efficacy to advance into Phase 3 development.   
 
Over the term of the collaboration, we are eligible to receive a license fee, development milestone payments, regulatory 
milestone payments and sales milestone payments. We are also eligible to receive tiered royalties from the high teens to 20 percent on 
net sales. From inception through December 31, 2024, we have generated more than $140 million in payments under this 
collaboration. 
 
Huntington’s Disease 
 
In 2013, we entered into an agreement with Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd, collectively Roche, to 
develop treatments for Huntington’s disease, or HD, based on our antisense technology. Under the agreement, we discovered and 
developed tominersen, an investigational antisense medicine targeting HTT protein. We developed tominersen through completion of 
our Phase 1/2 clinical study in people with early-stage HD. In 2017, upon completion of the Phase 1/2 study, Roche exercised its 
option to license tominersen. As a result, Roche is responsible for all global development, regulatory and commercialization activities 
and costs for tominersen.  
 
 
 
15

Over the term of the collaboration, we are eligible to receive a license fee, development milestone payments, regulatory 
milestone payments and sales milestone payments as tominersen advances. In addition, we are eligible to receive milestone payments 
for each additional medicine successfully developed. We are also eligible to receive tiered royalties up to the mid-teens on net sales of 
any product resulting from this collaboration. From inception through December 31, 2024, we have generated more than $150 million  
in payments under this collaboration.  
 
RNA-Targeting Medicines for Alzheimer's Disease and Huntington's Disease 
 
In September 2023, we entered into an agreement with Roche to develop two undisclosed early-stage programs for RNA-
targeting investigational medicines for the treatment of Alzheimer’s disease, or AD, and HD. Under the agreement, we are responsible 
for advancing the two programs through preclinical studies and Roche is responsible for clinical development, manufacturing and 
commercialization of the medicines. 
 
Over the term of the collaboration, we are eligible to receive an upfront payment, development milestone payments and sales 
milestone payments. In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales. From inception through 
December 31, 2024, we have generated more than $60 million in payments under this collaboration. 
 
Commercialization Partnerships 
 
Otsuka 
 
In December 2023, we entered into an agreement with Otsuka Pharmaceutical Co., Ltd., or Otsuka, to commercialize 
donidalorsen in Europe. In the second quarter of 2024, we expanded the agreement to include commercialization rights for 
donidalorsen in the Asia-Pacific region. We are responsible for the ongoing development of donidalorsen. 
 
In November 2024, we entered into an agreement with Otsuka to commercialize ulefnersen worldwide. We are responsible 
for the ongoing development of ulefnersen. 
 
Over the term of the collaborations, we are eligible to receive upfront payments, regulatory milestone payments and sales 
milestone payments. In addition, we are eligible to receive tiered royalties up to 30 percent on net sales. From inception through 
December 31, 2024, we have generated more than $110 million in payments under these collaborations. 
 
PTC Therapeutics 
 
In August 2018, we entered into an exclusive license agreement with PTC Therapeutics to commercialize TEGSEDI and 
WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from 
PTC in the mid-20 percent range on net sales for each medicine. In December 2021 and September 2023, we started receiving 
royalties from PTC for TEGSEDI and WAYLIVRA sales, respectively. From inception through December 31, 2024, we have 
generated more than $55 million in payments under this collaboration. 
 
Swedish Orphan Biovitrum AB (Sobi) 
 
We began commercializing TEGSEDI and WAYLIVRA in Europe in January 2021 and TEGSEDI in North America in 
April 2021 through distribution agreements with Sobi. Under our agreements, we are responsible for supplying finished goods 
inventory to Sobi and Sobi is responsible for selling each medicine to the end customer. In exchange, we earn a distribution fee on net 
sales from Sobi for each medicine. In October 2023, our agreement for TEGSEDI in North America was terminated and we 
discontinued TEGSEDI in North America in 2024. From inception through December 31, 2024, we have generated more than $60 
million in payments under this collaboration. 
 
Theratechnologies 
 
In December 2024, we entered into an agreement with Theratechnologies, Inc. to commercialize donidalorsen and olezarsen 
in Canada. We are responsible for the ongoing development of donidalorsen and olezarsen. 
 
 
 
16

Technology Enhancement Collaborations 
 
Bicycle Therapeutics 
 
In 2020, we entered into a collaboration agreement with Bicycle Therapeutics, or Bicycle, and obtained an option to license 
its peptide technology that we expect can expand our LICA platform to target both skeletal and cardiac muscle, and potentially deliver 
medicines across the blood brain barrier. In 2021, we exercised our option to license Bicycle's technology. Our payment to Bicycle for 
licensing its technology included an equity investment in Bicycle. In addition, we will pay Bicycle milestone payments and royalties 
that are contingent on the achievement of certain development, regulatory and sales events. 
 
Metagenomi 
 
In 2022, we entered into a collaboration and license agreement with Metagenomi to research, develop and commercialize 
investigational medicines for up to four initial genetic targets, and, upon the achievement of certain development milestones, four 
additional genetic targets using gene editing technologies. As a result, we paid Metagenomi to license its technologies and will pay 
Metagenomi certain fees for the selection of genetic targets. In addition, we will pay Metagenomi milestone payments and royalties 
that are contingent on the achievement of certain development, regulatory and sales events. We will also reimburse Metagenomi for 
certain of its costs in conducting its research and drug discovery activities under the collaboration.  
 
Vect-Horus 
 
In December 2023, we entered into a license agreement with Vect-Horus to provide us with a worldwide, exclusive license 
for a specified number of targets using Vect-Horus’ platform technology “VECTrans” for systemic delivery of RNA-targeted 
therapeutics that may cross the blood-brain barrier and address targets in the central nervous system. We will pay Vect-Horus 
milestone payments and royalties that are contingent on the achievement of certain development, regulatory and sales events. 
 
Other Agreements 
 
Alnylam Pharmaceuticals, Inc. 
 
Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate 
relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alnylam 
having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, we are eligible to earn 
a technology access fee, participate in fees from Alnylam’s partnering programs and earn future milestone and royalty payments from 
Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a limited number of double-
stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively 
licensed to us its patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry to research, develop and 
commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We 
also received a license to develop and commercialize double-stranded RNAi therapeutics targeting a limited number of therapeutic 
targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual 
property. Under this alliance, we and Alnylam each obtained exclusive license rights to four therapeutic programs. Alnylam granted us 
an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for 
oligonucleotides against four targets, including FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, 
royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides 
against four other targets. Alnylam also granted us a royalty-bearing, non-exclusive license to new platform technology arising from 
May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive 
license to new platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics. 
 
Manufacturing 
  
We manufacture most of the active pharmaceutical ingredients, or APIs, we use for our research and development, or R&D, 
activities ourselves. We have also manufactured API and commercial supply for our approved medicines. We have dedicated 
significant resources to develop ways to improve manufacturing efficiency and capacity. Since we can use variants of the same 
nucleotide building blocks and the same type of equipment to produce our oligonucleotide medicines, we found that the same 
techniques we used to efficiently manufacture one oligonucleotide medicine could help improve the manufacturing processes for our 
other medicines. By developing several proprietary chemical processes to scale up our manufacturing capabilities, we have greatly 
reduced the cost of producing oligonucleotide medicines. For example, we have significantly reduced the cost of raw materials 
through improved yield efficiency, while at the same time increasing our capacity to make our medicines. Through both our internal 
research and development programs and collaborations with outside vendors, we may achieve even greater efficiency and further cost 
reductions. 
 
 
 
17

Our manufacturing facility is located in a 26,800 square foot building in Carlsbad, California. We purchased this building in 
2017. In addition, we have a 25,800 square foot building that houses support functions for our manufacturing activities. We lease this 
facility under a lease that has a term ending in August 2026 with an option to extend the lease for an additional five-year period. Our 
manufacturing facility is subject to periodic inspections by the FDA and foreign equivalents to ensure that it is operating in 
compliance with current Good Manufacturing Practices, or cGMP, requirements.  
 
As part of our collaborations, we may agree to manufacture clinical trial material and/or commercial drug supply for our 
partners. For example, in the past we have manufactured clinical trial material for AstraZeneca, Biogen, GSK, Roche, and Novartis 
and commercial drug supply for Biogen.  
 
We believe we have sufficient manufacturing capacity at our own facility or at contract manufacturing organizations, or 
CMOs, to meet our current internal research, development and potential commercial needs, as well as our obligations under existing 
agreements with our partners for research, development and commercial material. We and/or our CMOs manufacture process 
performance qualification batches and pre-approval inspection batches of our Phase 3 medicines that may be used for regulatory 
submissions and, pending regulatory approval, commercial sale. We believe our current network of CMOs are capable of providing 
sufficient quantities to meet anticipated commercial demands. Additionally, we continue to evaluate relationships with additional 
suppliers to increase overall capacity and diversify our supply chain. We plan to leverage our relationships with CMOs to maintain 
long-term supply at competitive prices in the future. While we believe that there are alternate sources of supply that can satisfy our 
commercial requirements, it is possible that identifying and establishing relationships with such sources, if necessary, could result in 
significant delay or material additional costs. We also could experience a disruption in supply from our current CMOs.  
 
CMOs are subject to the FDA’s cGMP requirements and other rules and regulations prescribed by foreign regulatory 
authorities. We depend on our CMOs for continued compliance with cGMP requirements and applicable foreign standards. 
 
Specifically, we have the following in place for our commercial medicines and our late-stage medicines. 
 
TRYNGOLZA/Olezarsen 
 
For TRYNGOLZA’s commercial drug supply, we are using CMOs to produce API and finished goods.  For the ongoing 
olezarsen clinical studies, we and/or our CMOs have supplied the API and the finished drug product. We intend to leverage our 
relationships with CMOs to meet and maintain long-term commercial supply at competitive prices in the future. We plan to 
accomplish this through a combination of maintaining adequate levels of safety stock and increasing the batch sizes to support future 
indications. 
 
WAINUA/Eplontersen 
 
AstraZeneca is responsible for WAINUA's commercial drug supply. Our CMOs supplied the API and the finished drug 
product for WAINUA’s Phase 3 program. Pursuant to our collaboration with AstraZeneca, we will supply WAINUA using CMOs for 
the ongoing clinical trials.  
 
SPINRAZA 
 
Biogen is responsible for SPINRAZA drug supply. 
 
QALSODY 
 
Biogen is responsible for QALSODY drug supply. 
 
TEGSEDI and WAYLIVRA 
 
For TEGSEDI’s commercial drug supply, we are using CMOs to produce API and finished goods for ourselves, Sobi and 
PTC. For WAYLIVRA’s commercial drug supply, we are using API that we have manufactured and CMOs to produce the finished 
goods. 
 
Donidalorsen, Zilganersen, Ulefnersen 
 
We and/or our CMOs have supplied the API and the finished drug product for donidalorsen, zilganersen and ulefnersen that 
we believe will be sufficient through the completion of the Phase 3 programs for each medicine, including process performance 
qualification batches. 
 
 
 
18

ION582 
 
We supplied API and drug product for the ION582 Phase 1 and Phase 2 programs and will continue to supply drug for further 
clinical programs. 
 
Pelacarsen 
 
We supplied API and finished drug product for pelacarsen’s Phase 3 program. Pursuant to our collaboration with Novartis, 
Novartis is responsible for any further pelacarsen drug supply. 
 
Bepirovirsen 
 
We supplied API for bepirovirsen’s Phase 1 and Phase 2 programs. Pursuant to our collaboration with GSK, GSK is 
responsible for any further bepirovirsen drug supply. 
 
Sefaxersen (IONIS-FB-LRx) 
 
We supplied API for the sefaxersen Phase 1 and Phase 2 IgAN programs. Pursuant to our collaboration with Roche, Roche is 
responsible for any further drug supply for sefaxersen. 
 
Commercial Operations 
 
We have established sales and marketing capabilities to support our commercial launch of WAINUA and TRYNGOLZA in 
the U.S. and anticipated near-term commercial launch of donidalorsen. We began with our co-commercialization partnership with 
AstraZeneca for WAINUA in which we combine our experience in RNA-targeted therapeutics and deep knowledge of the TTR 
amyloidosis market with AstraZeneca's global scale in drug development and commercialization to enable market penetration for the 
benefit of patients.  
 
With our first independent commercial launch of TRYNGOLZA underway, we have entered a new chapter as a fully 
integrated commercial-stage biotechnology company. We have been refining our portfolio strategy and recruiting experienced 
professionals with relevant backgrounds in sales, marketing, patient education, market access, portfolio planning and market insight, 
new product commercial strategy and commercial operations in the pharmaceutical industry. We are focused on developing a unique 
and innovative approach to bring our medicines to patients living with serious diseases. We have built core capabilities and a 
commercial platform with the ability to scale as needed to meet our current and future commercialization needs. In addition, we 
established our TRYNGOLZA field sales team during 2024 and plan to build additional field teams as we approach each of our 
launches. 
 
Medical Affairs 
 
We have built medical affairs capabilities to disseminate information about our medicines and increase disease awareness 
through various channels of communication with key stakeholders. Our medical affairs function is responsible for funding and 
coordinating investigator-sponsored trials, communicating scientific and clinical information to healthcare providers, medical 
professionals and patients, and managing publications. 
 
Intellectual Proprietary Rights 
  
We rely on patents, trademarks, trade secrets, and proprietary know-how to develop and maintain a competitive position in 
RNA-targeted therapeutics generally and to protect our investment in specific products. To this end, we focus our resources on 
intellectual property, or IP, that drives value for our company.   
 
Product-Specific IP 
  
Each of our medicines is protected worldwide by product-specific patents claiming oligonucleotides having the nucleobase 
sequences and chemical modifications of our medicines; and methods of achieving cellular or clinical endpoints using such 
oligonucleotides. We pursue such patents in significant markets and/or countries for each medicine in development. We also seek to 
maximize patent term. In some cases, the patent term can be extended to recapture a portion of the term lost during regulatory review. 
Expiration dates listed below do not reflect any such extensions. 
 
Commercial products are also protected by trademarks filed throughout the world.     
 
 
 
19

Marketed Products 
 
TRYNGOLZA/Olezarsen and ApoC-III 
 
We believe TRYNGOLZA (olezarsen) is protected from generic competition in the U.S. and Europe until at least 2034. 
Additional patent applications to protect olezarsen in other foreign jurisdictions are being pursued. The table below lists some key 
issued patents protecting olezarsen in the U.S. and Europe. 
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States 
9,163,239 COMPOSITIONS AND METHODS 
FOR MODULATING 
APOLIPOPROTEIN C-III 
EXPRESSION 
2034 
Composition of olezarsen 
United States 
9,593,333 MODULATION OF 
APOLIPOPROTEIN C-III (APOCIII) 
EXPRESSION IN LIPOPROTEIN 
LIPASE DEFICIENT (LPLD) 
POPULATIONS 
2034 
Methods of treating lipoprotein lipase deficiency 
with an apo-CIII specific inhibitor wherein 
triglyceride levels are reduced 
United States 
9,157,082 MODULATION OF 
APOLIPOPROTEIN CIII (APOCIII) 
EXPRESSION 
2032 
Methods of using apo-CIII antisense compounds 
for reducing pancreatitis and chylomicronemia 
and increasing HDL 
Europe 
2991656 COMPOSITIONS AND METHODS 
FOR MODULATING 
APOLIPOPROTEIN C-III 
EXPRESSION 
2034 
Composition of olezarsen 
Europe 
2956176 
MODULATION OF 
APOLIPOPROTEIN C-III (APOCIII) 
EXPRESSION IN LIPOPROTEIN 
LIPASE DEFICIENT (LPLD) 
POPULATIONS 
2034 
Methods of treating lipoprotein lipase deficiency 
with an apo-CIII specific inhibitor wherein 
triglyceride levels are reduced 
Europe 
3357497 
MODULATION OF 
APOLIPOPROTEIN CIII (APOCIII) 
EXPRESSION 
2032 
Methods of using apo-CIII antisense compounds 
for reducing pancreatitis and chylomicronemia 
and increasing HDL 
Europe 
4119569 
CONJUGATED ANTISENSE 
COMPOUNDS FOR USE IN 
THERAPY 
2036 
Methods of administering olezarsen at identified 
doses 
 
Trademark 
 
The name “TRYNGOLZA” is protected by trademarks throughout the world.   
 
WAINUA/WAINZUA/Eplontersen and Transthyretin 
 
Patents 
 
We believe WAINUA/WAINZUA (eplontersen) is protected from generic competition in the U.S. and Europe until at least 
2034. Additional patent applications to protect WAINUA/WAINZUA in other foreign jurisdictions are being pursued. The table 
below lists some key issued patents protecting WAINUA/WAINZUA in the U.S. and Europe: 
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States 10,683,499 COMPOSITIONS AND METHODS 
FOR MODULATING TTR 
EXPRESSION 
2034 
Composition of eplontersen 
Europe 
3524680 COMPOSITIONS AND METHODS 
FOR MODULATING TTR 
EXPRESSION 
2034 
Composition of eplontersen 
 
 
 
20

Trademarks 
 
The names “WAINUA” and “WAINZUA” are protected by trademarks owned by our commercial partner Astra Zeneca.  
 
SPINRAZA and Survival Motor Neuron 2 
 
Patents 
 
We believe SPINRAZA (nusinersen) is protected from generic competition in the U.S. until at least 2035 and in Europe until 
at least 2030 by a suite of patents. These issued patents include: (i) patents licensed from the University of Massachusetts drawn to 
antisense compounds having the sequence of SPINRAZA, independent of chemical modification, and uses of such compounds for 
treating SMA, (ii) joint patents with Cold Spring Harbor Laboratory claiming fully modified 2’-MOE compounds targeting SMN2, 
including the precise composition of matter of SPINRAZA and methods of using such compositions; and (iii) dosing and therapeutic 
methods of using such compounds and compositions. With Biogen’s license of SPINRAZA, we assigned our interest in these patents 
to Biogen. The table below lists some key issued patents protecting SPINRAZA in the U.S. and Europe: 
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States 10,266,822 SPINAL MUSCULAR ATROPHY 
(SMA) TREATMENT VIA 
TARGETING OF SMN2 SPLICE SITE 
INHIBITORY SEQUENCES 
2025 
Methods of increasing exon-7 containing SMN2 
mRNA in a cell using an oligonucleotide having 
the sequence of SPINRAZA 
United States  
8,110,560  SPINAL MUSCULAR ATROPHY 
(SMA) TREATMENT VIA 
TARGETING OF SMN2 SPLICE SITE 
INHIBITORY SEQUENCES 
 
2025 
 Methods of using antisense oligonucleotides 
having sequence of SPINRAZA to alter splicing 
of SMN2 and/or to treat SMA 
Europe 
 
1910395 
 
COMPOSITIONS AND METHODS 
FOR MODULATION OF SMN2 
SPLICING 
 
2026 
 
Sequence and chemistry (full 2’-MOE) of 
SPINRAZA  
Europe 
3308788 
COMPOSITIONS AND METHODS 
FOR MODULATION OF SMN2 
SPLICING 
2026 
Pharmaceutical compositions that include 
SPINRAZA 
United States 
 
7,838,657 
 
SPINAL MUSCULAR ATROPHY 
(SMA) TREATMENT VIA 
TARGETING OF SMN2 SPLICE SITE 
INHIBITORY SEQUENCES 
 
2027 
 
Oligonucleotides having sequence of SPINRAZA 
United States 
 
8,361,977 
 
COMPOSITIONS AND METHODS 
FOR MODULATION OF SMN2 
SPLICING 
 
2030 
 
Sequence and chemistry (full 2’-MOE) of 
SPINRAZA  
United States 
8,980,853 COMPOSITIONS AND METHODS 
FOR MODULATION OF SMN2 
SPLICING IN A SUBJECT 
2030 
Methods of administering SPINRAZA 
United States 
9,717,750 COMPOSITIONS AND METHODS 
FOR MODULATION OF SMN2 
SPLICING IN A SUBJECT 
2030 
Methods of administering SPINRAZA to a 
patient  
Europe 
3449926 
COMPOSITIONS AND METHODS 
FOR MODULATION OF SMN2 
SPLICING IN A SUBJECT 
2030 
Pharmaceutical compositions that include 
SPINRAZA for treating SMA 
Europe 
3305302 
COMPOSITIONS AND METHODS 
FOR MODULATION OF SMN2 
SPLICING IN A SUBJECT 
2030 
Antisense compounds including SPINRAZA for 
treating SMA 
United States 
9,926,559 COMPOSITIONS AND METHODS 
FOR MODULATION OF SMN2 
SPLICING IN A SUBJECT 
2034 
SPINRAZA doses for treating SMA 
United States 10,436,802 METHODS FOR TREATING SPINAL 
MUSCULAR ATROPHY 
2035 
SPINRAZA dosing regimen for treating SMA 
 
 
 
21

Trademarks 
 
The name “SPINRAZA” is protected throughout the world by trademarks owned by our commercial partner Biogen.  
 
QALSODY and SOD-1 
 
Patents 
 
We believe QALSODY is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent 
applications designed to protect QALSODY in other foreign jurisdictions are being pursued. With Biogen’s license of QALSODY, we 
assigned our interest in these patents to Biogen. The table below lists some key issued patents protecting QALSODY in the U.S. and 
Europe: 
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States 
 
10,385,341 
 
COMPOSITIONS FOR MODULATING 
SOD-1 EXPRESSION 
2035 
Composition of QALSODY 
United States 
 
10,669,546 
 
COMPOSITIONS FOR MODULATING 
SOD-1 EXPRESSION 
2035 
Methods of treating a SOD-1 associated 
neurodegenerative disorder by administering 
QALSODY 
United States 10,968,453 COMPOSITIONS FOR MODULATING 
SOD-1 EXPRESSION 
2035 
Methods of treating a SOD-1 associated 
neurodegenerative disorder by administering a 
pharmaceutical composition of QALSODY 
Europe 
3126499 
COMPOSITIONS FOR MODULATING 
SOD-1 EXPRESSION 
2035 
Composition of QALSODY 
 
Trademarks 
 
The name “QALSODY” is protected throughout the world by trademarks owned by our commercial partner Biogen 
 
TEGSEDI and Transthyretin  
  
Patents 
 
We believe TEGSEDI (inotersen) is protected from generic competition in the U.S. and Europe until at least 2031. The table 
below lists some key issued patents protecting TEGSEDI in the U.S. and Europe: 
 
Jurisdiction Patent No. 
Title 
Expiration 
Description of Claims 
United States  
8,101,743  MODULATION OF 
TRANSTHYRETIN EXPRESSION 
 
2025 
 Antisense sequence and chemistry of TEGSEDI 
United States 
 
8,697,860 
 
DIAGNOSIS AND TREATMENT OF 
DISEASE 
 
2031 
 
Composition of TEGSEDI 
United States 
9,061,044 MODULATION OF 
TRANSTHYRETIN EXPRESSION 
2031 
Sodium salt composition of TEGSEDI 
United States 
9,399,774  MODULATION OF 
TRANSTHYRETIN EXPRESSION 
2031 
Methods of treating transthyretin amyloidosis by 
administering TEGSEDI 
Europe 
2563920 MODULATION OF 
TRANSTHYRETIN EXPRESSION 
2031 
Composition of TEGSEDI 
  
Trademarks 
 
The name “TEGSEDI” is protected by trademark throughout the world.  
 
 
 
22

WAYLIVRA and ApoC-III  
 
Patents 
  
We believe WAYLIVRA (volanesorsen) is protected from generic competition in Europe until at least 2034. We have 
obtained patent claims in the U.S. and Europe drawn to the use of antisense compounds complementary to a broad active region of 
human ApoC-III, including the site targeted by WAYLIVRA. We have also obtained issued patents claiming the specific sequence 
and chemical composition of WAYLIVRA in the U.S. and Europe. The table below lists some key issued patents protecting 
WAYLIVRA in the U.S. and Europe: 
 
Jurisdiction Patent No.
Title 
Expiration 
Description of Claims 
United States 
9,157,082 MODULATION OF 
APOLIPOPROTEIN C-III (APOCIII) 
EXPRESSION 
2032 
Methods of using apo-CIII antisense compounds 
for reducing pancreatitis and chylomicronemia 
and increasing HDL 
United States 
9,593,333 MODULATION OF 
APOLIPOPROTEIN C-III (APOCIII) 
EXPRESSION IN LIPOPROTEIN 
LIPASE DEFICIENT (LPLD) 
POPULATIONS 
2034 
Methods of treating lipoprotein lipase deficiency 
with an apo-CIII specific inhibitor wherein 
triglyceride levels are reduced 
Europe 
2956176 MODULATION OF 
APOLIPOPROTEIN C-III (APOCIII) 
EXPRESSION IN LIPOPROTEIN 
LIPASE DEFICIENT (LPLD) 
POPULATIONS 
2034 
Apo-CIII specific inhibitors including 
WAYLIVRA for treating lipoprotein lipase 
deficiency or FCS 
 
Trademark 
 
The name “WAYLIVRA” is protected by trademark in Europe.  
 
 
Late-Stage Ionis-Owned Programs 
 
Donidalorsen and PKK 
 
We believe donidalorsen is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent 
applications to protect donidalorsen in other foreign jurisdictions are being pursued. The table below lists some key issued patents 
protecting donidalorsen in the U.S. and Europe. 
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States 
9,315,811 METHODS FOR MODULATING 
KALLIKREIN (KLKB1) EXPRESSION 
2032 
Methods of treating HAE 
Europe 
2717923 METHODS FOR MODULATING 
KALLIKREIN (KLKB1) EXPRESSION 
2032 
Compounds for use in treating an inflammatory 
condition, including HAE 
United States 10,294,477 COMPOSITIONS AND METHODS 
FOR MODULATING PKK 
EXPRESSION 
2035 
Composition of donidalorsen 
Europe 
3137091 
COMPOSITIONS AND METHODS 
FOR MODULATING PKK 
EXPRESSION 
2035 
Composition of donidalorsen 
 
 
 
23

Zilganersen and GFAP 
 
We believe zilganersen is protected from generic competition in the U.S. until at least 2041. A patent application designed to 
protect zilganersen from generic competition is being pursued in Europe; a patent issuing from that application would have term until 
at least 2041. The table below lists a key issued patent protecting zilganersen in the U.S. and a pending application in Europe:  
 
Jurisdiction 
Patent No. 
(Patent 
Application No.) 
Title 
Expiration 
Description of Claims 
United States 
11,786,546 
COMPOUNDS AND METHODS 
FOR MODULATING GFAP 
2041 
Composition of zilganersen 
Europe 
(20846055.0) 
COMPOUNDS AND METHODS 
FOR MODULATING GFAP 
2041 
Composition of zilganersen 
 
ION582 and UBE3A 
 
We believe ION582 is protected from generic competition in the U.S. until at least 2040. A patent application designed to 
protect ION582 from generic competition is being pursued in Europe; a patent issuing from that application would have term until at 
least 2040. The table below lists a key issued patent protecting ION582 in the U.S. and Europe:  
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States 
 
 
11,261,446 
COMPOUNDS AND METHODS FOR 
MODULATING UBE3A-ATS 
2040 
Composition of ION582 
United States 
 
 
9,617,539 
MODULATION OF UBE3A-ATS 
EXPRESSION 
2033 
Methods of treating Angelman syndrome with 
an antisense compound targeting a region of 
UBE3A-ATS 
Europe 
 
3770258 
MODULATION OF UBE3A-ATS 
EXPRESSION 
2033 
Oligonucleotides complementary to a region of 
UBE3A-ATS for use in treating Angelman 
syndrome 
 
Late-Stage Partnered Programs 
 
Bepirovirsen and Hepatitis B Virus 
 
We believe bepirovirsen is protected from generic competition in the U.S. and Europe until at least 2032. Additional patent 
protection designed to protect bepirovirsen in other foreign jurisdictions is being pursued. With GSK’s license of bepirovirsen, we 
assigned our interest in these patents to GSK. The table below lists some key issued patents protecting bepirovirsen in the U.S. and 
Europe:  
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States 
8,642,752 
MODULATION OF HEPATITIS B 
VIRUS (HBV) EXPRESSION 
2032 
Composition of bepirovirsen  
Europe 
 
3505528 
MODULATION OF HEPATITIS B 
VIRUS (HBV) EXPRESSION 
2032 
Composition of bepirovirsen  
 
 
 
24

Pelacarsen and Apo(a)  
 
We believe pelacarsen is protected from generic competition in the U.S. and Europe until at least 2034. Additional patent 
protection designed to protect pelacarsen in other foreign jurisdictions is being pursued. The table below lists some key issued patents 
protecting pelacarsen in the U.S. and Europe:  
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States 
9,574,193 METHODS AND COMPOSITIONS 
FOR MODULATING 
APOLIPOPROTEIN (A) EXPRESSION 
2033 
Methods of lowering Apo(a) and/or Lp(a) levels 
with an oligonucleotide complementary within 
the nucleotide region of Apo(a) targeted by 
pelacarsen 
United States 
 
10,478,448 METHODS AND COMPOSITIONS 
FOR MODULATING 
APOLIPOPROTEIN (A) EXPRESSION 
2033 
Methods of treating hyperlipidemia with an 
oligonucleotide complementary within the 
nucleotide region of Apo(a) targeted by 
pelacarsen 
United States 
 
9,884,072 METHODS AND COMPOSITIONS 
FOR MODULATING 
APOLIPOPROTEIN (A) EXPRESSION 
2033 
Oligonucleotides complementary within the 
nucleotide region of Apo(a) targeted by 
pelacarsen  
Europe 
2855500 
METHODS AND COMPOSITIONS 
FOR MODULATING 
APOLIPOPROTEIN (A) EXPRESSION 
2033 
Oligonucleotides complementary within the 
nucleotide region of Apo(a) targeted by 
pelacarsen for decreasing Apo(a) expression 
United States 
 
9,181,550 COMPOSITIONS AND METHODS 
FOR MODULATING 
APOLIPOPROTEIN (a) EXPRESSION 
2034 
Composition of pelacarsen 
Europe 
2992009 
COMPOSITIONS AND METHODS 
FOR MODULATING 
APOLIPOPROTEIN (a) EXPRESSION 
2034 
Composition of pelacarsen 
 
Sefaxersen and Factor B 
 
We believe sefaxersen is protected from generic competition in the U.S. and Europe until at least 2035. Additional patent 
protection designed to protect sefaxersen in other foreign jurisdictions is being pursued. The table below lists some key issued patents 
protecting sefaxersen in the U.S. and Europe:  
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
Europe 
 
3043827 
MODULATORS OF COMPLEMENT 
FACTOR B 
2034 
Compound comprising the antisense 
oligonucleotide portion of sefaxersen 
United States 
10,280,423 COMPOSITIONS AND METHODS 
FOR MODULATING COMPLEMENT 
FACTOR B EXPRESSION 
2035 
Composition of sefaxersen 
Europe 
3137596 
COMPOSITIONS AND METHODS 
FOR MODULATING COMPLEMENT 
FACTOR B EXPRESSION 
2035 
Composition of sefaxersen 
 
Ulefnersen and FUS  
  
Patent applications designed to protect ulefnersen from generic competition are being pursued in the U.S. and Europe. Patents 
issued from these applications would have terms until at least 2040. The table below lists some key pending patent applications 
designed to protect ulefnersen in the U.S. and Europe:  
  
Jurisdiction  
Patent 
Application 
No. 
 
Title 
 Expiration  
Description of Claims 
United 
States 
17/613,183 COMPOUNDS AND METHODS FOR 
REDUCING FUS EXPRESSION 
2040 
Composition of ulefnersen 
Europe 
20815459.1 COMPOUNDS AND METHODS FOR 
REDUCING FUS EXPRESSION 
2040 
Composition of ulefnersen 
 
 
 
25

Platform IP 
 
In addition to the IP that provides exclusivity for specific products, we also pursue IP that provides exclusivity for our core 
technology in the field of oligonucleotides and RNA-targeting therapeutics more generally. Our core technology patents include 
claims to chemically modified oligonucleotides as well as designs utilizing these chemical modifications. Because these core claims 
are independent of specific therapeutic target, nucleic acid sequence, or clinical indication, they may reach several products.   
 
Chemically Modified Nucleosides and Oligonucleotides 
  
The most broadly applicable of our patents are those that claim modified nucleosides and oligonucleotides comprising the 
modified nucleosides that we incorporate into our medicines to increase their therapeutic efficacy. The following are some of our 
patents in this category in the U.S. and Europe: 
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States  
7,399,845  6-MODIFIED BICYCLIC NUCLEIC 
ACID ANALOGS 
 
2027 
 cEt nucleosides and oligonucleotides containing 
these nucleoside analogs 
United States  
7,741,457  6-MODIFIED BICYCLIC NUCLEIC 
ACID ANALOGS 
 
2027 
 cEt nucleosides and oligonucleotides containing 
these nucleoside analogs 
United States 
8,022,193 6-MODIFIED BICYCLIC NUCLEIC 
ACID ANALOGS 
2027 
Oligonucleotides containing cEt nucleoside 
analogs 
Europe 
 
1984381  6-MODIFIED BICYCLIC NUCLEIC 
ACID ANALOGS 
 
2027 
 cEt nucleosides and oligonucleotides containing 
these nucleoside analogs 
Europe 
2314594 
6-MODIFIED BICYCLIC NUCLEIC 
ACID ANALOGS 
2027 
Oligonucleotides containing cEt nucleoside 
analogs and methods of use 
United States 
7,569,686 COMPOUNDS AND METHODS FOR 
SYNTHESIS OF BICYCLIC NUCLEIC 
ACID ANALOGS 
2027 
Methods of synthesizing cEt nucleosides 
Europe 
 
2092065  ANTISENSE COMPOUNDS 
 
2027 
 Gapmer oligonucleotides having 2’-modifed and 
LNA nucleosides 
Europe 
2410053 ANTISENSE COMPOUNDS 
2027 
Gapmer oligonucleotides having wings 
comprised of 2’-MOE and bicyclic nucleosides 
Europe 
2410054 
ANTISENSE COMPOUNDS 
2027 
Gapmer oligonucleotides having a 2’-modifed 
nucleoside in the 5’-wing and a bicyclic 
nucleoside in the 3’-wing 
United States 
9,550,988 ANTISENSE COMPOUNDS 
2028 
Gapmer oligonucleotides having BNA 
nucleosides and 2’-MOE nucleosides 
United States 10,493,092 ANTISENSE COMPOUNDS 
2028 
Gapmer oligonucleotides having BNA 
nucleosides and 2’-MOE nucleosides and/or 2’-
OMe nucleosides 
Europe 
3067421 
OLIGOMERIC COMPOUNDS 
COMPRISING BICYCLIC 
NUCLEOTIDES AND USES 
THEREOF 
2032 
Gapmer oligonucleotides having at least one 
bicyclic, one 2’-modified nucleoside and one 2’-
deoxynucleoside 
United States 11,629,348 LINKAGE MODIFIED 
OLIGONUCLEOTIDES AND USES 
THEREOF 
2040 
Gapmer oligonucleotides having 2-4 mesyl 
phosphoramidate internucleoside linkages at 
specified positions in the gap 
 
 
 
26

LIgand-Conjugated Antisense (LICA) Technology  
 
We also have patent claims to new chemistries created to enhance targeting of antisense medicines to specific tissues and 
cells to improve a drug’s properties. We designed our GalNAc LICA medicines to provide an increase in potency for targets in the 
liver. We have successfully obtained issued patent claims covering our LICA technology conjugated to any modified oligonucleotide, 
including gapmers, double-stranded siRNA compounds, and fully modified oligonucleotides. The following patents are some 
examples of our issued patents in this category: 
 
Jurisdiction 
Patent No. 
Title 
Expiration 
Description of Claims 
United States  
9,127,276  CONJUGATED ANTISENSE 
COMPOUNDS AND THEIR USE 
 
2034 
 Preferred THA LICA conjugated to any group of 
nucleosides, including gapmers, double-stranded 
siRNA compounds, and fully modified 
oligonucleotides 
United States  
9,181,549  CONJUGATED ANTISENSE 
COMPOUNDS AND THEIR USE 
 
2034 
 Preferred THA conjugate having our preferred 
linker and cleavable moiety conjugated to any 
oligomeric compound or any nucleoside having a 
2’-MOE modification or a cEt modification 
Europe 
2991661 CONJUGATED ANTISENSE 
COMPOUNDS AND THEIR USE 
2034 
Preferred THA LICA conjugated to any group of 
nucleosides, including gapmers, double-stranded 
siRNA compounds, and fully modified 
oligonucleotides 
 
Manufacturing  
  
We also own patents claiming methods of manufacturing and purifying oligonucleotides and related compounds. These 
patents claim methods for improving oligonucleotide drug manufacturing, including processes for large-scale oligonucleotide 
synthesis and purification. 
 
Government Regulation 
  
Regulation by government authorities in the U.S. and other countries is a significant component in the development, 
manufacture and commercialization of pharmaceutical products and services. In addition to regulations enforced by the FDA and 
relevant foreign regulatory authorities, we are also subject to regulation under the Occupational Safety and Health Act, the 
Environmental Protection Act, the Toxic Substances Control Act, the Resource Conservation and Recovery Act and other present and 
potential future federal, state and local regulations. 
  
Extensive regulation by the U.S. and foreign governmental authorities governs the development, manufacture and sale of our 
medicines. In particular, our medicines are subject to a number of approval requirements by the FDA in the U.S. under the Federal 
Food, Drug and Cosmetic Act, or FDCA, and other laws and by comparable agencies in those foreign countries in which we conduct 
business. The FDCA and other various federal, state and foreign statutes govern or influence the research, testing, manufacture, safety, 
labeling, storage, recordkeeping, approval, promotion, marketing, distribution, post-approval monitoring and reporting, sampling, 
quality, and import and export of our medicines. State, local, and other authorities also regulate pharmaceutical manufacturing 
facilities and procedures. 
  
Our manufacturing facility and our CMOs are subject to periodic inspection by the FDA and other foreign equivalents to 
ensure that they are operating in compliance with cGMP requirements. In addition, marketing authorization for each new medicine 
may require a rigorous manufacturing pre-approval inspection by regulatory authorities. Post approval, there are strict regulations 
regarding changes to the manufacturing process, and, depending on the significance of the change, changes may require prior FDA 
approval. FDA regulations also require investigation and correction of any deviations from cGMP and impose reporting and 
documentation requirements upon us and any third-party manufacturers that we may decide to use. 
  
 
 
27

The FDA must approve any new medicine before a manufacturer can market it in the U.S. In order to obtain approval, we and 
our partners must complete clinical studies and prepare and submit an NDA to the FDA. If the FDA approves a medicine, it will issue 
an approval letter authorizing commercial marketing of the medicine and may require a risk evaluation and mitigation strategy, or 
REMS, to help ensure the benefits of the medicine outweigh the potential risks. The requirements for REMS can materially affect the 
potential market and profitability of our medicines. In foreign jurisdictions, the drug approval process is similarly demanding. 
 
Pricing and Reimbursement 
 
For any approved medicine, domestic and foreign sales of the medicine depend, in part, on the availability and amount of 
coverage and adequate reimbursement by third-party payers, including governments and private health plans. The process for 
determining whether a payer will provide coverage for a product may be separate from the process for setting the reimbursement rate 
that the payer will pay for the product, or procedures that utilize such product. Private health plans may seek to manage cost and use of 
our medicines by implementing coverage and reimbursement limitations. For example, third-party payers may limit coverage to 
specific products on an approved list, or formulary, which might not include all FDA-approved products for a particular indication. 
Moreover, a payer's decision to provide coverage for a medicine does not imply that an adequate reimbursement rate will be approved. 
Additionally, coverage and reimbursement for drugs can differ significantly from payer to payer. One third-party payer's decision to 
cover a particular medicine does not ensure that other payers will also provide coverage for the medicine or will provide coverage at 
an adequate reimbursement rate.  
 
Third-party payers are increasingly challenging the price and examining the medical necessity and cost-effectiveness of 
medicines and services, in addition to their safety and efficacy. To obtain coverage and reimbursement for any medicine that might be 
approved for sale, we may need to conduct expensive pharmacoeconomic studies to demonstrate the medical necessity and cost-
effectiveness of our medicine. These studies will be in addition to the studies required to obtain regulatory approvals. If third-party 
payers do not consider a medicine to be cost-effective compared to other available therapies, they may not cover the medicine after 
approval as a benefit under their plans or, if they do, the level of payment may not be sufficient to sell such medicine at a profit. 
 
In certain jurisdictions, governments may also regulate or influence coverage, reimbursement and/or pricing of our medicines 
to control cost or affect use. In the European community, governments influence the price of drugs through their pricing and 
reimbursement rules and control of national health care systems that fund a large part of the cost of those medicines to consumers. 
Some jurisdictions operate positive and negative list systems under which medicines may only be marketed once a reimbursement 
price has been agreed to by the government. To obtain reimbursement or pricing approval, some of these countries may require the 
completion of clinical studies that compare the cost effectiveness of a particular drug candidate to currently available therapies. Other 
member states allow companies to fix their own prices for medicines but monitor and control company profits. 
 
The marketability of any medicine for which we receive regulatory approval for commercial sale may suffer if the 
government or third-party payers fail to provide adequate coverage and reimbursement. In addition, the focus on cost containment 
measures in the U.S. and other countries has increased and we expect will continue to increase the pressure on pharmaceutical pricing. 
Coverage policies and third-party reimbursement rates may change at any time. Even if we attain favorable coverage and 
reimbursement status for one or more medicines for which we receive regulatory approval, less favorable coverage policies and 
reimbursement rates may be implemented in the future. 
 
Healthcare Reform 
 
Both the federal and state governments in the U.S. and foreign governments continue to propose and pass new legislation and 
regulations designed to contain or reduce the cost of healthcare.  
 
 
 
28

There has also been heightened governmental scrutiny over the manner in which manufacturers set prices for their marketed 
products, which has resulted in efforts to bring more transparency to drug pricing, review the relationship between pricing and 
manufacturer patient programs, and reform government program reimbursement methodologies for medicines. For example, in August 
2022, the Inflation Reduction Act of 2022, or the IRA, was signed into law, which includes key actions aimed at reducing the costs of 
prescription drugs and allows HHS to negotiate the price of certain single-source drugs covered under Medicare and establish a price 
cap on such drugs, known as the Maximum Fair Price. There are important exemptions to the Maximum Fair Price, including for 
medications that are orphan drug designated and approved for only one rare disease, and drugs with low Medicare spend as defined by 
the Centers for Medicare & Medicaid Services.  The IRA, among other things, (1) directs the U.S. Department of Health and Human 
Services, or HHS, to negotiate, through a negotiation program, the price of certain single-source drugs and biologics that have been on 
the market for at least seven years covered under Medicare, or the Medicare Drug Price Negotiation Program, and (2) imposes rebates 
under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation. These provisions began to take effect 
progressively starting in fiscal year 2023, although the Medicare Drug Price Negotiation Program is currently subject to legal 
challenges. Under this program, HHS has already announced the agreed-upon prices of the first drugs that were subject to price 
negotiations and will announce the agreed-upon prices of additional drugs in the coming years. In response to an October 2022 
executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the CMS Innovation Center, 
which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care. It is unclear 
whether the models will be utilized in any health reform measures in the future. Further, on December 7, 2023, the Biden 
administration announced an initiative to control the price of prescription drugs using march-in rights under the Bayh-Dole Act. On 
December 8, 2023, the National Institute of Standards and Technology, or NIST, published for comment a Draft Interagency Guidance 
Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an 
agency can use when deciding to exercise march-in rights. While march-in rights have not previously been exercised, it is uncertain if 
that will continue under the new NIST framework, if such framework is finalized. Further, additional health reform measures may be 
implemented in the future, particularly in light of the recent U.S. presidential and congressional elections. 
 
Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in 
payments from private payers.  Our future product sales may be subject to additional discounts from list price in the form of rebates 
and discounts provided to 340B covered entities. Changes to the 340B program or to Medicare or Medicaid programs at the federal or 
state level, including outcomes of ongoing litigation in our industry, may impact our product prices and rebate liability.  
 
In addition, the distribution of prescription pharmaceutical products is subject to the Drug Supply Chain Security Act, or 
DSCA, which regulates the distribution and tracing of prescription drugs and prescription drug samples at the federal level and sets 
minimum standards for the regulation of drug distributors by the states. The DSCA imposes requirements to ensure accountability in 
distribution and to identify and remove counterfeit and other illegitimate products from the market.  
 
Other healthcare laws that may affect our ability to operate include, for example, the following: 
 
● 
The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, as amended by the Health 
Information Technology for Economic and Clinical Health Act, which governs the conduct of certain electronic 
healthcare transactions and protects the security and privacy of protected health information;  
● 
Foreign and state laws governing the privacy and security of health information, such as the General Data Protection 
Regulation, or GDPR, in the EU and UK; and the California Consumer Privacy Act, or CCPA, in California, some of 
which are more stringent than HIPAA and many of which differ from each other in significant ways and may not have 
the same effect; and 
● 
The Physician Payments Sunshine Act, which requires manufacturers of medicines, devices, biologics, and medical 
supplies to report annually to the Centers for Medicare and Medicaid Services information related to payments and other 
transfers of value to physicians (defined to include doctors, dentists, optometrists, podiatrists, and chiropractors), other 
healthcare providers (such as physician assistants and nurse practitioners), and teaching hospitals, and ownership and 
investment interests held by physicians and their immediate family members. 
 
 
 
29

Sales and Marketing 
 
Numerous regulatory authorities in addition to the FDA, including, in the U.S., the Centers for Medicare and Medicaid 
Services, other divisions of the HHS, the U.S. Department of Justice, and similar foreign, state and local government authorities, 
regulate sales, promotion and other activities following drug approval. As described above, the FDA regulates all advertising and 
promotion activities for drugs under its jurisdiction both prior to and after approval. Only those claims relating to safety and efficacy 
that the FDA has approved may be used in labeling. Physicians may prescribe legally available drugs for uses that are not described in 
the drug’s labeling and that differ from those tested and that the FDA approved. The FDA does not regulate the behavior of physicians 
in their choice of treatments, but FDA regulations do impose stringent restrictions on manufacturers’ communications regarding off-
label uses. If we do not comply with applicable FDA requirements, we may face adverse publicity, enforcement action by the FDA, 
including corrective advertising, consent decrees and the full range of civil and criminal penalties available to the FDA. Promotion of 
off-label uses of drugs can also implicate the false claims laws described below. 
 
In the U.S., sales, marketing and scientific/educational programs must also comply with various federal and state laws 
pertaining to healthcare “fraud and abuse,” including anti-kickback laws and false claims laws. Anti-kickback laws make it illegal for 
a prescription drug manufacturer to solicit, offer, receive, or pay any remuneration in exchange for, or to induce, the referral of 
business, including the purchase or prescription of a particular drug. Despite our best efforts to comply with applicable law and 
regulations, due to the breadth of the statutory provisions, limited statutory exceptions and regulatory safe harbors, and the absence of 
guidance in the form of regulations and very few court decisions addressing industry practices, it is possible that our practices might 
be challenged under anti-kickback or similar laws. Moreover, healthcare reform legislation has strengthened these laws. For example, 
the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or 
Affordable Care Act, among other things, amends the intent requirement of the federal anti-kickback and criminal healthcare fraud 
statutes to clarify that a person or entity does not need to have actual knowledge of this statute or specific intent to violate it. In 
addition, the Affordable Care Act clarifies that the government may assert that a claim that includes items or services resulting from a 
violation of the federal anti-kickback statute constitutes a false or fraudulent claim for purposes of the false claims statutes. False 
claims laws prohibit anyone from knowingly and willingly presenting, or causing to be presented for payment, to third-party payers 
(including Medicare and Medicaid) claims for reimbursed drugs or services that are false or fraudulent, claims for items or services 
not provided as claimed, or claims for medically unnecessary items or services. Our activities relating to the sale and marketing of our 
drugs may be subject to scrutiny under these laws. Violations of fraud and abuse laws may be punishable by criminal and civil 
sanctions, including fines and civil monetary penalties, the possibility of exclusion from federal healthcare programs (including 
Medicare and Medicaid) and corporate integrity agreements, which impose, among other things, rigorous operational and monitoring 
requirements on companies. Similar sanctions and penalties also can be imposed upon executive officers and employees, including 
criminal sanctions against executive officers under the so-called “responsible corporate officer” doctrine, even in situations where the 
executive officer did not intend to violate the law and was unaware of any wrongdoing. 
 
Given the significant penalties and fines that can be imposed on companies and individuals if convicted, allegations of such 
violations often result in settlements even if the company or individual being investigated admits no wrongdoing. Settlements often 
include significant civil sanctions, including fines and civil monetary penalties, corporate integrity agreements, and could include 
criminal penalties. If the government alleged, or subsequently settled or convicted us or our executive officers of violating these laws, 
our business could be harmed. In addition, private individuals can bring similar actions. Our activities could be subject to challenge 
for the reasons discussed above and due to the broad scope of these laws and the increasing attention being given to them by law 
enforcement authorities. As described above, other healthcare laws that may affect our operations include HIPAA, analogous state 
laws governing the privacy and security of health information, some of which are more stringent than HIPAA and many of which 
differ from each other in significant ways and may not have the same effect, and the Physician Payments Sunshine Act. Further, there 
are an increasing number of state laws that require manufacturers to make reports to states on pricing and marketing information. 
Many of these laws contain ambiguities as to what is required to comply with the laws. Given the lack of clarity in laws and their 
implementation, our reporting actions could be subject to the penalty provisions of the pertinent state authorities. 
 
Similar rigid (and in some areas, heightened) restrictions are imposed on the promotion and marketing of drugs in the E.U. 
and other countries. Even in those countries where we may not be directly responsible for the promotion and marketing of our 
medicines, if our potential international distribution partners engage in inappropriate activity, it can have adverse implications for us. 
 
As discussed above, both the federal and state governments in the U.S. and foreign governments continue to propose and 
pass new legislation and regulations designed to contain or reduce the cost of healthcare, including new models aimed to lower of cost 
of drugs, promote accessibility, and improve quality of care and initiatives to control the price of prescription drugs using march-in 
rights under the Bayh-Dole Act.  
 
 
 
30

The Foreign Corrupt Practices Act 
 
The U.S. Foreign Corrupt Practices Act, or FCPA, prohibits certain individuals and entities, including us, from promising, 
paying, offering to pay, or authorizing the payment of anything of value to any foreign government official, directly or indirectly, to 
obtain or retain business or an improper advantage. The FCPA also requires publicly traded companies to maintain accurate books and 
records and establish and maintain a system of internal accounting controls. If we violate the FCPA, it could result in large civil and 
criminal penalties as well as have an adverse effect on our reputation, operations, and financial condition. We could also face 
collateral consequences such as debarment and the loss of export privileges. In addition, in many other countries, the healthcare 
providers who conduct clinical trials or prescribe pharmaceuticals are employed by their government, and the purchasers of 
pharmaceuticals are government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation 
under the FCPA. There is no certainty that all employees and third-party business partners (including our contract research 
organizations, contract manufacturing organizations, distributors, wholesalers, agents, contractors and other partners) will comply with 
the FCPA or local anti-bribery laws. Importantly, we do not control the actions of manufacturers and other third-party agents, although 
we may be liable for their actions. 
 
Competition 
 
Our Business in General 
 
Some of our medicines may compete with existing therapies for market share and some of our medicines in development 
may compete for patients in clinical trials. In addition, there are a number of companies pursuing the development of genetic 
medicines and the development of pharmaceuticals utilizing these technologies. These companies include biopharmaceutical 
companies and large pharmaceutical companies acting either independently or together. Our medicines are differentiated from 
traditional small molecule medicines by their chemistry, how they move in the body, how they act in the body, delivery technology, 
and formulations. 
 
Our commercial medicines and our medicines in development address numerous markets. The diseases our medicines target 
for which we have or may receive marketing authorization will determine our competition. For some of our medicines, an important 
factor may be the timing of market introduction of competitive products. Accordingly, the relative speed with which we can develop 
medicines, complete the clinical trials and marketing authorization processes and supply commercial quantities of the medicines to the 
market are important competitive factors. We expect to compete with products approved for sale based on a variety of factors, 
including, among other things, product efficacy, safety, mechanism of action, dosing administration, marketing and sales strategy and 
tactics, availability, price, and reimbursement. 
 
Below we have included what we believe to be medicines that compete or may compete directly with our marketed medicines 
and late-stage medicines. We included competitors and potential competitors that are past Phase 1 development. 
 
Marketed Medicines 
 
TRYNGOLZA/Olezarsen and WAYLIVRA 
 
We believe that the following medicines could compete with TRYNGOLZA/olezarsen and WAYLIVRA in FCS and sHTG: 
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
ARO-APOC3 
(Plozasiran) 
 
Arrowhead 
 
Targets APOCIII by utilizing 
Targeted RNAi Molecule 
Platform 
 
Submitted in US for FCS, 
Phase 3 sHTG 
 Subcutaneous Injection 
Pegozafermin 
 
89bio 
 
FGF21 analog 
 
Phase 3 sHTG 
 Subcutaneous Injection 
NST-1024 
 
NorthSea 
Therapeutics 
 
CETP Inhibitor 
Phase 2a 
 
Oral 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations. 
 
 
 
31

WAINUA/Eplontersen and TEGSEDI 
 
We consider the following medicines as competitors and potential future competitors to WAINUA/eplontersen and 
TEGSEDI for ATTRv-PN and/or ATTR-CM: 
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
Onpattro 
(Patisiran) 
 
Alnylam 
 
An RNAi medicine formulated 
with lipid nanoparticles to 
inhibit TTR mRNA 
 
Approved in US, EU, Japan 
and select other markets for 
ATTRv-PN 
 
Intravenous Infusion 
Vyndaqel/Vyndamax 
(Tafamidis and 
tafamidis 
meglumine) 
 
Pfizer 
 A small molecule medicine to 
stabilize TTR protein 
 
Approved in EU, Japan and 
select other markets for 
ATTRv-PN (not approved in 
the US); ATTR-CM 
approved in the US, EU and 
other geographies 
 
Oral 
Amvuttra 
(Vutrisiran) 
 
Alnylam 
 
An RNAi medicine conjugated 
with GalNAc to inhibit TTR 
mRNA 
 
Approved for ATTRv-PN in 
the US, EU and Japan; 
Submitted in US, EU for 
ATTR-CM 
 Subcutaneous Injection 
Attruby 
(Acoramidis) 
 
BridgeBio 
 Small molecule that binds and 
stabilizes TTR in the blood 
 Approved in US; Submitted 
in EU and Japan 
 
Oral 
NTLA-2001 
(Nexiguran 
Ziclumeran (nex-z)) 
 
Intellia/ 
Regeneron 
 
CRISPR therapeutic candidate 
designed to reduce circulating 
TTR protein levels 
 
Phase 3 ATTR-CM, 
Phase 3 ATTRv-PN 
 
Intravenous Infusion 
ALXN2220 
 
AstraZeneca 
 A monoclonal IgG1 which acts 
by depleting TTR protein 
 
Phase 3 ATTR-CM 
 
Intravenous Infusion 
NNC6019-0001 
 Novo Nordisk 
 
A monoclonal antibody to 
deplete amyloid  
 
Phase 2 ATTR-CM 
 
Intravenous Infusion 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations.  
 
SPINRAZA 
 
We consider the following medicines as competitors to SPINRAZA for the indication of SMA: 
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
Zolgensma 
(Onasemnogene 
abeparvovec) 
 
Novartis 
 
Gene therapy targeting the 
genetic root cause of SMA by 
replacing the missing or 
nonworking SMN1 gene 
 
Approved for pediatric SMA 
patients less than 2 years of 
age 
 
Intravenous Infusion 
Evrysdi 
(Risdiplam) 
 
Roche 
 
A small molecule medicine 
that modulates splicing of the 
SMN2 gene 
 
Approved for SMA in 
pediatric and adult patients  
Oral 
OAV101 
(Onasemnogene 
abeparvovec) 
 
Novartis 
 
Gene therapy targeting the 
genetic root cause of SMA by 
replacing the missing or 
nonworking SMN1 gene 
 
Phase 3 
 
Intrathecal Injection 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations. 
 
 
 
32

QALSODY 
 
We believe that the following medicine could compete with QALSODY in SOD1-ALS: 
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
NI-005 / AP-101 
 
Neurimmune 
(AL-S Pharma) / 
Lilly 
 
A human derived antibody 
targeting misfolded SOD1 
 
Phase 2 
 
Intravenous Infusion 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations.  
 
Late-Stage Ionis-Owned Programs 
 
Donidalorsen 
 
We believe that the following medicines could compete with donidalorsen as a prophylactic treatment for patients with HAE:  
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
Takhzyro 
(lanadelumab-flyo)  
Takeda 
 
A monoclonal antibody that 
inhibits plasma kallikrein 
activity 
 Approved for HAE patients 
two years and older 
 Subcutaneous Injection 
Cinryze 
(C1 esterase 
inhibitor) 
 
Takeda 
 
A human plasma protein that 
mediates inflammation and 
coagulation 
 Approved for HAE patients 
six years and older 
 
Intravenous Infusion 
Orladeyo 
(berotralstat) 
 
BioCryst 
 
Oral plasma kallikrein 
inhibitor 
 Approved for HAE patients 
12 years and older 
 
Oral 
Haegarda 
(C1 esterase 
inhibitor) 
 
CSL Behring 
 
C1 esterase inhibitor 
 Approved for HAE patients 
6 years and older 
 Subcutaneous Injection 
Garadacimab 
 
CSL Behring 
 
An anti-factor XIIa 
monoclonal antibody 
 
Approved for HAE patients 
12 years and older in 
Australia and the UK 
EC Decision Pending in EU; 
Received CRL in the US 
 Subcutaneous Injection 
Deucrictibant 
 
Pharvaris 
 An oral B2-receptor antagonist  
Phase 3 
 
Oral 
NTLA-2002 
 
Intellia 
 
CRISPR therapeutic candidate 
designed to inactivate the 
kallikrein B1 gene 
 
Phase 3 
 
Intravenous Infusion 
STAR-0215 
(Navenibart) 
 
Astria 
 
A monoclonal antibody 
inhibitor of plasma kallikrein 
 
Phase 2 
 Subcutaneous Injection 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations.  
 
Zilganersen 
 
We believe there are no medicines in clinical development for AxD. 
 
 
 
33

ION582 
 
We believe that the following medicines could compete with ION582 in Angelman syndrome: 
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
GTX-102 
 
Ultragenyx 
Pharma 
 
An ASO designed to inhibit 
expression of UBE3A-ATS 
 
Phase 3 
 
Intrathecal 
Alogabat 
 
Roche 
 
A small molecule that is 
GABA A alpha 5 receptor 
modulator 
 
Phase 2 
 
Oral 
NNZ-2591 
 
Neuren 
Pharmaceuticals  A small molecule, cGP analog, 
that targets IGF-1 
 
Phase 2 
 
Oral 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations. 
 
Late-Stage Partnered Programs 
 
Bepirovirsen 
 
We believe that the following medicines could compete with bepirovirsen in HBV 
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
Elebsiran 
(VIR-2218) 
 
Vir Biotech / 
Alnylam 
 
RNAi therapeutic to reduce 
HBV viral antigens 
 
Phase 2 
 Subcutaneous Injection 
Imdusiran 
(AB-729) 
 
Arbutus 
Biopharma 
 
RNAi therapeutic to reduce 
HBV viral antigens 
 
Phase 2 
 Subcutaneous Injection 
Tobevibart  
(VIR-3434) 
 
Vir Biotech 
 
Monoclonal antibody 
neutralizing hepatitis B virus 
 
Phase 2 
 Subcutaneous Injection 
Selgantolimod 
 Gilead Sciences  
Toll-like receptor 8 agonist 
 
Phase 2 
 
Oral 
Bersacapavir 
 
Johnson & 
Johnson 
 
Capsid assembly modulator 
 
Phase 2 
 
Oral 
REP 2139-Mg 
 
Replicor Inc. 
 
Nucleic acid polymer that 
blocks the assembly of subviral 
particles (SVPs) in hepatocytes 
 
Phase 2 
 Intravenous Infusion / 
Subcutaneous Injection 
VTP-300 
 Barinthus Bio 
 
Antigen-specific 
immunotherapy 
 
Phase 2 
 Intramuscular Injection 
BRII-179 
 Brii Biosciences  
Recombinant protein-based 
immunotherapy 
 
Phase 2 
 Intramuscular Injection 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations. 
 
Pelacarsen 
 
We believe that the following medicines could compete with pelacarsen in CVD in patients with elevated LP(a): 
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
Olpasiran 
 
Amgen/ 
Arrowhead 
 RNAi therapeutic designed to 
lower Lp(a) 
 
Phase 3 
 Subcutaneous Injection 
Lepodisiran 
 
Lilly 
 RNAi therapeutic designed to 
lower Lp(a) 
 
Phase 3 
 Subcutaneous Injection 
Zerlasiran 
 
Silence 
 RNAi therapeutic designed to 
lower Lp(a) 
 
Phase 2 
 Subcutaneous Injection 
Muvalaplin 
 
Lilly 
 
Small molecule therapy to 
lower Lp(a) 
 
Phase 2 
 
Oral 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations. 
 
 
 
34

Sefaxersen 
 
We believe that the following medicines could compete with sefaxersen in IgAN: 
 
Medicine 
 
Company 
 
Medicine Description (1) 
 
Phase (1) 
 
Route of 
Administration (1) 
Tarpeyo 
(budesonide) 
 
Asahi Kasei 
(Calliditas) 
 
A corticosteroid indicated to 
reduce proteinuria in adults 
with primary IgAN 
 
Approved for IgAN 
 
Oral 
Filspari  
(Sparsentan) 
 
Travere 
 
An endothelin & angiotensin II 
receptor antagonist to reduce 
proteinuria in adults with 
primary IgAN 
 
Approved for IgAN 
 
Oral 
Fabhalta 
(Iptacopan) 
 
Novartis 
(Chinook) 
 
A factor B inhibitor of the 
alternative complement 
pathway 
 
Approved for IgAN 
 
Oral 
Atrasentan 
 
Novartis 
(Chinook) 
 
An endothelin A receptor 
antagonist 
 
Phase 3 (IgAN); Submitted 
in US for accelerated 
approval 
 
Oral 
Zigakibart 
 
Novartis 
(Chinook) 
 
An anti-APRIL monoclonal 
antibody 
 
Phase 3 (IgAN) 
 Subcutaneous Injection 
Sibeprenlimab 
 
Otsuka 
(Visterra) 
 
A humanized IgG2 
monoclonal antibody that 
inhibits APRIL 
 
Phase 3 (IgAN) 
 
Intravenous Infusion 
Atacicept 
 
Vera 
 
A recombinant fusion protein a 
dual inhibitor of BLyS and 
APRIL 
 
Phase 3 (IgAN) 
 Subcutaneous Injection 
Ravulizumab 
 
Alexion 
(AstraZeneca) 
 
A humanized monoclonal 
antibody to complement factor 
5 
 
Phase 3 (IgAN) 
 Subcutaneous Injection 
Povetacicept 
 Alpine Immune 
Sciences 
 
A dual BAFF and APRIL 
inhibitor 
 
Phase 3 (IgAN) 
 Intravenous Infusion / 
Subcutaneous Injection 
Telitacicept 
 
RemeGen 
 
A dual BAFF and APRIL 
inhibitor 
 
Phase 3 (IgAN) 
 Subcutaneous Injection 
Vemircopan 
 
Alexion 
(AstraZeneca) 
 
A complement factor D 
inhibitor 
 
Phase 2 (IgAN) 
 
Oral 
Felzartamab 
 
Hi-Bio 
 
A monoclonal antibody 
directed against CD38 
 
Phase 2 (IgAN) 
 
Intravenous Infusion 
 
(1) 
Taken from public documents including respective company press releases, company presentations, and scientific presentations. 
 
Ulefnersen 
 
We believe there are no medicines in clinical development for FUS-ALS. 
 
Corporate Responsibility Initiatives 
 
We believe operating responsibly and sustainably creates long-term value for our company and our stakeholders. We 
recognize the importance of Corporate Responsibility, or CR, and Environmental, Social and Governance, or ESG, initiatives as it 
relates to our business strategy and risk assessment. We continue to evolve our CR program and established three strategic CR pillars 
and associated goals in 2023 to guide our approach and provide a framework for reporting on our performance.  
 
We began reporting on CR metrics in 2021 and have continued to expand disclosure since then. In 2024, we reported 
progress on our CR goals aligned to the three strategic CR pillars that we believe are most important to our business: 
 
 
 
35

Ionis Corporate Responsibility Strategic Pillars 
 
Innovate to improve the lives  
of people with serious diseases 
Empowering our 
employees and communities 
Operating 
responsibly and sustainably 
We innovate across the business and 
work tirelessly to discover, develop and 
deliver important new medicines for 
people with serious diseases. 
We are committed to fostering an 
inclusive culture that drives excellence, 
embraces diversity, and supports our 
communities. 
We operate with integrity to help create 
a better, more sustainable future for all 
through environmental stewardship and 
responsible business practices and 
stakeholder interactions. 
• 
Innovation and R&D 
• 
Access and Affordability 
• 
Patient Advocacy and Engagement 
• 
Workplace Culture, Talent 
Attraction and Development 
• 
Inclusion and Belonging 
• 
Social Impact and Community 
Engagement 
• 
Environmental Sustainability 
• 
Governance and Integrity 
• 
Data Privacy and Cybersecurity 
 
Our CR initiatives are driven by our Chief Executive Officer and executive-level CR Steering Committee, or CR Committee. 
The CR Committee consists of senior leaders in key functions across the company, including legal, finance, investor relations, human 
resources, research and development, manufacturing, commercial, compliance and corporate affairs.  
 
The CR Committee is part of our governance framework, which defines responsibilities and ensures we have the right 
systems and controls to oversee ethical and sustainable operations across our business. Our Board of Directors, specifically the 
Nominating, Governance and Review Committee, has oversight of our overall CR strategy and material CR risks and opportunities as 
outlined in the Committee’s charter. The Board receives updates related to corporate governance and corporate responsibility from the 
CR Committee at least once annually. We look to our stakeholders and third-party frameworks such as the Sustainability Accounting 
Standards Board Health Care – Biotechnology and Pharmaceuticals Standard and the Task Force on Climate-Related Financial 
Disclosures to inform our approach and our disclosures. 
 
We will share progress on our CR goals and more details on our initiatives in our 2024 CR Report, which we expect to 
publish in April 2025 and available on our website. Nothing in the report or on our website shall be deemed incorporated by reference 
into this Annual Report on Form 10-K. 
 
Employees and Human Capital 
  
As of February 13, 2025, we employed 1,069 people, the vast majority of whom reside in the U.S. A significant number of 
our management and professional employees have had prior experience with pharmaceutical, biotechnology or medical product 
companies. Our average employee turnover rate in 2023 was 6 percent, while the turnover for life sciences and medical device 
companies over this period was 21 percent according to a survey published by Radford – an Aon Hewitt Company. Given the 
uniqueness and complexity of our technology, it is critical to retain the knowledge and experience of outstanding long service 
employees. The experience and seniority of our employees is as critical to our future success as it has been to the success we have 
enjoyed to date. 
 
Collective bargaining agreements do not cover any of our employees, and management considers relations with our 
employees to be good. We believe that the future will be defined by outstanding people and we are committed to recruiting, 
developing, motivating, and rewarding them. 
 
We encourage you to visit our website for more detailed information regarding our Human Capital programs and initiatives. 
Nothing on our website shall be deemed incorporated by reference into this Annual Report on Form 10-K. 
 
 
 
36

Benefits 
 
We reward our employees individually on the basis of their responsibilities and accomplishments. We offer competitive 
compensation and benefits to our employees. In addition to salary and bonus programs, we also offer: 
 
● 
Comprehensive medical, dental and vision insurance; 
● 
401(k) matching; 
● 
Stock options, RSUs and an Employee Stock Purchase Plan, or ESPP; 
● 
Vacation, holiday, sick time and paid time off for volunteering; 
● 
Wellness programs; 
● 
Flexible spending accounts for health and dependent day care needs;  
● 
Family care benefits; 
● 
Life, AD&D insurance and long-term disability insurance coverage options; and 
● 
Employee Assistance Program, or EAP.  
 
We recognize achievements with salary increases, equity awards, promotions, and bonus opportunities. 
 
Pay Equity 
 
We are committed to paying our employees fairly, regardless of their gender, ethnicity, race, age or other personal 
characteristics. To ensure we are achieving our commitment, we benchmark and evaluate pay based on market data and consider 
factors such as an employee’s role and experience, an employee’s performance and internal equity. We also regularly review our 
compensation practices, in terms of our overall workforce and individual employees, to ensure our pay is fair and equitable. 
 
On an annual basis, we monitor our pay equity status and market competitiveness, and perform a pay equity analysis that 
reviews pay equity by gender, ethnicity, race and age. Our 2024 pay equity analysis confirmed we do not have a statistically 
significant difference in pay for the same or similar work, regardless of gender, ethnicity, race or age. 
 
A Culture of Inclusion 
 
At Ionis, prejudicial barriers to human potential and productivity are foreign to our values. We recognize that for the full 
potential of our workforce to be realized, we must cultivate an inclusive culture where all employees feel empowered to contribute 
fully in an environment that values different perspectives, leading to better ideas and increased innovation. We have several employee-
led resource groups dedicated to supporting engagement and empowerment and a diverse management team and board of directors. 
From our Executive Leadership Team to our newest hire, we strive for an environment where our employees feel a strong sense of 
belonging in our organization. 
 
Training and Development 
 
We designed our training and development programs to help employees gain important Ionis knowledge and develop the 
skills to be successful at Ionis. All of our trainings from new hire through senior leader, are focused on the Ionis culture and core 
principles and learning what we mean when we say: “Working the Ionis Way.” 
 
We empower our employees to build rewarding careers at Ionis, driven by a culture of having a bias to act that encourages 
personal and professional employee growth. Ionis offers robust training opportunities with course offerings and events available to 
every employee regardless of level or function. In addition, employees also have access to Ionis’ learning and development library that 
houses important information on career growth and planning. By supporting our employees, we know that each professional 
development milestone enables our continued success.  
 
 
 
37

Information about our Executive Officers 
  
The following sets forth certain information regarding our executive officers as of February 13, 2025: 
  
Name 
  
Age 
  
Position 
Brett P. Monia, Ph.D. 
 
63 
Chief Executive Officer  
Joseph T. Baroldi, M.A., M.B.A., 
M.S. 
47 
Executive Vice President, Chief Business Officer 
Brian Birchler 
59 
Executive Vice President, Corporate and Development Operations 
C. Frank Bennett, Ph.D. 
 
68 
 Executive Vice President, Chief Scientific Officer 
Shannon L. Devers 
54 
Executive Vice President, Chief Human Resources Officer 
Richard S. Geary, Ph.D. 
 
67 
 Executive Vice President, Chief Development Officer 
Elizabeth L. Hougen 
 
63 
 Executive Vice President, Finance and Chief Financial Officer 
Kyle Jenne 
49 
Executive Vice President, Chief Global Product Strategy Officer 
Patrick R. O’Neil, Esq. 
 
51 
 
Executive Vice President, Chief Legal Officer, General Counsel and Corporate 
Secretary 
Eugene Schneider, M.D. 
52 
Executive Vice President, Chief Clinical Development and Operations Officer 
Eric E. Swayze, Ph.D. 
59 
Executive Vice President, Research 
 
BRETT P. MONIA, Ph.D. 
  
Chief Executive Officer  
 
Dr. Monia was promoted to Chief Executive Officer in January 2020. From January 2018 to December 2019, Dr. Monia 
served as Chief Operating Officer. From January 2012 to January 2018, Dr. Monia served as Senior Vice President. From February 
2009 to January 2012, Dr. Monia served as our Vice President, Drug Discovery and Corporate Development and from October 2000 
to February 2009, he served as our Vice President, Preclinical Drug Discovery. From October 1989 to October 2000 he held various 
positions within our Molecular Pharmacology department. 
 
JOSEPH T. BAROLDI, M.A., M.B.A., M.S. 
 
Executive Vice President, Chief Business Officer  
 
Mr. Baroldi has served as Ionis’ Executive Vice President, Chief Business Officer since January 2022. Prior to rejoining 
Ionis in 2022, Mr. Baroldi was the chief operating officer at Avidity Biosciences, a biotechnology company focused on 
oligonucleotide-based therapies. Prior to Avidity, Mr. Baroldi was Vice President, Business Development at Ionis, where he held 
several roles of increasing responsibility from 2009 to 2020. Mr. Baroldi has also held positions in strategic planning and scientific 
research for Gen-Probe Inc. 
  
BRIAN BIRCHLER 
  
Executive Vice President, Corporate and Development Operations  
 
Mr. Birchler has served as Ionis’ Executive Vice President, Corporate and Development Operations since March 2022. From 
January 2008 to March 2022, Mr. Birchler served as our Senior Vice President, Drug Development Operations. From January 2005 to 
January 2008 he served as our Vice President, Drug Development Operations and from January 2003 to January 2005, as our Vice 
President, Development Chemistry and Operations. Mr. Birchler joined Ionis in 1995 as Senior Scientist/Senior Research Associate. 
Prior to joining Ionis, Mr. Birchler was employed by CIBA Vision Corp. and Burroughs Wellcome Pharmaceuticals in various 
engineering, development and commercial positions. 
 
C. FRANK BENNETT, Ph.D. 
  
Executive Vice President, Chief Scientific Officer  
 
Dr. Bennett has served as Ionis’ Executive Vice President, Chief Scientific Officer since April 2020. In January 2020, Dr. 
Bennett was promoted to Chief Scientific Officer. From January 2006 to December 2019, Dr. Bennett served as Senior Vice President, 
Antisense Research. From June 1995 to January 2006, Dr. Bennett served as our Vice President, Research. From March 1993 to June 
1995, he was Director, Molecular Pharmacology, and from May 1992 to March 1993, he was an Associate Director in our Molecular 
and Cellular Biology department. Prior to joining Ionis in 1989, Dr. Bennett was employed by SmithKline and French Laboratories in 
various research positions. He is a member of the Board of Directors of the Hereditary Disease Foundation. 
 
 
 
38

SHANNON L. DEVERS 
 
Executive Vice President, Chief Human Resources Officer  
 
Ms. Devers was promoted to Chief Human Resources Officer in September 2024. From April 2020 to September 2024, Ms. 
Devers served as our Senior Vice President, Human Resources. From August 2013 to March 2020, Ms. Devers served as our Vice 
President, Human Resources. Ms. Devers joined Ionis in 2001 as Senior Human Resources Manager. Prior to joining Ionis, Ms. 
Devers was employed by Target Corporation, Nike, Inc. and Taco Bell Corporation in various human resources roles. 
 
RICHARD S. GEARY, Ph.D. 
  
Executive Vice President, Chief Development Officer 
  
Dr. Geary has served as Ionis’ Executive Vice President, Chief Development Officer since April 2020. From August 2008 to 
March 2020, Dr. Geary served as our Senior Vice President, Development. From August 2003 to August 2008, Dr. Geary served as 
our Vice President, Preclinical Development. From November 1995 to August 2003, he held various positions within the Preclinical 
Development department. Prior to joining Ionis in 1995, Dr. Geary was Senior Research Scientist and Group Leader for the 
bioanalytical and preclinical pharmacokinetics group in the Applied Chemistry Department at Southwest Research Institute.  
 
ELIZABETH L. HOUGEN 
  
Executive Vice President, Finance and Chief Financial Officer 
  
Ms. Hougen has served as Ionis’ Executive Vice President and Chief Financial Officer since April 2020. From January 2013 
to March 2020, Ms. Hougen served as our Senior Vice President, Finance and Chief Financial Officer. From January 2007 to 
December 2012, Ms. Hougen served as our Vice President, Finance and Chief Accounting Officer and from May 2000 to January 
2007, she served as our Vice President, Finance. Prior to joining Ionis in 2000, Ms. Hougen was Executive Director, Finance and 
Chief Financial Officer for Molecular Biosystems, Inc., a public biotechnology company. She is a member of the Board of Directors 
and Audit Committee chair for Artiva Biotherapeutics. 
 
KYLE JENNE 
 
Executive Vice President, Chief Global Product Strategy Officer 
 
Mr. Jenne has served as Ionis’ Executive Vice President, Chief Global Product Strategy Officer since February 2024. Prior to 
rejoining Ionis in 2024, Mr. Jenne served in senior commercial leadership roles at Ionis and Akcea from May 2017 to August 2022. 
Prior to joining Akcea in 2017, Mr. Jenne was employed by Schering Plough, King Pharmaceuticals, Acorda Therapeutics and Praecis 
Pharmaceuticals in various commercial roles.  
  
PATRICK R. O’NEIL, Esq. 
  
Executive Vice President, Chief Legal Officer, General Counsel and Corporate Secretary 
  
Mr. O’Neil has served as Ionis’ Executive Vice President, Chief Legal Officer and General Counsel since September 2021. 
Mr. O’Neil also serves as our Corporate Secretary. From March 2020 to September 2021, Mr. O’Neil served as our Executive Vice 
President, Legal & General Counsel and Chief Compliance Officer. From January 2013 to March 2020, Mr. O’Neil served as our 
Senior Vice President, Legal and General Counsel. From September 2010 to January 2013, Mr. O’Neil served as our Vice President, 
Legal and General Counsel and from January 2009 to September 2010, he served as our Vice President, Legal and Senior Transactions 
Counsel. From October 2001 to January 2009 he held various positions within our Legal department. Prior to joining Ionis, Mr. 
O’Neil was an associate at Cooley LLP. 
 
 
 
39

EUGENE SCHNEIDER, M.D. 
 
Executive Vice President, Chief Clinical Development and Operations Officer 
 
Dr. Schneider has served as Ionis’ Executive Vice President and Chief Clinical Development and Operations Officer since 
September 2023. From January 2021 to September 2023, Dr. Schneider served as our Executive Vice President and Chief Clinical 
Development Officer. From August 2018 to December 2020, Dr. Schneider served as our Senior Vice President, Head of Clinical 
Development. From April 2015 to July 2018, Dr. Schneider was our Vice President, Clinical Development, Severe and Rare Diseases. 
Dr. Schneider joined Ionis in December 2013 as Executive Director, Clinical Development. Dr. Schneider has two decades of 
experience in clinical development primarily in the rare diseases space. Prior to joining Ionis, Dr. Schneider was senior medical 
director at both Synageva BioPharma and Biovail Technologies Ltd. 
 
ERIC E. SWAYZE, Ph.D. 
  
Executive Vice President, Research 
 
Dr. Swayze has served as Ionis’ Executive Vice President, Research since April 2020 and is responsible for leading 
preclinical antisense drug discovery and antisense technology research. In January 2020, Dr. Swayze was promoted to Senior Vice 
President of Research. Previously, Dr. Swayze was Vice President of Chemistry and Neuroscience Drug Discovery at Ionis, 
overseeing the advancement of multiple programs to clinical development. He joined Ionis in 1994 and has contributed to key 
technology advancements, including Ionis’ Generation 2.5 chemistry and LICA technology. 
 
Item 1A. RISK FACTORS 
 
Investing in our securities involves a high degree of risk. You should carefully consider the following information about the 
risks described below, together with the other information contained in this report and in our other public filings in evaluating our 
business. If any of the following risks actually occur, our business could be materially harmed, and our financial condition and results 
of operations could be materially and adversely affected. As a result, the trading price of our securities could decline, and you might 
lose all or part of your investment. 
 
Risks Related to the Commercialization of our Medicines 
 
We have limited experience as a company in commercializing medicines and we will have to continue to invest significant 
resources to develop our capabilities. If we are unable to effectively establish and maintain marketing, sales, market access, 
distribution, and related functions, or enter into agreements with third parties to commercialize our medicines, we may not be 
able to successfully commercialize our medicines. 
 
We have historically relied on third parties to commercialize our marketed medicines and have limited experience as a 
company in commercializing medicines. TRYNGOLZA is our first independently launched medicine and we expect to independently 
launch additional medicines in the future. Any failure to effectively commercialize our medicines, including our failure to allocate 
resources to our commercial launches efficiently or timely, could adversely impact the revenue we generate from our medicines. If  
the commercialization of TRYNGOLZA and future sales are less successful than anticipated by us or our investors or securities 
analysts, our stock price could decline and our business may be harmed. 
 
We will have to continue to invest significant financial and management resources to build and maintain the infrastructure 
required to successfully commercialize our medicines. We will need to establish and maintain effective sales teams for each of our 
independently launched medicines and there are significant risks involved in managing a sales organization, including our ability to 
hire, retain and incentivize qualified individuals, generate sufficient sales leads, provide adequate training to sales and marketing 
personnel, and effectively manage a geographically dispersed sales and marketing team. We must also continue to scale-up existing 
internal support functions to aid our commercialization efforts. Further, these existing support functions will need to work effectively 
in coordination with new commercial functional areas. Any failure to establish or maintain an effective commercialization 
infrastructure, including our sales, marketing, market access, distribution, and related capabilities, scale-up our existing support 
functions, or effectively integrate new functional areas, could adversely affect our ability to successfully commercialize our 
medicines.  
 
If we choose to rely on third parties to assist us in commercializing our medicines, we may not be able to enter into 
collaborations or hire consultants or external service providers on acceptable financial terms, or at all. In addition, if we continue to 
engage third parties to assist us in the commercialization of our medicines, our product revenues and profitability may be lower than if 
we commercialized such medicines ourselves. 
 
The proximity of our planned upcoming independent launches could increase the likelihood that such risks will occur. 
 
 
 
40

If the market does not accept our medicines, including our commercial medicines and our medicines in development, we are 
not likely to generate substantial revenues or become consistently profitable. 
 
Even if our medicines are authorized for marketing, our success will depend upon the medical community, patients and third-
party payers accepting our medicines as medically useful, cost-effective, safe and convenient. Even when the FDA or foreign 
regulatory authorities authorize our or our partners’ medicines for commercialization, doctors may not prescribe our medicines to treat 
patients. Furthermore, we and our partners may not successfully commercialize additional medicines. 
 
Additionally, in many of the markets where we or our partners may sell our medicines in the future, if we or our partners 
cannot agree with the government or other third-party payers regarding the price we can charge for our medicines, we may not be able 
to sell our medicines in that market. Similarly, cost control initiatives by governments or third-party payers could decrease the price 
received for our medicines or increase patient coinsurance to a level that makes our medicines, including our commercial medicines 
and our medicines in development, economically unviable. If the pricing of any of our medicines decreases for any reason, it will 
reduce our revenue for such medicine. For example, Biogen has in the past disclosed that SPINRAZA revenue decreased in part due to 
lower pricing in the U.S. and certain rest-of-world markets. 
 
The degree of market acceptance for our medicines, including our commercial medicines and our medicines in development, 
depends upon a number of factors, including the: 
 
● 
receipt and scope of marketing authorizations; 
● 
establishment and demonstration in the medical and patient community of the efficacy and safety of our medicines, 
public perception regarding our medicines and their potential advantages over competing products;  
● 
cost and effectiveness of our medicines compared to other available therapies; 
● 
patient convenience of the dosing regimen for our medicines; and 
● 
reimbursement policies of government and third-party payers.  
 
Based on the profile of our medicines, physicians, patients, patient advocates, payers or the medical community in general 
may not accept or use any of the medicines that we or our partners may develop. 
 
For example, the product label for WAYLIVRA in the EU requires regular blood monitoring, which has negatively affected 
our ability to attract and retain patients for this medicine.  
 
If government or other third-party payers fail to provide adequate coverage and payment rates for our medicines, including 
our commercial medicines and our medicines in development, our revenue will be limited. 
 
In both domestic and foreign markets, sales of our current and future products will depend in part upon the availability of 
coverage and reimbursement from third-party payers. The majority of patients in the U.S. who would fit within our target patient 
populations for our medicines have their healthcare supported by a combination of Medicare coverage, other government health 
programs such as Medicaid, managed care providers, private health insurers and other organizations. Coverage decisions may depend 
upon clinical and economic standards that disfavor new medicines when more established or lower cost therapeutic alternatives are 
already available or subsequently become available. Assuming coverage is approved, the resulting reimbursement payment rates 
might not be enough to make our medicines affordable. Even if favorable coverage status and adequate reimbursement rates are 
attained, less favorable coverage policies and reimbursement rates may be implemented in the future. Accordingly, our commercial 
medicines and our medicines in development will face competition from other therapies and medicines for limited financial resources. 
Furthermore, we or our partners may need to conduct post-marketing studies to demonstrate the cost-effectiveness of any future 
products to satisfy third-party payers. These studies might require us to commit a significant amount of management time and 
financial and other resources. In addition, third-party payers may never consider our future products as cost-effective and adequate 
third-party coverage and reimbursement might not be available to enable us to maintain price levels sufficient to realize an appropriate 
return on investment in product development. 
 
Third-party payers, whether foreign or domestic, or governmental or commercial, are developing increasingly sophisticated 
methods of controlling healthcare costs. In addition, in the U.S., no uniform policy of coverage and reimbursement for medicines 
exists among third-party payers. Therefore, coverage and reimbursement for medicines can differ significantly from payer to payer. 
For example, the Affordable Care Act, or ACA, was passed in March 2010, and substantially changed the way healthcare is financed 
by both governmental and private insurers and continues to significantly impact the U.S. pharmaceutical industry. There have been 
judicial and Congressional challenges to certain aspects of the ACA, as well as efforts to repeal or replace certain aspects of the ACA. 
It is unclear how future litigation and healthcare reform measures will impact the ACA and our business. 
 
 
 
41

Further, we believe that future coverage, reimbursement and pricing will likely be subject to increased restrictions both in the 
U.S. and in international markets. In the U.S., recent health reform measures have resulted in reductions in Medicare and other 
healthcare funding, and there have been several recent U.S. Congressional inquiries, legislation and executive orders designed to, 
among other things, reduce drug prices, increase competition (including by enhancing support for generic and biosimilar drugs), lower 
out-of-pocket drug costs for patients, curtail spread pricing practices by pharmacy benefit managers, and foster scientific innovation to 
promote better health care and improved health. In addition, the Inflation Reduction Act of 2022, or the IRA, includes key actions 
aimed at reducing the costs of prescription drugs and allows HHS to negotiate the price of certain single-source drugs covered under 
Medicare and establish a price cap on such drugs. The IRA, among other things, (1) directs HHS to negotiate the price of certain 
single-source drugs and biologics that have been on the market for at least seven years covered under Medicare, or the Medicare Drug 
Price Negotiation Program, and (2) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that 
outpace inflation. These provisions began to take effect progressively starting in fiscal year 2023, although the Medicare Drug Price 
Negotiation Program is currently subject to legal challenges. Under this program, HHS has already announced the agreed-upon prices 
of the first drugs that were subject to price negotiations and will announce the agreed-upon prices of additional drugs in the coming 
years. In response to an October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for 
testing by the CMS Innovation Center that will be evaluated on their ability to lower the cost of drugs, promote accessibility, and 
improve quality of care. It is unclear whether the models will be utilized in any health reform measures in the future. Further, on 
December 7, 2023, the Biden administration announced an initiative to control the price of prescription drugs using march-in rights 
under the Bayh-Dole Act. On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft 
Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a 
product as one factor an agency can use when deciding to exercise march-in rights. While march-in rights have not previously been 
exercised, it is uncertain if that will continue under the new framework. It is unclear whether or how these selected models or similar 
policy initiatives will impact prescription drug pricing in the future, particularly in light of the recent U.S. presidential and 
congressional elections. 
 
Any reduction in reimbursement from Medicare and other government programs may result in a similar reduction in 
payments from private payers. Our future product sales may be subject to additional discounts from list price in the form of rebates 
and discounts provided to covered entities under the Public Health Service Act 340B drug pricing program. Changes to the 340B 
program or to Medicare or Medicaid programs at the federal or state level, including outcomes of ongoing litigation in our industry, 
may impact our product prices and rebate liability.  
 
At the state level, legislatures have increasingly passed legislation and implemented 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. For example, on January 5, 2024, the FDA approved Florida’s Section 804 Importation Program, 
or SIP, proposal to import certain drugs from Canada for specific state healthcare programs. It is unclear how this program will be 
implemented, including which drugs will be chosen, and whether it will be subject to legal challenges in the United States or Canada. 
Other states have also submitted SIP proposals that are pending review by the FDA. Any such approved importation plans, when 
implemented, may result in lower drug prices for products covered by those programs. Third-party coverage and reimbursement for 
medicines may not be available or adequate in either the U.S. or international markets, which would negatively affect the potential 
commercial success of our products, our revenue and our profits. 
 
If we or our partners fail to compete effectively, our medicines, including our commercial medicines and our medicines in 
development, will not generate significant revenues. 
 
Our competitors engage in drug discovery throughout the world, are numerous, and include, among others, major 
pharmaceutical companies and specialized biopharmaceutical firms. In addition, other companies are engaged in developing RNA-
targeted technology. Our competitors may succeed in developing medicines that are: 
 
● 
priced lower than our medicines; 
● 
reimbursed more favorably by government and other third-party payers than our medicines;  
● 
safer than our medicines; 
● 
more effective than our medicines; or 
● 
more convenient to use than our medicines. 
 
These competitive developments could make our medicines, including our commercial medicines and our medicines in 
development, obsolete or non-competitive. 
 
 
 
42

Certain of our partners are pursuing other technologies or developing other medicines either on their own or in collaboration 
with others, including our competitors, to treat some of the same diseases our own collaborative programs target. Competition may 
negatively impact a partner’s focus on and commitment to our medicines and, as a result, could delay or otherwise negatively affect 
the commercialization of our medicines, including our commercial medicines and our medicines in development. 
 
Many of our competitors have substantially greater financial, technical and human resources than we do. In addition, many of 
these competitors have significantly greater experience than we do in conducting preclinical testing and human clinical studies of new 
pharmaceutical products, in obtaining FDA and other regulatory authorizations of such products and in commercializing such 
products. Accordingly, our competitors may succeed in obtaining regulatory authorization for products earlier than we do or more 
successfully commercialize their products. 
 
There are several pharmaceutical and biotechnology companies engaged in the development or commercialization in certain 
geographic markets of products against targets that are also targets of products in our development pipeline or of medicines we are 
commercializing. For example:  
 
● 
Onasemnogene abeparvovec and risdiplam compete with SPINRAZA; 
● 
Acoramidis, patisiran, tafamidis, tafamidis meglumine and vutrisiran compete with WAINUA; 
● 
Nexiguran ziclumeran, ALXN2220 and NNC6019-0001 could compete with WAINUA; 
● 
Plozasiran, pegozafermin and NST-1024 could compete with TRYNGOLZA and WAYLIVRA; 
● 
Lanadelumab-flyo, C1 esterase inhibitor, berotralstat, C1 esterase inhibitor subcutaneous, garadacimab, deucrictibant,  
NTLA-2002 and STAR-0215 could compete with donidalorsen; 
● 
Olpasiran, zerlasiran, lepodisiran and muvalaplin could compete with pelacarsen; 
● 
NI-005/AP-101 could compete with QALSODY; 
● 
VIR-2218, VIR-3434, BRII-179, AB-729, selgantolimod, bersacapavir,  REP 2139-Mg and VTP-300 could complete 
with bepirovirsen;  
● 
Budesonide, sparsentan, atrasentan, iptacopan, zigakibart, sibeprenlimab, atacicept, ravulizumab, vemircopan, 
felzartamab, telitacicept and povetacicept could compete with sefaxersen; and 
●  GTX-102, alogabat and NNZ-2591 could compete with ION582. 
  
SPINRAZA injection for intrathecal use is an antisense medicine indicated for the treatment of SMA patients of all ages 
approved in over 50 countries. Specifically, SPINRAZA faces competition from onasemnogene abeparvovec, a gene therapy product 
that was approved in the U.S. in May 2019 and in the EU in May 2020 for the treatment of SMA, as well as risdiplam, an oral product 
for the treatment of SMA that was approved in the U.S. in August 2020 and in the EU in March 2021. Biogen has in the past disclosed 
that SPINRAZA revenue decreased due to a reduction in demand as a result of increased competition and that future sales of 
SPINRAZA may be adversely affected by competing products. 
 
Additionally, companies that are developing medicines that target the same patient populations as our medicines in 
development may compete with us to enroll participants in the clinical trials for such medicines, which could make it more difficult 
for us to complete enrollment for these clinical trials. 
 
Our medicines could be subject to regulatory limitations following approval. 
 
Following approval of a medicine, we and our partners must comply with comprehensive government regulations regarding 
the manufacture, marketing and distribution of medicines. Promotional communications regarding prescription medicines must be 
consistent with the information in the product’s approved labeling. We or our partners may not obtain the labeling claims necessary or 
desirable to successfully commercialize our medicines, including our commercial medicines and our medicines in development. 
 
The FDA and foreign regulatory bodies have the authority to impose significant restrictions on an approved medicine through 
the product label and on advertising, promotional and distribution activities.  
 
Prescription medicines may be promoted only for the approved indication(s) in accordance with the approved label. The 
FDA and other regulatory authorities actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a 
company that is found to have improperly promoted off-label uses may be subject to significant liability. 
 
 
 
43

In addition, when approved, the FDA or a foreign regulatory authority may condition approval on the performance of post-
approval clinical studies or patient monitoring, which could be time consuming and expensive. For example, in connection with the 
conditional marketing approval for WAYLIVRA in the EU, we are required to conduct a post-authorization safety study to evaluate 
the safety of WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. If the results of such post-
marketing studies are not satisfactory, the FDA, EC or other foreign regulatory authorities may withdraw marketing authorization or 
may condition continued marketing on commitments from us or our partners that may be expensive and time consuming to fulfill. 
 
If we or others identify side effects after any of our medicines are on the market, or if manufacturing problems occur 
subsequent to regulatory approval, or if we, our CMOs or our partners fail to comply with regulatory requirements, we or our partners 
may, among other things, lose regulatory approval and be forced to withdraw products from the market, need to conduct additional 
clinical studies, incur restrictions on the marketing, distribution or manufacturing of the product, and/or change the labeling of our 
medicines. 
 
We depend on our collaborations with Biogen for the development and commercialization of SPINRAZA and QALSODY. 
 
We have entered into separate collaborative arrangements with Biogen to develop and commercialize SPINRAZA and 
QALSODY. We entered into these collaborations primarily to: 
 
● 
fund our development activities for SPINRAZA and QALSODY; 
● 
seek and obtain regulatory approvals for SPINRAZA and QALSODY; and 
● 
successfully commercialize SPINRAZA and QALSODY. 
 
We are relying on Biogen to obtain additional regulatory approvals for SPINRAZA and QALSODY, generate additional 
clinical data for SPINRAZA and QALSODY, manufacture SPINRAZA and QALSODY, and successfully commercialize SPINRAZA 
and QALSODY. In general, we cannot control the amount and timing of resources that Biogen devotes to our collaborations. If 
Biogen fails to further develop SPINRAZA or QALSODY, obtain additional regulatory approvals for SPINRAZA or QALSODY, 
manufacture SPINRAZA or QALSODY, or successfully commercialize SPINRAZA or QALSODY, or if Biogen’s efforts in any of 
these respects are ineffective, revenues for SPINRAZA or QALSODY would be negatively affected. 
 
In addition, our collaborations with Biogen may not continue for various reasons. Biogen can terminate our collaborations at 
any time. If Biogen stops developing or commercializing SPINRAZA or QALSODY, we would have to seek or spend additional 
funding, and SPINRAZA’s or QALSODY’s commercialization may be harmed. 
 
We depend on our collaboration with AstraZeneca for the joint development and commercialization of WAINUA. 
 
We have entered into a collaborative arrangement with AstraZeneca to develop and commercialize WAINUA. Under the 
terms of the collaboration agreement, we and AstraZeneca will co-develop and co-commercialize WAINUA in the U.S. and 
AstraZeneca will have the sole right to commercialize WAINUA in all other countries. As a company we do not have experience with 
co-commercialization arrangements. We also do not have control over (1) the amount and timing of resources that AstraZeneca 
devotes to our collaboration, particularly outside of the U.S; (2) the pricing and reimbursement strategies for WAINUA; and (3) 
whether AstraZeneca elects to terminate the collaborative arrangement. If the co-commercialization arrangement for WAINUA is not 
successful for any reason, WAINUA may not meet our commercial objectives and our revenues for WAINUA may be limited. 
 
In addition, a Joint Steering Committee, or JSC, having equal membership from us and AstraZeneca, and various 
subcommittees oversee and coordinate the development, manufacturing, commercialization and other exploitation activities for 
WAINUA in the U.S. by mutual agreement. If any subcommittee cannot reach unanimous agreement on any matter within its 
respective scope of authority, such matter may be referred to the JSC for resolution. If the JSC cannot come to a mutual agreement on 
any particular matter, this could delay our ability to develop or commercialize WAINUA. 
 
If we are not successful in expanding our manufacturing capabilities or cannot manufacture our medicines or contract with a 
third party to manufacture our medicines at costs that allow us to charge competitive prices to buyers, we cannot market our 
products profitably. 
 
To successfully commercialize any of our medicines, we need to optimize and manage large-scale commercial manufacturing 
capabilities either on a standalone basis or through a third-party manufacturer. As our drug development and commercial pipeline 
increases and matures, we will have a greater need for clinical trial and commercial manufacturing capacity. We will also need to 
ensure that we have the manufacturing capabilities in place to support advances in our drug development activities, such as new 
chemistries. While we believe our current capabilities and those we obtain through third-party manufacturers support our 
manufacturing needs now, it will be important to expand our manufacturing infrastructure in the future, which will likely require 
substantial expenditures. If we are not successful in executing this expansion, it could limit our ability to meet our manufacturing 
requirements and commercial objectives in the future. 
 
 
 
44

In addition, we have limited experience manufacturing pharmaceutical products of the chemical class represented by our 
medicines, called oligonucleotides, on a commercial scale for the systemic administration of a medicine. There are a small number of 
suppliers for certain capital equipment and raw materials that we use to manufacture our medicines, and some of these suppliers will 
need to increase their scale of production to meet our projected needs for commercial manufacturing. If a supplier chooses to devote 
more resources to other products, especially products with higher manufacturing capacity needs, that could impact such supplier’s 
capability to deliver our requirements timely. Further, we must continue to improve our manufacturing processes to allow us to reduce 
our drug costs. We or our partners may not be able to manufacture our medicines at a cost or in quantities necessary to make 
commercially successful products. 
 
Manufacturers, including us, must adhere to the FDA’s cGMP regulations and similar regulations in foreign countries, which 
the applicable regulatory authorities enforce through facilities inspection programs. We, our partners and our contract manufacturers 
may not comply or maintain compliance with cGMP, or similar foreign regulations. Non-compliance could significantly delay or 
prevent receipt of marketing authorizations for our medicines, including authorizations for our commercial medicines and our 
medicines in development, or could result in enforcement action after authorization that might limit the commercial success of our 
medicines. 
 
We rely on third-party manufacturers to supply the drug substance and drug product for TRYNGOLZA and WAINUA and 
drug product for WAYLIVRA. The operations of our suppliers, many of which are located outside of the United States, are subject to 
additional risks that are beyond our control. For example, there have been Congressional legislative proposals, such as the recent bill 
titled the BIOSECURE Act, to discourage contracting with Chinese companies for the development or manufacturing of 
pharmaceutical products. In addition, merger and acquisition activity within the commercial manufacturing space could reduce the 
availability of resources from our third-party manufacturers. Delays or disruption to our own or third-party commercial manufacturing 
capabilities for any reason could limit the commercial success of our medicines. 
 
Risks Related to the Development and Regulatory Approval of our Medicines 
 
If we or our partners fail to obtain regulatory approval for our medicines and additional approvals for our commercial 
medicines, we or our partners cannot sell them in the applicable markets. 
 
We cannot guarantee that any of our medicines will be considered safe and effective or will be approved for 
commercialization. In addition, it is possible that our commercial medicines may not be approved in additional markets or for 
additional indications. We and our partners must conduct time-consuming, extensive and costly clinical studies to demonstrate the 
safety and efficacy of each of our medicines before they can be approved or receive additional approvals for sale. We and our partners 
must conduct these studies in compliance with FDA regulations and with comparable regulations in other countries. 
 
We and our partners may not obtain necessary regulatory approvals on a timely basis, if at all, for our medicines. It is 
possible that regulatory authorities will not approve our medicines for marketing or our commercial medicines in additional markets or 
for additional indications. If the FDA or another regulatory authority believes that we or our partners have not sufficiently 
demonstrated the safety or efficacy of any of our medicines, including our commercial medicines or our medicines in development, 
the authority will not approve the specific medicine or will require additional studies, which could be time consuming and expensive 
and delay or harm commercialization of the medicine. For example, in August 2018 we received a complete response letter from the 
FDA regarding the new drug application for WAYLIVRA in which the FDA determined that the safety concerns identified with 
WAYLIVRA in our clinical development program outweighed the expected benefits of triglyceride lowering in patients with FCS. We 
also received a Notice of Non-Compliance Withdrawal Letter, or Non-W, from Health Canada for WAYLIVRA in November 2018.  
 
The FDA or other comparable foreign regulatory authorities can delay, limit or deny approval of a medicine for many 
reasons, including: 
 
● 
such authorities may disagree with the design or implementation of our clinical studies; 
● 
we or our partners may be unable to demonstrate to the satisfaction of the FDA or other regulatory authorities that a 
medicine is safe and effective for any indication; 
● 
such authorities may not accept clinical data from studies conducted at clinical facilities that have deficient clinical 
practices or that are in countries where the standard of care is potentially different from the U.S.; 
● 
we or our partners may be unable to demonstrate that our medicine’s clinical and other benefits outweigh its safety risks 
to support approval; 
● 
such authorities may disagree with the interpretation of data from preclinical or clinical studies; 
● 
such authorities may find deficiencies in the manufacturing processes or facilities of third-party manufacturers who 
manufacture clinical and commercial supplies for our medicines; and 
● 
the approval policies or regulations of such authorities or their prior guidance to us or our partners during clinical 
development may significantly change in a manner rendering our clinical data insufficient for approval. 
 
 
 
45

Failure to receive marketing authorization for our medicines in development, or failure to receive additional marketing 
authorizations for our commercial medicines, or delays in these authorizations, could prevent or delay commercial introduction of the 
medicine, and, as a result, could negatively impact our ability to generate revenue from product sales. 
 
If the results of clinical testing indicate that any of our medicines are not suitable for commercial use, we may need to abandon 
one or more of our drug development programs. 
 
Drug discovery and drug development have inherent risks and the historical failure rate for drugs is high. Antisense 
medicines are a relatively new approach to therapeutics. If we cannot demonstrate that our medicines are safe and effective for human 
use in the intended indication(s), we may need to abandon one or more of our drug development programs. 
 
Even if our medicines are successful in preclinical and human clinical studies, the medicines may not be successful in late-stage 
clinical studies. Similarly, topline, preliminary or interim data we release for any of our clinical studies may not be indicative 
of full or final results from such study. 
 
Successful results in preclinical or initial human clinical studies, including the Phase 2 results for some of our medicines in 
development, may not predict the results of subsequent clinical studies. If any of our medicines in Phase 3 clinical studies do not show 
sufficient safety and efficacy in patients with the targeted indication, or if such studies are discontinued for any other reason, it could 
negatively impact our development and commercialization goals for these medicines and our stock price could decline. In addition, we 
may release topline, preliminary or interim data for any of our clinical studies.  The interim, topline or preliminary results we report 
may differ from future results of the same studies, or different conclusions or considerations may qualify such results, once additional 
data have been received and fully evaluated.  As a result, such data should be viewed with caution until the final data are available. 
 
In the past, we have invested in clinical studies of medicines that have not met the primary clinical endpoints in their Phase 3 
studies or have been discontinued for other reasons. For example, in October 2021, Biogen reported that QALSODY did not meet the 
primary clinical endpoint in the Phase 3 VALOR study; however, trends favoring QALSODY were seen across multiple secondary 
and exploratory measures of disease activity and clinical function. In addition, in March 2021, Roche decided to discontinue dosing in 
the Phase 3 GENERATION HD1 study of tominersen in patients with manifest Huntington’s disease based on the results of a pre-
planned review of data from the Phase 3 study conducted by an unblinded Independent Data Monitoring Committee. Similar results 
could occur in clinical studies for our other medicines. 
 
There are a number of factors that could cause a clinical study to fail or be delayed, including: 
 
● 
the clinical study may produce negative or inconclusive results; 
● 
regulators may require that we hold, suspend or terminate clinical research for noncompliance with regulatory 
requirements; 
● 
we, our partners, the FDA or foreign regulatory authorities could suspend or terminate a clinical study due to adverse 
side effects of a medicine on subjects or lack of efficacy in the trial; 
● 
we or our partners may decide, or regulators may require us, to conduct additional preclinical testing or clinical studies; 
● 
enrollment in our clinical studies may be slower than we anticipate; 
● 
we or our partners, including our independent clinical investigators, contract research organizations and other third-party 
service providers on which we rely, may not identify, recruit or train suitable clinical investigators at a sufficient number 
of study sites or timely enroll a sufficient number of study subjects in the clinical study; 
● 
the institutional review board for a prospective site might withhold or delay its approval for the study; 
● 
people who enroll in the clinical study may later drop out due to adverse events, a perception they are not benefiting 
from participating in the study, fatigue with the clinical study process or personal issues; 
● 
a clinical study site may deviate from the protocol for the study; 
● 
the cost of our clinical studies may be greater than we anticipate; 
● 
our partners may decide not to exercise any existing options to license and conduct additional clinical studies for our 
medicines; and 
● 
the supply or quality of our medicines or other materials necessary to conduct our clinical studies may be insufficient, 
inadequate or delayed. 
 
Further, the FDA or other regulatory authorities could request, among other things, additional information or commitments 
before we can start or continue a clinical study, protocol amendments, increased safety monitoring, additional product labeling 
information, and post-approval commitments. This happened in connection with the conditional marketing approval for WAYLIVRA 
in the EU, as the European Commission is requiring us to conduct a post-authorization safety study to evaluate the safety of 
WAYLIVRA on thrombocytopenia and bleeding in FCS patients taking WAYLIVRA. In addition, under accelerated approval the 
FDA is requiring completion of the ongoing Phase 3 trial for QALSODY to confirm the clinical benefit of QALSODY.  
 
 
 
46

Moreover, our commercial medicines are chemically similar to each other. As a result, a safety observation we encounter 
with one of our medicines could have, or be perceived by a regulatory authority to have, an impact on a different medicine we are 
developing. This could cause the FDA or other regulators to ask questions or take actions that could harm or delay our ability to 
develop and commercialize our medicines or increase our costs. Any failure or delay in our clinical studies could reduce the 
commercial potential or viability of our medicines. 
 
We depend on third parties to conduct clinical studies for our medicines and any failure of those parties to fulfill their 
obligations could adversely affect our development and commercialization plans. 
 
We depend on independent clinical investigators, contract research organizations and other third-party service providers to 
conduct our clinical studies for our medicines and expect to continue to do so in the future. For example, we use clinical research 
organizations, such as Icon Clinical Research Limited, Medpace, Inc., Parexel International Corporation, Syneos Health, Inc. and 
Thermo Fisher Scientific Inc. for the clinical studies for our medicines, including WAINUA for the treatment of ATTR-CM, 
donidalorsen, olezarsen, ulefnersen and zilganersen. We rely heavily on these parties for successful execution of our clinical studies, 
but do not control many aspects of their activities. For example, the investigators are not our employees, but we are responsible for 
ensuring that such investigators conduct each of our clinical studies in accordance with the general investigational plan and approved 
protocols for the study. Third parties may not complete activities on schedule or may not conduct our clinical studies in accordance 
with regulatory requirements or our stated protocols. For example, some of our key vendors have in the past experienced labor 
shortages, which impacted their ability to perform services for us for certain of our clinical trials. Subsequent failures of these third 
parties to carry out their obligations, or a termination of our relationship with such third parties, could delay or prevent the 
development, marketing authorization and commercialization of our medicines. 
 
In addition, while we do not have any clinical trial sites in Russia, Ukraine or Gaza, we do have a limited number of clinical 
trial sites in Israel that may be materially impacted by the ongoing military conflicts in Israel and elsewhere in the Middle East and 
could result in difficulties enrolling or completing our clinical trials in such areas on schedule. 
 
Since corporate partnering is part of our strategy to fund the advancement and commercialization of our development 
programs, if any of our collaborative partners fail to fund our collaborative programs, or if we cannot obtain additional 
partners, we may have to delay or stop progress on our drug development programs. 
 
To date, corporate partnering has played a significant role in our strategy to fund our development programs and to add key 
development resources. While we are now commercializing some of our medicines independently, we still plan to continue to rely on 
additional collaborative arrangements to develop and commercialize some of our unpartnered medicines. However, we may not be 
able to negotiate favorable collaborative arrangements for these drug programs. If we cannot continue to secure additional 
collaborative partners, our revenues could decrease and the development of our medicines could suffer. 
 
Our corporate partners are developing and funding many of the medicines in our development pipeline. For example, we are 
relying on: 
 
● 
AstraZeneca for the joint development and funding of WAINUA;  
● 
Novartis for development and funding of pelacarsen; 
● 
GSK for development and funding of bepirovirsen; and 
● 
Roche for development and funding of sefaxersen. 
 
If any of these pharmaceutical companies stops developing and funding these medicines, our business could suffer and we 
may not have, or be willing to dedicate, the resources available to develop these medicines on our own. Our collaborators can 
terminate their relationships with us under certain circumstances, many of which are outside of our control. For example, in 2022, 
Pfizer and Bayer decided to discontinue the clinical development programs for vupanorsen and fesomersen, respectively. 
 
Even with funding from corporate partners, if our partners do not effectively perform their obligations under our agreements 
with them, it would delay or stop the progress of our drug development and commercial programs. 
 
In addition to receiving funding, we enter into collaborative arrangements with third parties to: 
 
● 
conduct clinical studies; 
● 
seek and obtain marketing authorizations; and 
● 
manufacture and commercialize our medicines. 
 
 
 
47

Once we have secured a collaborative arrangement to further develop and commercialize one of our drug development 
programs, such as our collaborations with AstraZeneca, Biogen, GSK, Novartis, Otsuka and Roche, these collaborations may not 
continue or result in commercialized medicines, or may not progress as quickly as we anticipated. 
 
For example, a collaborator such as AstraZeneca, Biogen, GSK, Novartis, Otsuka or Roche, could determine that it is in its 
financial interest to: 
 
● 
pursue alternative technologies or develop alternative products that may be competitive with the medicine that is part of 
the collaboration with us; 
● 
pursue higher-priority programs or change the focus of its own development programs; or 
● 
choose to devote fewer resources to our medicines than it does to its own medicines. 
 
If any of these occur, it could affect our partner’s commitment to the collaboration with us and could delay or otherwise 
negatively affect the commercialization of our medicines, including QALSODY, SPINRAZA, WAINUA, bepirovirsen, donidalorsen, 
sefaxersen and pelacarsen. 
 
We may not be able to benefit from designations for our medicines from regulatory authorities that are intended to confer 
benefits such as financial incentives or an accelerated regulatory pathway. 
 
In the U.S., under the Orphan Drug Act, the FDA may designate a medicine as an Orphan Drug if it is intended to treat a 
rare disease or condition affecting fewer than 200,000 individuals in the U.S. Orphan Drug designation does not convey any advantage 
in, or shorten the duration of, the regulatory review and approval process, but it can provide financial incentives, such as tax 
advantages and user-fee waivers, as well as longer regulatory exclusivity periods. The FDA has granted Orphan Drug designation to 
TRYNGOLZA for the treatment of patients with FCS, to WAINUA for the treatment of patients with ATTR, to ulefnersen for the 
treatment of patients with FUS-ALS, to ION582 for the treatment of patients with Angelman syndrome, and to some of our earlier 
stage medicines. The FDA and EMA have granted Orphan Drug designation to donidalorsen for the treatment of patients with HAE, 
to WAYLIVRA for the treatment of patients with FCS, to tominersen for the treatment of patients with HD, and to some of our earlier 
stage medicines. In addition, the EMA has granted Orphan Drug designation to WAYLIVRA for the treatment of patients with FPL. 
Even if approval is obtained on a medicine that has been designated as an Orphan Drug, we may lose Orphan Drug exclusivity if the 
FDA or EMA determines that the request for designation was materially defective or if we cannot assure sufficient quantity of the 
applicable medicine to meet the needs of patients with the rare disease or condition, or if a competitor is able to gain approval for the 
same or a substantially similar medicine in a safer or more effective form or that makes a major contribution to patient care. If we lose 
Orphan Drug exclusivity on any of our medicines, we may face increased competition and lose market share for such medicine. 
 
We may also seek rare pediatric disease designation for some of our medicines. The FDA defines “rare pediatric disease” as a 
serious or life-threatening disease in which the serious or life-threatening manifestations primarily affect individuals aged from birth 
to 18 years or is a rare disease or condition within the meaning of the Orphan Drug Act. Designation of a medicine as a medicine for a 
rare pediatric disease does not guarantee that a marketing application for such medicine will meet the eligibility criteria for a rare 
pediatric disease priority review voucher, or PRV, at the time the application is approved. Under the FDCA, we will need to request a 
rare pediatric disease PRV in our original marketing application for any potential medicine for which we have received rare pediatric 
disease designation. The FDA may determine that a marketing application for any such medicine, if approved, does not meet the 
eligibility criteria for a PRV. Under the current statutory sunset provisions, after December 20, 2024, the FDA may only award a PRV 
for an approved rare pediatric disease application if the sponsor has rare pediatric disease designation for the drug or biologic that is 
the subject of such application, and that designation was granted by December 20, 2024. After September 30, 2026, the FDA may not 
award any rare pediatric disease PRVs. However, it is possible the authority for FDA to award rare pediatric disease PRV will be 
further extended by Congress.  
 
 
 
48

Risks Associated with our Businesses as a Whole 
 
Risks related to our financial condition 
 
If we fail to obtain timely funding, we may need to curtail or abandon some of our programs. 
 
Many of our medicines are undergoing clinical studies or are in the early stages of research and development. Most of our 
programs will require significant additional research, development, manufacturing, preclinical and clinical testing, marketing 
authorizations, preclinical activities and commitment of significant additional resources prior to their successful commercialization. In 
addition, as we commercialize more medicines on our own, we will need to invest significant financial resources to continue 
developing the infrastructure required to successfully commercialize our medicines, including building and maintaining new support 
functions and scaling up existing internal support functions and expanding our manufacturing capabilities. All of these activities will 
require significant cash. As of December 31, 2024, we had cash, cash equivalents and short-term investments equal to $2.3 billion. If 
we or our partners do not meet our goals to successfully commercialize our medicines, including our commercial medicines, or to 
license certain medicines and proprietary technologies, we will need additional funding in the future. Our future capital requirements 
will depend on many factors such as: 
 
● 
successful commercialization of our commercial medicines; 
● 
the profile and launch timing of our medicines in development; 
● 
changes in existing collaborative relationships and our ability to establish and maintain additional collaborative 
arrangements; 
● 
continued scientific progress in our research, drug discovery and development programs; 
● 
the size of our programs and progress with preclinical and clinical studies; 
● 
the time and costs involved in obtaining marketing authorizations; 
● 
competing technological and market developments, including the introduction by others of new therapies that address 
our markets; and 
● 
our manufacturing requirements and capacity to fulfill such requirements. 
 
If we need additional funds, we may need to raise them through public or private financing. Additional financing may not be 
available on acceptable terms or at all. If we raise additional funds by issuing equity securities, the shares of existing stockholders will 
be diluted and the price, as well as the price of our other securities, may decline. For example, in September 2024, we completed an 
underwritten public offering of 11,500,000 shares of our common stock for total net proceeds, after deducting underwriting discounts 
and commissions and other offering expenses payable by us, of approximately $489.1 million. If adequate funds are not available or 
not available on acceptable terms, we may have to cut back on one or more of our research, drug discovery or development programs, 
or commercial operations. Alternatively, we may obtain funds through arrangements with collaborative partners or others, which 
could require us to give up rights to certain of our technologies or medicines. 
 
We have incurred losses, and our business will suffer if we fail to consistently achieve profitability in the future. 
 
Because drug discovery and development require substantial lead-time and money prior to commercialization, our expenses 
have generally exceeded our revenue since we were founded in January 1989. As of December 31, 2024, we had an accumulated 
deficit of approximately $2.2 billion and stockholders’ equity of approximately $0.6 billion. Most of our income has historically come 
from collaborative arrangements, including commercial revenue from royalties and R&D revenue, with additional income from 
research grants and the sale or licensing of our patents, as well as interest income. We will now and continuing into the foreseeable 
future need to invest significant financial resources to commercialize medicines on our own and expect that our income in the future 
will be driven primarily by commercial sales. If we do not earn substantial revenue from commercial sales, we may incur additional 
operating losses in the future, which could restrict our ability to successfully develop additional medicines or sustain future 
profitability. 
 
We may not be entitled to obtain additional milestone payments under our royalty monetization agreement with Royalty 
Pharma. 
 
In January 2023, we entered into a Royalty Purchase Agreement with Royalty Pharma Investments. In addition to the $500 
million we received at closing, this agreement makes available to us up to an additional $625 million in milestone payments. 
However, these additional milestone payments are subject to satisfaction of certain conditions related to the regulatory approval or 
commercial sales of pelacarsen, in certain cases by specific deadlines. Should we not satisfy such conditions by the applicable 
deadlines, or if we fail to meet our obligations or default under this agreement, the actual amount of additional payments to us could 
be substantially less than the maximum amounts available thereunder. 
 
 
 
49

Risks related to our intellectual property 
 
If we cannot protect our patent rights or our other proprietary rights, others may compete more effectively against us. 
 
Our success depends to a significant degree upon whether we can continue to develop, secure and maintain intellectual 
property rights to proprietary products and services. However, we may not receive issued patents on any of our pending patent 
applications in the U.S. or in other countries and we may not be able to obtain, maintain or enforce our patents and other intellectual 
property rights, any of which could impact our ability to compete effectively. In addition, the scope of any of our issued patents may 
not be sufficiently broad to provide us with a competitive advantage. Furthermore, other parties may successfully challenge, invalidate 
or circumvent our issued patents or patents licensed to us so that our patent rights do not create an effective competitive barrier or 
revenue source. 
 
We cannot be certain that the U.S. Patent and Trademark Office, or U.S. PTO, and courts in the U.S. or the patent offices and 
courts in foreign countries will consider the claims in our patents and applications covering our commercial medicines, or any of our 
medicines in development, as patentable. Method-of-use patents protect the use of a product for the specified method. This type of 
patent does not prevent a competitor from making and marketing a product that is identical to our product for an indication that is 
outside the scope of the patented method. Moreover, even if competitors do not actively promote their product for our targeted 
indications, physicians may prescribe these products off-label. Although off-label prescriptions may infringe or contribute to the 
infringement of method-of-use patents, the practice is common and such infringement is difficult to prevent, even through legal action. 
 
If we or any licensor partner loses or cannot obtain patent protection for our commercial medicines or any of our medicines in 
development, it could have a material adverse impact on our business. 
 
Intellectual property litigation could be expensive and prevent us from pursuing our programs. 
 
From time to time, we have to defend our intellectual property rights. If we are involved in an intellectual property dispute, 
we may need to litigate to defend our rights or assert them against others. Disputes can involve arbitration, litigation or proceedings 
declared by the U.S. PTO or the International Trade Commission or foreign patent authorities. 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.  
 
If a third party claims that our medicines or technology infringe its patents or other intellectual property rights, we may have 
to discontinue an important product or product line, alter our products and processes, pay license fees or cease certain activities. We 
may not be able to obtain a license to needed intellectual property on favorable terms, if at all. There are many patents issued or 
applied for in the biotechnology industry, and we may not be aware of patents or patent applications held by others that relate to our 
business. This is especially true since patent applications in the U.S. are filed confidentially for the first 18 months. Moreover, the 
validity and breadth of biotechnology patents involve complex legal and factual questions for which important legal issues remain. 
 
Risks related to product liability 
 
We are exposed to potential product liability claims, and insurance against these claims may not be available to us at a 
reasonable rate in the future or at all. 
 
Our business exposes us to potential product liability risks that are inherent in the testing, manufacturing, marketing and sale 
of therapeutic products, including potential product liability claims related to our commercial medicines and our medicines in 
development. We have clinical study insurance coverage and commercial product liability insurance coverage. However, this 
insurance coverage may not be adequate to cover claims against us, or be available to us at an acceptable cost, if at all. Regardless of 
their merit or eventual outcome, product liability claims may result in decreased demand for our medicines, injury to our reputation, 
withdrawal of clinical study volunteers and loss of revenues. Thus, whether or not we are insured, a product liability claim or product 
recall may result in losses that could be material. 
 
 
 
50

Risks related to our personnel 
 
The loss of key personnel, or the inability to attract and retain highly skilled personnel, could make it more difficult to run our 
business and reduce our likelihood of success. 
 
We are dependent on the principal members of our management, scientific and commercial staff. We do not have 
employment agreements with any of our employees that would prevent them from leaving us. The loss of our key management, 
scientific or commercial employees might slow the achievement of important research and development or commercial goals. It is also 
critical to our success that we recruit and retain qualified scientific personnel to perform research and development work and that we 
recruit and retain qualified marketing, sales, market access, distribution, and related personnel to commercialize our medicines. We 
may not be able to attract and retain skilled and experienced personnel on acceptable terms because of intense competition for 
experienced personnel among many pharmaceutical and health care companies, universities and non-profit research institutions. In 
addition, failure to succeed in clinical studies or in commercializing our medicines may make it more challenging to recruit and retain 
qualified personnel.  
 
Risks related to health epidemics, climate change and other events 
 
Our business may be adversely affected by health epidemics, climate change, extreme weather events, fires, earthquakes, war, 
civil or political unrest, terrorism or other catastrophic events. 
 
Our business could be adversely affected by health epidemics in regions where we or our partners are commercializing our 
medicines, have concentrations of clinical trial sites or other business operations, and could cause disruption in the operations of third-
party manufacturers and contract research organizations upon whom we rely. For example, enrollment in some of our clinical trials 
was delayed due to the COVID-19 pandemic.   
 
In recent years, extreme weather events and changing weather patterns have become more common. As a result, we are 
potentially exposed to varying natural disaster or extreme weather risks such as fires, hurricanes, tornadoes, droughts, floods, or other 
events that may result from the impact of climate change on the environment, any of which could impact our business and 
manufacturing operations. The potential impacts of climate change may also include increased operating costs associated with 
additional regulatory requirements and investments in reducing energy, water use and greenhouse gas emissions. In addition, we 
currently manufacture most of our research and clinical supplies in a manufacturing facility located in Carlsbad, California, and 
various regions within California have recently experienced numerous catastrophic wildfires. We manufacture the finished drug 
product for TRYNGOLZA, WAYLIVRA and eplontersen for ongoing clinical trials at third-party contract manufacturers. Biogen 
manufactures the finished drug product for SPINRAZA and QALSODY and AstraZeneca is responsible for WAINUA’s commercial 
drug supply. The facilities and the equipment we, our partners and our contract manufacturers use to research, develop and 
manufacture our medicines would be costly to replace and could require substantial lead time to repair or replace.  
 
Our facilities or those of our partners or contract manufacturers may be harmed by natural disasters or other events outside 
our control, such as earthquakes, war, civil or political unrest, deliberate acts of sabotage, terrorism or industrial accidents such as fire 
and explosion, whether due to human or equipment error, and if such facilities are affected by a disaster or other event, our 
development and commercialization efforts would be delayed. Although we possess property damage and business interruption 
insurance coverage, this insurance may not be sufficient to cover all of our potential losses and may not continue to be available to us 
on acceptable terms, or at all. In addition, our development and commercialization activities could be harmed or delayed by a 
shutdown or significant disruption of the U.S. government, including the FDA or the U.S. PTO.  
 
 
 
51

Risks related to personal information, cybersecurity, social media and artificial intelligence 
 
We are dependent on data as well as information technology systems and infrastructure, which exposes us to data protection 
risks. 
 
We are dependent upon our own and third-party data as well as information technology systems and infrastructure, including 
mobile technologies, to operate our business. The personal information we process subjects us to stringent and evolving U.S. and 
foreign laws, rules and regulations, contractual obligations, industry standards and other obligations related to data privacy and 
security. Our personal information obligations require us to implement and maintain certain practices, including those in relation to 
cross-border transfers of personal information. The multitude and complexity of our information technology systems and 
infrastructure make them vulnerable to a variety of evolving threats that may result in systems or data interruption, corruption, 
destruction, disruption of data integrity, malicious intrusion, or random attacks or other compromise (such as due to malfunctions, 
software vulnerabilities, natural disasters, telecommunications failures, malicious actors and personnel error). Data privacy or security 
incidents or breaches pose a risk that sensitive data, including our intellectual property, trade secrets or personal information of our 
employees, patients, customers or other business partners may be exposed to unauthorized persons. Cyber-attacks are increasing in 
their frequency, sophistication and intensity, particularly as companies (including us) continue to move to more remote work 
structures. In addition, the number and frequency of cybersecurity events globally may be heightened during times of geopolitical 
tension or instability between countries, including, for example, the ongoing war between Russia and Ukraine and military conflicts in 
the Middle East and the surrounding areas, or collectively, conflicts in Eastern Europe and the Middle East, as well as related political 
or economic responses and counter-responses by various global actors. 
 
Cybersecurity related events could include the deployment or use of harmful malware or malicious code, denial-of-service 
attacks, credential stuffing attacks, credential harvesting attacks, social engineering attacks (including deep fakes), ransomware and 
other means to affect the confidentiality, integrity or availability of our data as well as information systems and infrastructure. Our 
current, past and prospective business partners face similar risks and any security breaches of their systems could adversely affect our 
security posture. A security breach or privacy violation (including perceived breaches or violations) could result in any of the 
following, any of which could disrupt our business and result in increased costs or loss of revenue: 
 
● 
harm our reputation; 
● 
delay progress on the development of our medicines; 
● 
compel us to comply with applicable security or data breach notification obligations (including laws);  
● 
result in the diversion of monetary funds and other company resources; 
● 
subject us to financial or other penalties, regulatory investigations or actions, including mandatory and costly corrective 
actions; and 
● 
require us to verify the correctness of database contents and otherwise subject us to litigation or other liabilities.  
 
Risk mitigation strategies such as liability limitations in our contracts and insurance coverage may prove inadequate if there 
is a security breach or privacy violation. While we have invested, and continue to invest, in the protection of our data and information 
technology systems and infrastructure, our efforts may not be successful. Non-compliance with relevant data protection obligations or 
a failure to secure our data, information technology systems or infrastructure could adversely affect our business and operations and 
result in the loss of critical or sensitive information, which could result in financial, legal, business or reputational harm to us.  
 
The increasing use of social media platforms and artificial intelligence based software presents new risks and challenges. 
 
Social media is increasingly being used to communicate about our medicines and the diseases our therapies are designed to 
treat. Social media practices in the biopharmaceutical industry continue to evolve and regulations relating to such use are not always 
clear and create uncertainty and risk of noncompliance with regulations applicable to our business. There is also a risk of inappropriate 
disclosure of sensitive information or negative or inaccurate posts or comments about us on social media. We may also encounter 
criticism on social media regarding our company, management, or medicines. Our reputation could be damaged by negative publicity 
or if adverse information concerning us is posted on social media platforms or similar mediums, which we may not be able to reverse. 
If any of these events were to occur or we otherwise fail to comply with applicable regulations, we could incur liability, face 
restrictive regulatory actions or incur other harm to our business.  
 
Additionally, artificial intelligence, or AI, based software is increasingly being used in the biopharmaceutical industry. Use of 
AI based software may lead to the release of confidential proprietary information, which may impact our ability to realize the benefit 
of our intellectual property. 
 
 
 
52

Risks related to our securities and the global credit markets 
 
If we do not progress in our programs as anticipated, the price of our securities could decrease. 
 
For planning purposes, we estimate and may disclose the timing of a variety of clinical, regulatory and other milestones, such 
as when we anticipate a certain medicine will enter clinical trials, when we anticipate disclosing clinical data, when we anticipate 
completing a clinical study, or when we anticipate filing an application for, or obtaining, marketing authorization, or when we or our 
partners plan to commercially launch a medicine. We base our estimates on present facts and a variety of assumptions, many of which 
are outside of our control. If we do not achieve milestones in accordance with our or our investors’ or securities analysts’ expectations, 
including milestones related to our commercial medicines and medicines in development, the price of our securities could decrease. In 
addition, our share price may be dependent upon the valuations and recommendations of the analysts who cover our business. If our 
results do not meet these analysts’ forecasts, the expectations of our investors or the financial guidance we provide to investors in any 
period, the market price of our common stock could decline. Our ability to meet analysts’ forecasts, investors’ expectations and our 
financial guidance is substantially dependent on our ability to maintain or increase sales of our commercial medicines, both partnered 
and unpartnered. 
 
If the price of our securities continues to be highly volatile, this could make it harder to liquidate your investment and could 
increase your risk of suffering a loss. 
 
The market price of our common stock, like that of the securities of many other biopharmaceutical companies, has been and 
is likely to continue to be highly volatile. These fluctuations in our common stock price may significantly affect the trading price of 
our securities. During the 12 months preceding December 31, 2024, the closing market price of our common stock ranged from $53.55 
to $33.73 per share. Many factors can affect the market price of our securities, including, for example, fluctuations in our operating 
results, financing transactions, announcements of collaborations, clinical study results, technological innovations or new products 
being developed by us or our competitors, the commercial success of our approved medicines, governmental regulation, marketing 
authorizations, changes in payers’ reimbursement policies, developments in patent or other proprietary rights and public concern 
regarding the safety of our medicines.  
 
Broad market factors may materially harm the market price of our common stock irrespective of our operating performance. 
For example, events such as the ongoing conflicts in Eastern Europe and the Middle East have caused disruptions of global financial 
markets and resulted in increased volatility in the trading price of our common stock. In addition, industry factors may materially harm 
the market price of our common stock. Nasdaq, and the market for biotechnology companies in particular, have historically 
experienced extreme price and volume fluctuations that have often been unrelated or disproportionate to the operating performance of 
the particular companies affected. The trading prices and valuations of these stocks, and of ours, may not be predictable. A loss of 
investor confidence in the market for biotechnology or pharmaceutical stocks or the stocks of other companies that investors perceive 
to be similar to us, the opportunities in the biotechnology and pharmaceutical market or the stock market in general, could depress our 
stock price regardless of our business, prospects, financial conditions or results of operations. 
 
Negative conditions in the global credit markets and financial services and other industries may adversely affect our business, 
financial condition or stock price. 
 
The global credit and financial markets have experienced extreme volatility and disruptions recently, including as a result of 
the ongoing conflicts in Eastern Europe and the Middle East. These disruptions can result in severely diminished liquidity and credit 
availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates and uncertainty about 
economic stability. There can be no assurance that further deterioration in credit and financial markets and confidence in economic 
conditions will not occur. If the current equity and credit markets deteriorate, it may make any necessary debt or equity financing 
more difficult, more costly and more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms 
could have a material adverse effect on our operations, growth plans, financial performance or stock price. In addition, our insurance 
carriers and insurance policies covering all aspects of our business may become financially unstable or may not be sufficient to cover 
any or all of our losses and may not continue to be available to us on acceptable terms, or at all. 
 
 
 
53

A variety of risks associated with operating our business and marketing our medicines internationally could adversely affect 
our business. In addition to our U.S. operations, we are commercializing WAYLIVRA in the EU, Latin America and certain 
Caribbean countries. We face risks associated with our international operations, including possible unfavorable regulatory, pricing and 
reimbursement, political, tax and labor conditions, which could harm our business. Because we have international operations, we are 
subject to numerous risks associated with international business activities, including: 
 
● 
compliance with differing or unexpected regulatory requirements for our medicines and foreign employees; 
● 
complexities associated with managing multiple payer reimbursement regimes, government payers or patient self-pay 
systems; 
● 
difficulties in staffing and managing foreign operations; 
● 
in certain circumstances, increased dependence on the commercialization efforts and regulatory compliance of third-
party distributors or strategic partners; 
● 
foreign government taxes, regulations and permit requirements; 
● 
U.S. and foreign government tariffs, trade and export restrictions, price and exchange controls and other regulatory 
requirements; 
● 
anti-corruption laws, including the Foreign Corrupt Practices Act, or the FCPA, and its equivalent in foreign 
jurisdictions; 
● 
economic weakness, including inflation, natural disasters, war, acts of terrorism, political instability or public health 
issues or health epidemics, in particular foreign countries or globally; 
● 
fluctuations in currency exchange rates, which could result in increased operating expenses and reduced revenue, and 
other obligations related to doing business in another country; 
● 
the potential for a local seller, faced with higher local prices, importing medicines from an international market with 
lower prices rather than buying such medicines locally, which is referred to as parallel importation; 
● 
compliance with tax, employment, privacy, immigration and labor laws, regulations and restrictions for employees living 
or traveling abroad; 
● 
workforce uncertainty in countries where labor unrest is more common than in the U.S.; and 
● 
changes in diplomatic and trade relationships. 
 
Our business activities outside of the U.S. are subject to the FCPA and similar anti-bribery or anti-corruption laws, 
regulations or rules of other countries in which we operate, including the United Kingdom’s Bribery Act 2010. In many other 
countries, the healthcare providers who prescribe pharmaceuticals are employed by their government, and the purchasers of 
pharmaceuticals are government entities; therefore, any dealings with these prescribers and purchasers may be subject to regulation 
under the FCPA. There is no certainty that all employees and third-party business partners (including our contract research 
organizations, contract manufacturing organizations, distributors, wholesalers, agents, contractors and other partners) will comply with 
anti-bribery laws. Importantly, we do not control the actions of manufacturers and other third-party agents, although we may be liable 
for their actions. Violation of these laws may result in civil or criminal sanctions, which could include monetary fines, criminal 
penalties, and disgorgement of past profits, which could have an adverse impact on our business and financial condition. 
 
Provisions in our certificate of incorporation, bylaws, convertible notes documents, call spread hedge transaction documents 
and Delaware law may prevent stockholders from receiving a premium for their shares. 
 
Our certificate of incorporation provides for classified terms for the members of our board of directors. Our certificate also 
includes a provision that requires at least 66 2/3 percent of our voting stockholders to approve a merger or certain other business 
transactions with, or proposed by, any holder of 15 percent or more of our voting stock, except in cases where certain directors 
approve the transaction or certain minimum price criteria and other procedural requirements are met. 
 
Our certificate of incorporation also requires that any action required or permitted to be taken by our stockholders must be 
taken at a duly called annual or special meeting of stockholders and may not be taken by written consent. In addition, only our board 
of directors, chairperson of the board or chief executive officer can call special meetings of our stockholders. We have in the past, and 
may in the future, implement a stockholders’ rights plan, also called a poison pill, which could make it uneconomical for a third party 
to acquire our company on a hostile basis. In addition, our board of directors has the authority to fix the rights and preferences of, and 
issue shares of preferred stock, which may have the effect of delaying or preventing a change in control of our company without 
action by our stockholders. 
 
The provisions of our convertible senior notes could make it more difficult or more expensive for a third party to acquire us. 
Upon the occurrence of certain transactions constituting a fundamental change, holders of the notes will have the right, at their option, 
to require us to repurchase all of their notes or a portion of their notes, which may discourage certain types of transactions in which 
our stockholders might otherwise receive a premium for their shares over the then-current market prices. 
 
 
 
54

In 2023, we completed a $575 million offering of 1.75% Notes and used $488.2 million of the net proceeds from the issuance 
of the 1.75% Notes to repurchase $504.4 million of our 0.125% Notes. In 2021, we completed a $632.5 million offering of 0% Notes 
and used $319.0 million of the net proceeds from the issuance of the 0% Notes to repurchase the remaining $309.9 million of our 1% 
Notes. In 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain 
holders of our existing 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue 
$109.5 million of our 0.125% Notes. Additionally, in connection with the pricing of our 0% Notes and 0.125% Notes, we entered into 
call spread transactions in which we purchased note hedges and sold warrants. For our 0.125% Notes, the note hedges expired upon 
maturity of the 0.125% Notes and the warrants will expire in March 2025. Terminating or unwinding the call spread transactions for 
our 0% Notes could require us to make substantial payments to the counterparties under those agreements or may increase our stock 
price. The costs or any increase in stock price that may arise from terminating or unwinding such agreements could make an 
acquisition of our company significantly more expensive to the purchaser. 
 
These provisions, as well as Delaware law, including Section 203 of the Delaware General Corporation Law, and other of our 
agreements, may discourage certain types of transactions in which our stockholders might otherwise receive a premium for their 
shares over then-current market prices, and may limit the ability of our stockholders to approve transactions that they think may be in 
their best interests. 
 
Future sales of our common stock in the public market could adversely affect the trading price of our securities. 
 
Future sales of substantial amounts of our common stock in the public market, or the perception that such sales could occur, 
could adversely affect trading prices of our securities. For example, we may issue approximately 21.6 million shares of our common 
stock upon conversion of our 1.75% Notes and 0% Notes. In connection with the issuance of the 0% Notes, we entered into certain 
call spread transactions covering 10.9 million shares that we expect will offset the dilution to holders of common stock upon any 
conversion of those notes. However, the anti-dilutive effect of the convertible note hedges is offset by certain warrant transactions we 
entered into in connection with the issuance of the 0% Notes. The addition of any of these shares into the public market may have an 
adverse effect on the price of our securities. 
 
In addition, pursuant to the call spread transactions we entered into in connection with the pricing of our 0% Notes, the 
counterparties are likely to modify their hedge positions from time to time at or prior to the conversion or maturity of the notes by 
purchasing and selling shares of our common stock, other of our securities, or other instruments, including over-the-counter derivative 
instruments, that they may wish to use in connection with such hedging, which may have a negative effect on the conversion value of 
those notes and an adverse impact on the trading price of our common stock. The call spread transactions are expected generally to 
reduce potential dilution to holders of our common stock upon any conversion of our 0% Notes or offset any cash payments we are 
required to make in excess of the principal amount of the converted 0% Notes, as the case may be. However, the warrant transactions 
could separately have a dilutive effect to the extent that the market value per share of our common stock exceeds the applicable strike 
price of the warrants. 
 
Risks related to compliance with laws 
 
Our operations are subject to extensive legal and regulatory requirements affecting the health care industry. 
 
Our operations are subject to extensive legal and regulatory requirements affecting the health care industry, including federal 
and state anti-kickback laws, false claims laws, transparency laws, such as the federal Sunshine Act, and health information privacy 
and security laws, which are subject to change at any time. 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. Penalties for violations of applicable healthcare laws and regulations may include significant civil, 
criminal and administrative penalties, damages, disgorgement, fines, imprisonment, exclusion of products from government funded 
healthcare programs, such as Medicare and Medicaid, and additional reporting requirements and oversight if we enter into a corporate 
integrity agreement or similar agreement to resolve allegations of non-compliance with these laws. In addition, violations may also 
result in reputational harm, diminished profits and future earnings. 
 
 
 
55

Because we use biological materials, hazardous materials, chemicals and radioactive compounds, if we do not comply with 
laws regulating the protection of the environment and health and human safety, our business could be adversely affected. 
 
Our research, development and manufacturing activities involve the use of potentially harmful biological materials as well as 
materials, chemicals and various radioactive compounds that could be hazardous to human health and safety or the environment. We 
store most of these materials and various wastes resulting from their use at our facilities in Carlsbad, California pending ultimate use 
and disposal. We cannot completely eliminate the risk of contamination, which could cause: 
 
● 
interruption of our research, development and manufacturing efforts; 
● 
injury to our employees and others; 
● 
environmental damage resulting in costly clean up; and 
● 
liabilities under federal, state and local laws and regulations governing health and human safety, as well as the use, 
storage, handling and disposal of these materials and resultant waste products. 
 
In such an event, we may be held liable for any resulting damages, and any liability could exceed our resources. Although we 
carry insurance for pollution liability in amounts and types that we consider commercially reasonable, the coverage or coverage limits 
of our insurance policies may not be adequate. If our losses exceed our insurance coverage, our financial condition would be adversely 
affected. 
 
Our business is subject to changing regulations for corporate governance and public disclosure that has increased both our 
costs and the risk of noncompliance. 
 
Each year we are required to evaluate our internal control systems to allow management to report on, and our Independent 
Registered Public Accounting Firm to attest to, our internal controls as required by Section 404 of the Sarbanes-Oxley Act. As a 
result, we continue to incur additional expenses and divert our management’s time to comply with these regulations. In addition, if we 
cannot continue to comply with the requirements of Section 404 in a timely manner, we might be subject to sanctions or investigation 
by regulatory authorities, such as the SEC, the Public Company Accounting Oversight Board, or PCAOB, or The Nasdaq Global 
Select Market. Any such action could adversely affect our financial results and the market price of our common stock. 
 
The SEC and other regulators have continued to adopt new rules and regulations and make additional changes to existing 
regulations that require our compliance. In July 2010, the Dodd-Frank Wall Street Reform and Protection Act, or the Dodd-Frank Act, 
was enacted, and in August 2022, the SEC adopted additional rules and regulations under the Dodd-Frank Act related to “say on pay” 
and proxy access. Stockholder activism, the current political environment and the current high level of government intervention and 
regulatory reform may lead to substantial new regulations and disclosure obligations, which has and may in the future lead to 
additional compliance costs and impact the manner in which we operate our business. 
 
Risks related to taxes  
 
Our ability to use our net operating loss carryovers and certain other tax attributes may be limited. 
 
Under the Internal Revenue Code of 1986, as amended, or the Code, a corporation is generally allowed a deduction for net 
operating losses, or NOLs, carried over from a prior taxable year. Under the Code, we can carry forward our NOLs to offset our future 
taxable income, if any, until such NOLs are used or expire. The same is true of other unused tax attributes, such as tax credits. 
 
Under the current U.S. federal income tax law, U.S. federal NOLs generated in taxable years beginning after December 31, 
2017 may be carried forward indefinitely, but the deductibility of such U.S. federal NOLs is limited to 80 percent of taxable income.  
 
In addition, under Sections 382 and 383 of the Code, and corresponding provisions of state law, if a corporation undergoes an 
“ownership change,” which is generally defined as a greater than 50 percentage-point cumulative change, by value, in its equity 
ownership over a three-year period, the corporation’s ability to use its pre-change NOL carryforwards and other pre-change tax 
attributes to offset its post-change income or taxes may be limited. We may experience ownership changes in the future as a result of 
subsequent shifts in our stock ownership, some of which may be outside of our control. If an ownership change occurs and our ability 
to use our NOL carryforwards or other tax attributes is materially limited, it would harm our future operating results by effectively 
increasing our future tax obligations. As a result of our merger with Akcea Therapeutics, Inc. in 2020, or the Akcea Merger, we are 
subject to the separate return limitation year, or SRLY, rules. Under the SRLY rules, our utilization of Akcea’s pre-merger NOL and 
tax credit carryforwards is limited to the amount of income that Akcea contributes to our consolidated taxable income. The Akcea pre-
merger tax attributes cannot be used to offset any of the income that Ionis contributes to our consolidated taxable income. In addition, 
at the state level, there may be periods during which the use of NOLs is suspended or otherwise limited, which could accelerate or 
permanently increase state taxes owed. For example, in June 2024, California enacted Senate Bill 167, or SB 167, which, with certain 
exceptions, suspends the ability to use California net operating losses to offset California income and limits the ability to use 
California business tax credits to offset California taxes, for taxable years beginning after 2023 and before 2027.  
 
 
 
56

Our future taxable income could be impacted by changes in tax laws, regulations and treaties. 
 
A change in tax laws, treaties or regulations, or their interpretation, of any country in which we operate could materially 
affect us. 
 
We could be subject to additional tax liabilities. 
 
We are subject to U.S. federal, state, local and foreign income taxes, sales taxes in the U.S., withholding taxes and transaction 
taxes in foreign jurisdictions. Significant judgment is required in evaluating our tax positions and our worldwide provision for taxes. 
During the ordinary course of business, there are many activities and transactions for which the ultimate tax determination is 
uncertain. In addition, our tax obligations and effective tax rates could be adversely affected by changes in the relevant tax, accounting 
and other laws, regulations, principles and interpretations, including those relating to income tax nexus, by recognizing tax losses or 
lower than anticipated earnings in jurisdictions where we have lower statutory rates and higher than anticipated earnings in 
jurisdictions where we have higher statutory rates, by changes in foreign currency exchange rates, or by changes in the valuation of 
our deferred tax assets and liabilities. In particular, our tax obligations and effective tax rate in the jurisdictions in which we conduct 
business could increase in the future as a result of the base erosion and profit shifting, or BEPS,  project led by the Organization for 
Economic Co-operation and Development, or OECD, and other initiatives led by the OECD or the European Commission. The OECD 
is leading work on an iteration of the BEPS project based on two “pillars” (subject to certain revenue thresholds), involving the 
reallocation of taxing rights in respect of certain multinational enterprises above a fixed profit margin to the jurisdictions in which they 
carry on business  ) (referred to as “Pillar One”) and imposing a minimum effective corporate tax rate on certain multinational 
enterprises (referred to as “Pillar Two”). Based on the minimum revenue thresholds we do not expect to fall within the scope of these 
requirements in the near term. 
 
We may be audited in various jurisdictions, and such jurisdictions may assess additional income, sales and value-added or 
other taxes against us. Although we believe our tax estimates are reasonable, the final determination of any tax audits or litigation 
could be materially different from our historical tax provisions and accruals, which could have a material adverse effect on our 
operating results or cash flows in the period for which a determination is made. 
 
Item 1B. Unresolved Staff Comments 
 
Not applicable. 
 
Item 1C. Cybersecurity 
 
Risk management and strategy 
 
We have implemented and maintain various information security processes designed to detect, respond to, recover, and 
protect our technology ecosystem from cybersecurity threats. These processes are designed to identify, assess, and manage material 
risks that may result from cybersecurity threats and apply to our critical technologies inclusive of networks, third party hosted 
services, communications systems, hardware, software, and critical data, including intellectual property and confidential information 
that is proprietary, strategic, or competitive in nature.  
 
Our Information Technology department, led by our Senior Vice President, Information Technology, helps to detect, respond 
to, and manage cybersecurity threats and risks by monitoring and evaluating our threat environment using various manual and 
automated tools in certain environments and systems and other methods including, for example: 
 
● 
analyzing reports of certain threats and actors; 
● 
conducting scans of the threat environment; 
● 
evaluating our and our industry’s risk profile; 
● 
evaluating certain threats reported to us; 
● 
conducting internal and external audits; 
● 
conducting threat assessments for certain internal and external threats; and  
● 
conducting vulnerability assessments designed to identify vulnerabilities.  
 
 
 
57

Depending on the environment, system and data, we have implemented and maintain various technical, physical, and 
organizational measures, processes, standards, and policies designed to manage and mitigate material risks from cybersecurity threats 
to our critical technologies and data, including, for example: 
 
● 
incident response plan; 
● 
disaster recovery/business continuity plans; 
● 
risk assessments;  
● 
encryption of certain data; 
● 
network security and access controls for certain systems; 
● 
physical security; 
● 
asset management, tracking and disposal; 
● 
systems monitoring; and 
● 
employee training. 
 
Our assessment and management of material risks from cybersecurity threats are integrated into the Company’s overall risk 
management processes. For example, cybersecurity risk is assessed as a component of our enterprise risk management program. In 
addition, we have developed a process whereby our senior management evaluates material risks from cybersecurity threats against our 
overall business objectives and reports certain cybersecurity incidents to the Audit Committee of the Board of Directors, which 
evaluates our overall enterprise risk.  
 
We use third-party providers to perform various functions throughout our business, such as application providers and hosting 
companies. We use third-party providers to assist us from time to time in an effort to identify, assess, and manage material risks from 
cybersecurity threats, including, for example, legal counsel, cybersecurity consultants, cybersecurity software providers, penetration 
testing firms, and forensic investigators. The Company maintains a risk-based approach and process designed to identify and oversee 
cybersecurity risks presented by third parties, including vendors, service providers and other external users of the Company’s systems, 
as well as the systems of third parties that could materially impact our business if there is a cybersecurity incident affecting those 
third-party systems.  
 
For an additional description of the risks from cybersecurity threats that may materially affect us and how they may do so, 
see our risk factors under Item 1A, Risk Factors, in this Annual Report on Form 10-K, including the risk factor titled “We are 
dependent on data as well as information technology systems and infrastructure, which exposes us to data protection risks.”  
 
Governance  
 
Our Board of Directors addresses our cybersecurity risk management as part of its general oversight function. The Audit 
Committee of the Board of Directors is responsible for overseeing our cybersecurity risk management processes, including oversight 
and mitigation of risks from cybersecurity threats. The Audit Committee also oversees our internal audit department and 
management’s internal controls over financial reporting, including with respect to cybersecurity. 
 
Our cybersecurity risk assessment and management processes are implemented and maintained by our Senior Vice President, 
Information Technology, who holds an undergraduate degree in Computer Engineering and has served in information technology and 
security roles dedicated to the pharmaceutical and biotechnology sector for approximately 18 years, including serving as the Chief 
Information Officer of two public biopharmaceutical companies. 
   
 
Our Senior Vice President, Information Technology is responsible for hiring appropriate personnel, helping to integrate 
cybersecurity risk considerations into our overall risk management strategy, communicating key priorities to relevant personnel, 
helping prepare for cybersecurity incidents, approving cybersecurity processes, and reviewing security assessments and other security-
related reports. 
 
Our cybersecurity incident response plan is designed to escalate certain cybersecurity incidents, depending on the 
circumstances, to our senior management team and Audit Committee of the Board of Directors. The Audit Committee of the Board of 
Directors receives reports from our Senior Vice President, Information Technology concerning our significant cybersecurity threats 
and risks (including certain cybersecurity threats) and the processes we have implemented that are designed to address them.  
 
 
 
58

Item 2. Properties 
 
As of February 13, 2025, the following are the primary facilities in which we operate:  
 
Property Description 
 
Location 
 
Square 
Footage 
 
Owned 
or Leased 
 
Initial Lease 
Term End Date 
 
Lease 
Extension Options 
Laboratory and office 
space facility 
 
Carlsbad, CA 
 
176,300 
 
Leased 
 
2037 
 
Two, five-year options to 
extend 
Office and meeting 
space facility 
 
Carlsbad, CA 
 
74,000 
 
Leased 
 
2037 
 
Two, five-year options to 
extend 
Manufacturing facility 
 
Carlsbad, CA 
 
26,800 
 
Owned 
 
 
 
 
Manufacturing support 
facility  
 
Carlsbad, CA 
 
25,800 
 
Leased 
 
2026 
 
One, five-year option to 
extend 
Office space facility 
 
Boston, MA 
 
14,300 
 
Leased 
 
2029 
 
One, five-year option to 
extend 
Office space facility 
 
Carlsbad, CA 
 
5,800 
 
Leased 
 
2027 
 
None 
Warehouse facility 
 
Carlsbad, CA 
 
4,200 
 
Leased 
 
2028 
 
None 
Office space facility 
 
Dublin, 
Ireland 
 
3,900 
 
Leased 
 
2025 
 
None 
 
 
 
 
331,100 
 
 
 
 
 
 
 
We believe that our current and future facilities will be adequate for the foreseeable future. Refer to Part IV, Section 15, Note 
7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for details on real estate 
transactions. 
 
Item 3. Legal Proceedings  
 
For details of legal proceedings, refer to Part IV, Item 15, Note 11, Legal Proceedings, in the Notes to the Consolidated 
Financial Statements.  
 
Item 4. Mine Safety Disclosures 
 
Not applicable. 
 
PART II 
 
Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities 
 
Market Information and Dividends  
 
Our common stock is traded publicly through The Nasdaq Global Select Market under the symbol “IONS.” As of February 
13, 2025, there were approximately 447 stockholders of record of our common stock. Because many of our shares are held by brokers 
and other institutions on behalf of stockholders, we are unable to estimate the total number of stockholders represented by these record 
holders. 
 
We have never paid dividends and do not anticipate paying any dividends in the foreseeable future. 
 
 
 
59

Performance Graph (1) 
 
Set forth below is a table and chart comparing the total return on an indexed basis of $100 invested on December 31, 2019 in 
our common stock, the Nasdaq Composite Index (total return) and the Nasdaq Biotechnology Index. The total return assumes 
reinvestment of dividends. 
 
 
*  $100 invested on December 31, 2019 in stock or index, including reinvestment of dividends. Fiscal year ending December 31. 
 
 
COMPARISON OF 5 YEAR CUMULATIVE TOTAL RETURN 
Among Ionis Pharmaceuticals, Inc., the Nasdaq Composite Index, 
and the Nasdaq Biotechnology Index 
  
  
  
Dec-19 
  
Dec-20 
  
Dec-21 
  
Dec-22 
  
Dec-23 
 
Dec-24 
Ionis Pharmaceuticals, Inc.  
 $ 
100.00  $ 
93.59  $ 
50.37  $ 
62.52  $ 
83.74  $ 
57.87
Nasdaq Composite Index  
 $ 
100.00  $ 
144.92  $ 
177.06  $ 
119.45  $ 
172.77  $ 
223.87
Nasdaq Biotechnology Index  
 $ 
100.00  $ 
126.42  $ 
126.45  $ 
113.65  $ 
118.87  $ 
118.20
___________ 
(1) This section is not “soliciting material,” is not deemed “filed” with the SEC, is not subject to the liabilities of Section 18 of the 
Exchange Act and is not to be incorporated by reference in any of our filings under the Securities Act or the Exchange Act, 
whether made before or after the date hereof and irrespective of any general incorporation language in any such filing. 
 
 
 
60

Item 6. Reserved 
 
Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations 
 
This financial review presents our operating results for each of the two years in the period ended December 31, 2024, and our 
financial condition as of December 31, 2024. Refer to Part II, Item 7, Management's Discussion and Analysis of Financial Condition 
and Results of Operations, in our 2023 Form 10-K for our results of operations for 2023 compared to 2022. Except for the historical 
information contained herein, the following discussion contains forward-looking statements that are subject to known and unknown 
risks, uncertainties and other factors that may cause our actual results to differ materially from those expressed or implied by such 
forward-looking statements. We discuss such risks, uncertainties and other factors throughout this report and specifically under Part I, 
Item 1A, Risk Factors. In addition, the following review should be read in conjunction with the information presented in our 
consolidated financial statements and the related notes to our consolidated financial statements included in Part II, Item 8, Financial 
Statements and Supplementary Data, of this report. 
 
Overview 
 
As noted in our Business Overview in Part I, Item 1, Business, for three decades, we have invented medicines that we believe 
bring better futures to people with serious diseases. Today, as a pioneer in RNA-targeted medicines, we continue to drive innovation 
in RNA therapies. We currently have six marketed medicines: TRYNGOLZA, WAINUA, SPINRAZA, QALSODY, TEGSEDI and 
WAYLIVRA. We also have a rich innovative late- and mid-stage pipeline in neurology, cardiology and rare diseases. We currently 
have nine medicines in Phase 3 development and additional medicines in early and mid-stage development. Refer to Part I, Item 1, 
Business, for further details on our business and key developments in our medicines. 
 
Results of Operations 
 
Below we have included our results of operations for 2024 compared to 2023. Refer to Part II, Item 7, Management's 
Discussion and Analysis of Financial Condition and Results of Operations, of our 2023 Form 10-K for our results of operations for 
2023 compared to 2022. The following table provides selected summary information from our consolidated statements of operations 
for 2024 and 2023 (in millions): 
 
 
Year Ended December 31, 
  
2024 
 
2023 
 
 
 
Total revenue 
$ 
705.1
$ 
787.6
Total operating expenses 
$  
1,180.2
$  
1,141.4
Loss from operations 
$ 
(475.1)
$  
(353.7)
Net loss 
$ 
(453.9)
$ 
(366.3)
Cash, cash equivalents and short-term investments 
$ 
2,297.7
$ 
2,331.2
 
 
 
61

Revenue 
 
Total revenue for 2024 was $705.1 million compared to $787.6 million in 2023 and was comprised of the following (in 
millions):  
 
Year Ended December 31, 
2024 
 
2023 
Revenue: 
 
 
Commercial revenue:  
 
SPINRAZA royalties 
$ 
216.1  $ 
240.4
WAINUA royalties 
20.2  
—
Other commercial revenue: 
 
TEGSEDI and WAYLIVRA revenue, net 
34.2  
34.9
Other revenue 
22.6  
33.3
Total other commercial revenue 
56.8  
68.2
Total commercial revenue 
293.1  
308.6
R&D revenue:  
 
 
Amortization from upfront payments 
131.4  
125.3
Milestone payments 
106.4  
100.5
License fees 
71.3  
116.8
Other services 
23.5  
10.0
Collaborative agreement revenue 
332.6  
352.6
WAINUA joint development revenue 
79.4  
126.4
Total R&D revenue 
412.0   
479.0
Total revenue 
$ 
705.1  $ 
787.6
 
Commercial revenue in 2024 included new sources of commercial revenue with the launch of WAINUA in the U.S. in late 
January 2024 and the launch of TRYNGOLZA in the U.S. in late December 2024. SPINRAZA royalties in 2024 compared to 2023 
were impacted from an annual order from a single country that did not recur in 2024. 
 
R&D revenue decreased in 2024 compared to 2023 primarily due to the decrease in WAINUA joint development revenue as 
development activities relating to ATTRv-PN wound down with the commercial launch of WAINUA. In addition, R&D revenue 
decreased due to the timing of significant partner payments. 
 
WAINUA (Eplontersen) Collaboration with AstraZeneca 
 
Our financial results for the years ended December 31, 2024 and 2023 reflected the cost-sharing provisions related to our 
collaboration with AstraZeneca to develop and commercialize WAINUA for the treatment of ATTR. Under the terms of the 
collaboration agreement, AstraZeneca is currently paying 55 percent of the costs associated with the ongoing global Phase 3 
development program. Because we are leading and conducting the Phase 3 development program, we are recognizing as R&D revenue 
the 55 percent of cost-share funding AstraZeneca is responsible for, net of our share of AstraZeneca’s development expenses, in the 
same period we incur the related development expenses. 
 
As AstraZeneca is responsible for the vast majority of the medical affairs and commercial costs in the U.S. and all costs 
associated with bringing WAINUA to market outside the U.S., we are recognizing cost-share funding we receive from AstraZeneca 
related to these activities as a reduction of our medical affairs and commercialization expenses, which we classify as R&D and selling, 
general and administrative, or SG&A, expenses, respectively. We expect our medical affairs and commercialization expenses to 
increase as WAINUA advances toward the market under our collaboration with AstraZeneca. 
 
The following table sets forth information on revenue and expenses under this collaboration (in millions): 
 
Year Ended December 31, 
2024 
 
2023 
WAINUA joint development revenue 
$ 
79.4
$ 
126.4 
Research and development expenses related to Phase 3 
development expenses for WAINUA 
107.2
150.8 
Medical affairs expenses for WAINUA 
7.1
4.1 
Commercialization expenses for WAINUA 
26.7
15.6 
 
 
 
62

Our WAINUA joint development revenue in 2024 and 2023 includes a $30 million milestone payment from AstraZeneca that 
we earned when the MHRA approved WAINUA for ATTRv-PN in the UK as WAINZUA and a $50 million milestone payment from 
AstraZeneca that we earned when the FDA approved WAINUA for ATTRv-PN in the U.S., respectively. 
 
Operating Expenses 
 
The following table sets forth information on operating expenses (in millions): 
 
Year Ended December 31, 
2024 
 
2023 
Operating expenses, excluding non-cash compensation 
expense related to equity awards 
$ 
1,050.0
$ 
1,035.7 
Non-cash compensation expense related to equity awards 
130.2
105.7 
Total operating expenses 
$ 
1,180.2
$ 
1,141.4 
 
Operating expenses, excluding non-cash compensation expense related to equity awards, increased slightly in 2024 compared 
to 2023. SG&A expenses increased year over year primarily due to the launches of WAINUA and TRYNGOLZA, including 
establishing the TRYNGOLZA field team in the second quarter of 2024, and advancing launch preparation activities for donidalorsen. 
R&D expenses were essentially flat year over year as several late-stage studies ended. 
 
Non-cash compensation expense related to equity awards increased in 2024 compared to 2023 due to increased headcount 
and a higher stock price on the grant date of annual equity awards in 2024 compared to 2023. We believe non-cash compensation 
expense related to equity awards is not indicative of our operating results or cash flows from our operations. 
 
Cost of Sales 
 
Our cost of sales is comprised of costs related to our commercial revenue, which consisted of manufacturing costs, including 
certain fixed costs, transportation and freight, indirect overhead costs primarily associated with the manufacturing and distribution of 
TRYNGOLZA, TEGSEDI and WAYLIVRA and certain associated period costs.  
 
The following table sets forth information on cost of sales (in millions): 
 
Year Ended December 31, 
2024 
 
2023 
Cost of sales, excluding non-cash compensation expense 
related to equity awards 
$ 
10.4
$ 
8.7 
Non-cash compensation expense related to equity awards 
0.8
0.4 
Total cost of sales  
$ 
11.2
$ 
9.1 
 
Research, Development and Patent Expenses 
 
Our research, development and patent expenses consist of expenses for drug discovery, drug development, medical affairs, 
manufacturing and development chemistry and R&D support expenses. 
 
The following table sets forth information on research, development and patent expenses (in millions): 
 
Year Ended December 31, 
 
2024 
 
2023 
Research, development and patent expenses, excluding non-
cash compensation expense related to equity awards 
$ 
809.1
$ 
821.7
Non-cash compensation expense related to equity awards 
92.4
77.9
Total research, development and patent expenses 
$ 
901.5
$ 
899.6
 
Drug Discovery 
 
We use our proprietary technologies to generate information about the function of genes and to determine the value of genes 
as drug discovery targets. We use this information to direct our own drug discovery research, and that of our partners. Drug discovery 
is also the function that is responsible for advancing our core technology. This function is also responsible for making investments in 
complementary technologies to expand the reach of our technologies. 
 
 
 
63

The following table sets forth information on drug discovery expenses (in millions): 
 
Year Ended December 31, 
 
2024 
 
2023 
Drug discovery expenses, excluding non-cash compensation 
expense related to equity awards 
$ 
114.4
$ 
125.6
Non-cash compensation expense related to equity awards 
18.4
16.2
Total drug discovery expenses 
$ 
132.8
$ 
141.8
 
Drug discovery expenses, excluding non-cash compensation expense related to equity awards, decreased in 2024 compared to 
2023. In 2023, we recognized $15 million in R&D expense for licensing Vect-Horus’ platform technology. 
 
Drug Development 
 
The following table sets forth drug development expenses, including expenses for our marketed medicines and those in Phase 
3 development for which we have incurred significant costs (in millions): 
 
Year Ended December 31, 
 
2024 
 
2023 
WAINUA 
$ 
103.7 $ 
115.5
TEGSEDI and WAYLIVRA 
11.2 
8.1
Olezarsen 
147.4 
138.3
Donidalorsen 
16.6 
24.9
Zilganersen 
7.6 
8.4
Ulefnersen 
15.0 
10.8
Other development projects 
89.9 
101.0
Development overhead expenses 
135.9 
123.3
Total drug development, excluding non-cash compensation 
expense related to equity awards 
527.3 
530.3
Non-cash compensation expense related to equity awards 
41.2 
34.5
Total drug development expenses 
$ 
568.5 $ 
564.8
 
Our development expenses, excluding non-cash compensation expense related to equity awards, were essentially flat in 2024 
compared to 2023. We expect our development expenses will continue to be stable as several late-stage studies end and we reallocate 
resources toward earlier stage programs. 
 
We may conduct multiple clinical trials on a drug candidate, including multiple clinical trials for the various indications we 
may be studying. Furthermore, as we obtain results from trials, we may elect to discontinue clinical trials for certain drug candidates in 
certain indications in order to focus our resources on more promising drug candidates or indications. Our Phase 1 and Phase 2 
programs are clinical research programs that fuel our Phase 3 pipeline. When our medicines are in Phase 1 or Phase 2 clinical trials, 
they are in a dynamic state in which we may adjust the development strategy for each medicine. Although we may characterize a 
medicine as “in Phase 1” or “in Phase 2,” it does not mean that we are conducting a single, well-defined study with dedicated 
resources. Instead, we allocate our internal resources on a shared basis across numerous medicines based on each medicine’s particular 
needs at that time. This means we are constantly shifting resources among medicines. Therefore, what we spend on each medicine 
during a particular period is usually a function of what is required to keep the medicines progressing in clinical development, not what 
medicines we think are most important. For example, the number of people required to start a new study is large, the number of people 
required to keep a study going is modest and the number of people required to finish a study is large. However, such fluctuations are 
not indicative of a shift in our emphasis from one medicine to another and cannot be used to accurately predict future costs for each 
medicine. Because we always have numerous medicines in preclinical and varying stages of clinical research, the fluctuations in 
expenses from medicine to medicine, in large part, offset one another. If we partner a medicine, it may affect the size of a trial, its 
timing, its total cost and the timing of the related costs. 
 
Medical Affairs 
 
Our medical affairs function is responsible for funding and coordinating investigator-sponsored trials, communicating 
scientific and clinical information to healthcare providers, medical professionals and patients, and managing publications. 
 
 
 
64

The following table sets forth information on medical affairs expenses (in millions): 
 
Year Ended December 31, 
 
2024 
 
2023 
Medical affairs expenses, excluding non-cash compensation 
expense related to equity awards 
$ 
27.2
$ 
19.5
Non-cash compensation expense related to equity awards 
4.7
3.4
Total medical affairs expenses 
$ 
31.9
$ 
22.9
 
Medical affairs expenses, excluding non-cash compensation expense related to equity awards, increased in 2024 compared to 
2023 as we continued advancing our late-stage pipeline. 
 
Manufacturing and Development Chemistry 
 
Expenditures in our manufacturing and development chemistry function consist primarily of personnel costs, specialized 
chemicals for oligonucleotide manufacturing, validation batches to support regulatory approvals, laboratory supplies and outside 
services. Our manufacturing and development chemistry function is responsible for providing drug supplies to drug development and 
our collaboration partners. Our manufacturing procedures include testing to satisfy good laboratory and good manufacturing practice 
requirements. 
 
The following table sets forth information on manufacturing and development chemistry expenses (in millions): 
 
Year Ended December 31, 
 
2024 
 
2023 
Manufacturing and development chemistry expenses, excluding 
non-cash compensation expense related to equity awards 
$ 
57.7
$ 
65.3
Non-cash compensation expense related to equity awards 
9.4
8.8
Total manufacturing and development chemistry expenses 
$ 
67.1
$ 
74.1
 
Manufacturing and development chemistry expenses, excluding non-cash compensation expense related to equity awards, 
decreased in 2024 compared to 2023 due to the timing of manufacturing performed by our contract manufacturing organizations for 
drug product related to several late-stage programs. Refer to the section titled, Manufacturing, in Part I, Item 1, Business, for further 
details on the activities and types of costs we incur in our manufacturing process. 
 
R&D Support 
 
In our research, development and patent expenses, we include support costs such as rent, repair and maintenance for 
buildings and equipment, utilities, depreciation of laboratory equipment and facilities, amortization of our intellectual property, 
information technology costs, procurement costs and waste disposal costs. We call these costs R&D support expenses. 
 
The following table sets forth information on R&D support expenses (in millions): 
 
Year Ended December 31, 
 
2024 
 
2023 
Personnel costs 
$ 
31.4 $ 
27.2
Occupancy 
28.5
28.7
Consulting 
0.4
4.8
Patent expenses 
5.3
4.3
Insurance 
3.3
3.6
Computer software and licenses 
8.4
2.7
Other 
5.3
9.7
Total R&D support expenses, excluding non-cash 
compensation expense related to equity awards 
82.6
81.0
Non-cash compensation expense related to equity awards 
18.6
15.0
Total R&D support expenses 
$ 
101.2 $ 
96.0
 
R&D support expenses, excluding non-cash compensation expense related to equity awards, were essentially flat in 2024 
compared to 2023. 
 
 
 
65

Selling, General and Administrative Expenses  
 
SG&A expenses include personnel and outside costs associated with the pre-commercialization and commercialization 
activities for our medicines and costs to support our company, our employees and our stockholders including, legal, human resources, 
investor relations and finance. Additionally, we include in SG&A expenses such costs as rent, repair and maintenance of buildings and 
equipment, depreciation and utilities costs that we need to support the corporate functions listed above. We also include fees we owe 
under our in-licensing agreements related to SPINRAZA and QALSODY. 
 
The following table sets forth information on SG&A expenses (in millions): 
 
Year Ended December 31, 
 
2024 
 
2023 
Selling, general and administrative expenses, excluding non-
cash compensation expense related to equity awards 
$ 
230.5 $ 
205.1
Non-cash compensation expense related to equity awards 
37.0
27.5
Total selling, general and administrative expenses 
$ 
267.5 $ 
232.6
 
SG&A expenses, excluding non-cash compensation expense related to equity awards, increased in 2024 compared to 2023 
due to the launches of WAINUA and TRYNGOLZA, including establishing the TRYNGOLZA field team in the second quarter of 
2024, and advancing launch preparation activities for donidalorsen. We expect SG&A expenses to increase as we continue to invest in 
our independent commercial launches. 
 
Investment Income 
 
Investment income for 2024 was $107.0 million compared to $89.0 million for 2023. The increase in investment income was 
primarily due to an increase in interest rates associated with our investments during a majority of 2024 compared to 2023. In addition, 
our cash available for investing increased due to the $489.1 million net proceeds we received from our public common stock offering 
in September 2024. Refer to Note 8, Stockholders' Equity, for further details on the public offering.  
 
Interest Expense 
 
The following table sets forth information on interest expense (in millions): 
 
Year Ended December 31, 
 
2024 
 
2023 
Convertible senior notes: 
Non-cash amortization of debt issuance costs 
$ 
6.1 $ 
5.9
Interest expense payable in cash 
10.5
6.4
Interest on mortgage for primary R&D and manufacturing 
facilities 
0.4
0.4
Total interest expense 
$ 
17.0 $ 
12.7
 
Interest expense for 2024 was $17.0 million compared to $12.7 million for 2023. In June 2023, we completed a $575.0 
million offering of our 1.75% Notes and repurchased $504.4 million in principal of our 0.125% Notes. As a result, beginning in the 
second quarter of 2023, our interest expense related to our convertible notes included interest expense incurred for our 1.75% Notes. 
Interest expense in 2024 included a full year of interest expense related to our 1.75% Notes.  
 
Interest Expense Related to Sale of Future Royalties 
 
We recorded $73.5 million and $68.8 million of interest expense related to the sale of future royalties in 2024 and 2023, 
respectively. These amounts are related to the Royalty Pharma Investments, or Royalty Pharma, transaction, in which we sold a 
minority interest in our future SPINRAZA and pelacarsen royalties to Royalty Pharma for a $500 million upfront payment and $625 
million of potential future payments. Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the 
Consolidated Financial Statements for further details. 
 
 
 
66

Loss on Investments 
 
We recorded a $2.9 million and $1.9 million loss on investments for 2024 and 2023, respectively. The period-over-period 
fluctuation in our loss on investments was primarily driven by changes in the fair value of our investments in privately held and 
publicly traded biotechnology companies. 
 
Other Income (Expense) 
 
In 2023, we completed a $575.0 million offering of our 1.75% Notes and used $488.2 million of the net proceeds to 
repurchase $504.4 million in principal of our 0.125% Notes. As a result of these repurchases, we recorded a $13.4 million gain on 
early retirement of debt in 2023, which reflects the difference between the amounts we paid to repurchase portions of our 0.125% 
Notes and the net carrying balance of the liability at the time that we repurchased the debt. Refer to Part IV, Item 15, Note 7, Long-
Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further details regarding our 
convertible debt. 
 
Income Tax Expense (Benefit) 
 
We recorded an income tax benefit of $6.2 million for 2024 compared to an income tax expense of $32.3 million for 2023. 
 
The income tax benefit during 2024 primarily related to adjustments to prior year tax return positions for the royalty purchase 
agreement with Royalty Pharma and deductions related to foreign SPINRAZA royalties.  
 
The decrease in income tax expense for 2024 compared to 2023 primarily related to the impact of the Royalty Pharma 
transaction in 2023. We reflected the Royalty Pharma transaction as a taxable sale, which required us to include the proceeds from the 
sale, net of currently deductible issuance costs, as taxable income in 2023. 
 
We continue to maintain a full valuation allowance on all our net deferred tax assets. 
 
Net Loss and Net Loss per Share 
 
We generated a net loss of $453.9 million for 2024 compared to $366.3 million for 2023. Our net loss increased for 2024 
compared to 2023 primarily due to factors discussed in the sections above. Basic and diluted net loss per share for 2024 were $3.04 
compared to $2.56 for 2023. Our net loss per share increased for 2024 compared to 2023 primarily due to factors discussed in the 
sections above. 
 
Liquidity and Capital Resources 
 
We have financed our operations primarily from research and development collaborative agreements. We also financed our 
operations from commercial revenue from SPINRAZA royalties and TEGSEDI and WAYLIVRA commercial revenue. In addition, 
we began receiving commercial revenue from WAINUA royalties in 2024. From our inception through December 31, 2024, we have 
earned approximately $7.9 billion in revenue. We have also financed our operations through the sale of our equity securities, the 
issuance of long-term debt, the sale leaseback of facilities and the sale of future royalties. From the time we were founded through 
December 31, 2024, we have raised net proceeds of approximately $2.6 billion from the sale of our equity securities, which includes 
our sale of 11.5 million shares of common stock for net proceeds of $489 million in September 2024. Additionally, from our inception 
through December 31, 2024, we have borrowed approximately $2.7 billion under long-term debt arrangements and received proceeds 
of approximately $0.5 billion from the sale of future royalties to finance a portion of our operations.  
 
Our working capital increased from 2023 to 2024 primarily due to a decrease in current liabilities as a result of lower deferred 
contract revenue as of December 31, 2024 compared to December 31, 2023. During the same period, our long-term obligations did not 
change significantly. 
 
 
 
67

The following table summarizes our contractual obligations, excluding our liability related to the sale of future royalties, as of 
December 31, 2024. The table provides a breakdown of when obligations become due. We provide a more detailed description of the 
major components of our debt in Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated 
Financial Statements. 
 
Contractual Obligations 
 
Payments Due by Period  
(in millions) 
(selected balances described below) 
  
Total 
  Less than 1 year   More than 1 year 
1.75% Notes (principal and interest payable) 
$ 
610.3 $ 
10.1
$ 
600.2
0% Notes (principal payable) 
 
632.5  
—  
632.5
Operating leases  
 
260.3  
20.9  
239.4
Building mortgage payments (principal and interest payable) 
 
9.6  
0.5  
9.1
Other obligations (principal and interest payable)  
 
0.7  
0.1  
0.6
Total  
 
$ 
1,513.4  $ 
31.6  $ 
1,481.8
 
Our contractual obligations consist primarily of our convertible debt. In addition, we also have a facility mortgage, facility 
leases, equipment financing arrangements and other obligations. We believe our cash, cash equivalents and short-term investments, as 
well as plans for cash in the future, will be sufficient to fund our planned operations and these obligations. We have not entered into, 
nor do we currently have, any off-balance sheet arrangements (as defined under SEC rules).  
 
Convertible Debt and Call Spread 
 
Refer to our Convertible Debt and Call Spread accounting policies in Part IV, Item 15, Note 1, Organization and Significant 
Accounting Policies, and Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for 
the significant terms of each convertible debt instrument. 
 
Operating Facilities 
 
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial 
Statements for further details on our operating facilities. 
 
Operating Leases 
 
Refer to Part IV, Item 15, Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial 
Statements for further details on our operating leases. 
 
Royalty Revenue Monetization 
 
In 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA 
and pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively. Refer to Part IV, Item 15, 
Note 7, Long-Term Obligations and Commitments, in the Notes to the Consolidated Financial Statements for further details on this 
agreement. 
 
Other Obligations 
 
In addition to contractual obligations, we had outstanding purchase orders as of December 31, 2024 for the purchase of 
services, capital equipment and materials as part of our normal course of business. 
 
We may enter into additional collaborations with partners which could provide for additional revenue to us and we may incur 
additional cash expenditures related to our obligations under any of the new agreements we may enter into. We currently intend to use 
our cash, cash equivalents and short-term investments to finance our activities. However, we may also pursue other financing 
alternatives, like issuing additional shares of our common stock, issuing debt instruments, refinancing our existing debt, securing lines 
of credit or executing royalty monetization agreements. Whether we use our existing capital resources or choose to obtain financing 
will depend on various factors, including the future success of our business, the prevailing interest rate environment and the condition 
of financial markets generally. 
 
 
 
68

Critical Accounting Estimates 
 
We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the U.S. As 
such, we make certain estimates, judgments and assumptions that we believe are reasonable, based upon the information available to 
us. These judgments involve making estimates about the effect of matters that are inherently uncertain and may significantly impact 
our quarterly or annual results of operations and financial condition. Each quarter, our senior management reviews the development, 
selection and disclosure of such estimates with the audit committee of our board of directors. In the following paragraphs, we describe 
the specific risks associated with these critical accounting estimates and we caution that future events rarely develop exactly as one 
may expect, and that best estimates may require adjustment. Our significant accounting policies are outlined in Part IV, Item 15, Note 
1, Organization and Significant Accounting Policies, in the Notes to the Consolidated Financial Statements. 
 
The following are our significant accounting estimates, which we believe are the most critical to aid in fully understanding 
and evaluating our reported financial results: 
 
● 
Assessing the propriety of revenue recognition and associated deferred revenue; 
● 
Determining the appropriate cost estimates for unbilled preclinical studies and clinical development activities; and 
● 
Assessing the appropriate estimate of anticipated future royalty payments under our royalty purchase agreement 
 
The following are descriptions of our critical accounting estimates.  
 
Revenue Recognition 
 
We earn revenue from several sources. The judgements and estimates we make vary between each source of our revenue. At 
contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint operating activities 
performed by parties that are both active participants in the activities and exposed to significant risks and rewards dependent on the 
commercial success of such activities and therefore within the scope of Accounting Standards Codification, or ASC, Topic 808, 
Collaborative Arrangements, or ASC 808. For collaboration arrangements within the scope of ASC 808 that contain multiple 
elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and are therefore within the 
scope of ASC 606, Revenue from Contracts with Customers. When we determine elements of a collaboration do not reflect a vendor-
customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to authoritative 
accounting literature.  
 
The following is a summary of the critical accounting estimates we make with respect to our revenue.  
 
Research and development revenue under collaborative agreements 
 
We recognize R&D revenue from numerous collaboration agreements. Our collaboration agreements typically contain 
multiple elements, or performance obligations, including technology licenses or options to obtain technology licenses, R&D services, 
and manufacturing services. Upon entering into a collaboration agreement, we are required to make the following judgements: 
 
● 
Identifying the performance obligations contained in the agreement 
 
Our assessment of what constitutes a separate performance obligation requires us to apply judgement. Specifically, we 
have to identify which goods and services we are required to provide under the contract are distinct.  
 
● 
Determining the transaction price, including any variable consideration 
 
To determine the transaction price, we review the amount of consideration we are eligible to earn under the agreement. 
We do not typically include any payments we may receive in the future in our initial transaction price since the payments 
are typically not probable because they are contingent upon certain future events. We reassess the total transaction price 
at each reporting period to determine if we should include additional payments in the transaction price that have become 
probable. 
 
 
 
69

● 
Allocating the transaction price to each of our performance obligations 
 
When we allocate the transaction price to more than one performance obligation, we make estimates of the relative 
stand-alone selling price of each performance obligation because we do not typically sell our goods or services on a 
stand-alone basis. The estimate of the relative stand-alone selling price requires us in some cases to make significant 
judgements. For example, when we deliver a license at the start of an agreement, we use valuation methodologies, such 
as the relief from royalty method, to value the license. Under this method we are required to make estimates including 
future sales, royalties on future product sales, contractual milestones, expenses, income taxes and discount rates. 
Additionally, when we estimate the selling price for R&D services, we make estimates, including: the number of internal 
hours we will spend on the services, the cost of work we and third parties will perform and the cost of clinical trial 
material we will use.  
 
The R&D revenue we recognize each period is comprised of several types of revenue, including amortization from upfront 
payments, milestone payments, license fees and other services that we recognize immediately or amortize over the period in which we 
satisfy our performance obligation. Each of these types of revenue require us to make various judgements and estimates.  
 
R&D Services with Upfront Payments 
 
We recognize revenue from the amortization of upfront payments as we perform R&D services. We use an input method to 
estimate the amount of revenue to recognize each period. This method requires us to make estimates of the total costs we expect to 
incur to complete our R&D services performance obligation or the total amount of effort it will take us to complete our R&D services 
performance obligation. If we change our estimates, we may have to adjust our revenue.  
 
Milestone Payments  
 
When recognizing revenue related to milestone payments, we typically make the following judgements and estimates: 
 
● 
Whether a milestone payment is probable (discussed in detail above under “Determining the transaction price, including 
any variable consideration”); and 
● 
If we are performing services, we recognize revenue over our estimated period of performance in a similar manner to the 
amortization of upfront payments (discussed above under “R&D Services with Upfront Payments”).  
 
License Fees  
 
When we grant a license for a medicine in clinical development, we generally recognize as R&D revenue the total amount we 
determine to be the relative stand-alone selling price of a license when we deliver the license to our partner. Refer to Part IV, Item 15, 
Note 1, Organization and Significant Accounting Policies, in the Notes to the Consolidated Financial Statements for our revenue 
recognition policy. We discuss the estimates we make related to the relative stand-alone selling price of a license in detail above under 
“Allocating the transaction price to each of our performance obligations.”  
 
Estimated Liability for Clinical Development Costs 
 
We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. On at least a 
quarterly basis, we estimate our liability for preclinical and clinical development costs we have incurred and services that we have 
received but for which we have not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to third-
party clinical management costs, laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability 
using assumptions about study and patient activities and the related expected expenses for those activities determined based on the 
contracted fees with our service providers. The assumptions we use represent our best estimates of the activity and expenses at the 
time of our accrual and involve inherent uncertainties and the application of our judgment. Upon settlement, these costs may differ 
materially from the amounts accrued in our consolidated financial statements. Our historical accrual estimates have not been 
materially different from our actual amounts. 
 
As of December 31, 2024, a hypothetical 10 percent increase in our liability for preclinical and clinical development costs 
would have resulted in an increase in our loss before income tax benefit and accrued liabilities of approximately $7.7 million. 
 
 
 
70

Liability Related to Sale of Future Royalties 
 
In 2023, we entered into a royalty purchase agreement with Royalty Pharma to monetize a portion of our future SPINRAZA 
and pelacarsen royalties we are entitled to under our agreements with Biogen and Novartis, respectively. Under our agreement with 
Royalty Pharma, we calculate the liability related to the sale of future royalties, effective interest rate and the related interest expense 
using our current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on 
internal projections and information from our partners who are responsible for commercializing the medicines. The amount that 
Royalty Pharma will receive under the agreement is based on sales of SPINRAZA, our currently commercialized medicine, and 
pelacarsen, a product candidate that is not currently commercialized. As such, the repayment amounts that we estimate related to 
projections of future pelacarsen revenues contain more subjective estimation which we believe could lead to larger changes in 
estimates in the future. If there is a material change in our estimate, we will prospectively adjust the effective interest rate and the 
related interest expense. 
 
There are numerous factors, most of which are not within our control, that could materially impact the amount and timing of 
future royalty payments, particularly those from Novartis for pelacarsen, and could result in changes to our estimate of future royalty 
payments to Royalty Pharma. Such factors include, but are not limited to, the regulatory approval and commercial sales of pelacarsen, 
competing products or other significant events. These factors and other events or circumstances could result in reduced royalty 
payments from sales of pelacarsen, which would result in a reduction of our non-cash royalty revenue and non-cash interest expense 
over the life of the agreement. Conversely, if sales of pelacarsen are more than amounts we estimated, the non-cash royalty revenue 
and non-cash interest expense we record would be greater over the life of the arrangement. 
 
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 
 
We are exposed to changes in interest rates primarily from our investments in certain short-term investments. We primarily 
invest our excess cash in highly liquid short-term investments of the U.S. Treasury and reputable financial institutions, corporations, 
and U.S. government agencies with strong credit ratings. We typically hold our investments for the duration of the term of the 
respective instrument. We do not utilize derivative financial instruments, derivative commodity instruments or other market risk 
sensitive instruments, positions or transactions to manage exposure to interest rate changes. Accordingly, we believe that, while the 
securities we hold are subject to changes in the financial standing of the issuer of such securities, we were not subject to any material 
risks arising from changes in interest rates, foreign currency exchange rates, commodity prices, equity prices or other market changes 
that affect market risk sensitive instruments as of December 31, 2024 and will not be subject to any material risks arising from these 
changes in the foreseeable future. 
 
Item 8. Financial Statements and Supplementary Data 
 
We filed our consolidated financial statements and supplementary data required by this item as exhibits hereto, and listed 
them under Item 15(a)(1) and (2), and incorporate them herein by reference. 
 
 
 
71

Item 9. Changes in and Disagreements with Accountants on Accounting and Financial Disclosure 
 
None. 
 
Item 9A. Controls and Procedures 
 
Disclosure Controls and Procedures 
 
We maintain 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 Exchange Act) that are designed to ensure that information we are required to disclose in our Exchange 
Act reports is recorded, processed, summarized and reported within the time periods specified in the SEC’s rules and forms, and that 
such information is accumulated and communicated to our management, including our Chief Executive Officer and Chief Financial 
Officer, as appropriate, to allow timely decisions regarding required disclosure. We designed and evaluated our disclosure controls 
and procedures recognizing that any controls and procedures, no matter how well designed and operated, can provide only reasonable 
assurance and not absolute assurance of achieving the desired control objectives. 
 
As of the end of the period covered by this report on Form 10-K, we carried out an evaluation of our disclosure controls and 
procedures under the supervision of, and with the participation of our management, including our Chief Executive Officer and Chief 
Financial Officer. Based on our evaluation, our Chief Executive Officer and Chief Financial Officer concluded that our disclosure 
controls and procedures were effective as of December 31, 2024. 
 
Management’s Report on Internal Control over Financial Reporting 
 
Our management is responsible for establishing and maintaining adequate internal control over financial reporting, as defined 
in Exchange Act Rules 13a-15(f). Our internal control over financial reporting is a process designed under the supervision of our 
Chief Executive Officer and Chief Financial Officer to provide reasonable assurance regarding the reliability of financial reporting 
and the preparation of our financial statements for external purposes in accordance with U.S. generally accepted accounting principles. 
 
As of December 31, 2024, we assessed the effectiveness of our internal control over financial reporting based on the criteria 
for effective internal control over financial reporting under the 2013 “Internal Control—Integrated Framework,” issued by the 
Committee of Sponsoring Organizations, or COSO, of the Treadway Commission, under the supervision of, and with the participation 
of our management, including our Chief Executive Officer and Chief Financial Officer. Based on that assessment, our management 
concluded that we maintained effective internal control over financial reporting as of December 31, 2024. 
 
Ernst & Young LLP, an independent registered public accounting firm, audited the effectiveness of our internal control over 
financial reporting as of December 31, 2024, as stated in their attestation report, which is included elsewhere herein. 
 
Changes in Internal Control over Financial Reporting 
 
The above assessment did not identify any change in our internal control over financial reporting that occurred during our 
latest fiscal quarter and that has materially affected, or is reasonably likely to materially affect, our internal control over financial 
reporting. 
 
 
 
72

 
REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM 
 
 
To the Stockholders and the Board of Directors of Ionis Pharmaceuticals, Inc.  
 
Opinion on Internal Control Over Financial Reporting 
 
We have audited Ionis Pharmaceuticals, Inc.’s internal control over financial reporting as of December 31, 2024, based on criteria 
established in Internal Control—Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway 
Commission (2013 framework) (the COSO criteria). In our opinion, Ionis Pharmaceuticals, Inc. (the Company) maintained, in all 
material respects, effective internal control over financial reporting as of December 31, 2024, based on the COSO criteria. 
 
We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) 
(PCAOB), the consolidated balance sheets of the Company as of December 31, 2024 and 2023, the related consolidated statements of 
operations, comprehensive loss, stockholders’ equity and cash flows for each of the three years in the period ended December 31, 
2024, and the related notes and our report dated February 19, 2025 expressed an unqualified opinion thereon. 
 
Basis for Opinion 
 
The Company’s management is responsible for maintaining effective internal control over financial reporting and for its assessment of 
the effectiveness of internal control over financial reporting included in the accompanying Management’s Report on Internal Control 
over Financial Reporting. Our responsibility is to express an opinion on the Company’s internal control over financial reporting based 
on our audit. We are a public accounting firm registered with the 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 audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit 
to obtain reasonable assurance about whether effective internal control over financial reporting was maintained in all material respects. 
 
Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material weakness 
exists, testing and evaluating the design and operating effectiveness of internal control based on the assessed risk, and performing such 
other procedures as we considered necessary in the circumstances. We believe that our audit provides a reasonable basis for our 
opinion. 
 
Definition and Limitations of Internal Control Over Financial Reporting 
 
A company’s internal control over financial reporting is a process designed to provide reasonable assurance regarding the reliability of 
financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting 
principles. A company’s internal control over financial reporting includes those policies and procedures that (1) pertain to the 
maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the assets of the 
company; (2) provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in 
accordance with generally accepted accounting principles, and that receipts and expenditures of the company are being made only in 
accordance with authorizations of management and directors of the company; and (3) provide reasonable assurance regarding 
prevention or timely detection of unauthorized acquisition, use, or disposition of the 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. Also, 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. 
 
/s/ Ernst & Young LLP 
 
San Diego, California 
February 19, 2025 
 
 
 
73

Item 9B. Other Information 
 
Trading Plans 
 
During the quarter ended December 31, 2024, our directors and officers (as defined in Rule 16a-1(f) under the Exchange 
Act), or Section 16 officers and directors, adopted or terminated contracts, instructions or written plans for the purchase or sale of our 
securities as noted in the table below. 
 
* 
Contract, instruction or written plan intended to satisfy the affirmative defense conditions of Rule 10b5-1(c) under the Exchange 
Act. 
** “Non-Rule 10b5-1 trading arrangement” as defined in item 408(c) of Regulation S-K under the Exchange Act. 
 
 
 
Action 
 
Date 
 
Trading Arrangement 
 
Total 
Shares to 
be Sold 
 Expiration Date 
Rule 
10b5-1* 
 
Non-
Rule 
10b5-1** 
Joseph Wender, Board 
Member 
 
Adoption 
 
December 26, 
2024 
 
X 
 
 
 
104,079 
 
February 28, 
2026 
 
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 
 
Not applicable.  
 
PART III 
 
Item 10. Directors, Executive Officers and Corporate Governance 
 
We incorporate by reference the information required by this Item with respect to directors and the Audit Committee from the 
information under the caption “ELECTION OF DIRECTORS,” including in particular the information under “Nominating, 
Governance and Review Committee” and “Audit Committee,” contained in our definitive Proxy Statement, which we will file with the 
Securities and Exchange Commission within 120 days after the end of the fiscal year ended December 31, 2024, or the Proxy 
Statement. 
 
We include information concerning our executive officers in the section titled, Information about our Executive Officers, in 
this report on the Form 10-K in Part I, Item 1, Business. 
 
We incorporate by reference the required information concerning our Code of Ethics from the information under the caption 
“Code of Ethics and Business Conduct” contained in the Proxy Statement. Our Code of Ethics and Business Conduct is posted on our 
website at www.ionispharma.com(1). We intend to make all required disclosures regarding any amendments to, or waivers from, 
provisions of our Code of Ethics and Business conduct on our website. 
 
The Company has adopted insider trading policies and procedures governing the purchase, sale and other dispositions of the 
Company’s securities by its directors, officers and employees that are reasonably designed to promote compliance with insider trading 
laws, rules and regulations, and any listing standards applicable to the Company. In addition, it is the Company’s practice to comply 
with both the letter and the spirit of applicable laws and regulations relating to insider trading. 
 
We incorporate by reference the information required by item 402(x) to the information under the caption “Policies and 
practices related to the grant of certain equity awards close in time to the release of material nonpublic information” contained in the 
Proxy Statement. 
___________ 
(1) Any information that is included on or linked to our website is not part of this Form 10-K. 
 
Delinquent Section 16(a) Reports 
 
Part I, Item 1, Business, of this Report contains information concerning our executive officers. We incorporate by reference 
the information required by this Item concerning compliance with Section 16(a) of the Exchange Act from the information under the 
caption “Delinquent Section 16(a) Reports” contained in the Proxy Statement. 
 
 
 
74

Item 11. Executive Compensation 
 
We incorporate by reference the information required by this item to the information under the caption “EXECUTIVE 
COMPENSATION,” “Compensation Committee Interlocks and Insider Participation” and “COMPENSATION COMMITTEE 
REPORT” contained in the Proxy Statement. 
 
We incorporate by reference the information required by Item 402(x) of Regulation S-K to the information under the caption 
“Policies and practices related to the grant of certain equity awards close in time to the release of material nonpublic information” 
contained in the Proxy Statement. 
 
Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters 
 
We incorporate by reference the information required by this item to the information under the captions “SECURITY 
OWNERSHIP OF CERTAIN BENEFICIAL OWNERS AND MANAGEMENT” contained in the Proxy Statement. 
 
Securities Authorized for Issuance under Equity Compensation Plans 
 
The following table sets forth information regarding outstanding options and shares reserved for future issuance under our 
equity compensation plans as of December 31, 2024. 
  
Plan Category 
  
Number of Shares to 
be Issued Upon Exercise 
of Outstanding Options  
Weighted Average 
Exercise Price of 
Outstanding Options  
Number of Shares 
Remaining 
Available 
for Future Issuance   
Equity compensation plans approved by stockholders 
(a)  
 
14,717,114  $ 
48.23  
8,800,341(b) 
Total  
 
14,717,114  $ 
48.43  
8,800,341  
________________ 
(a) Consists of five Ionis plans: 1989 Stock Option Plan, Amended and Restated 2002 Non-Employee Directors’ Stock Option Plan, 
2011 Equity Incentive Plan, 2020 Equity Incentive Plan and Employee Stock Purchase Plan, or ESPP. 
(b) Of these shares, 270,482 were available for purchase under the ESPP as of December 31, 2024.  
 
For additional details about our equity compensation plans, including a description of each plan, refer to Part IV, Item 15, 
Note 8, Stockholders’ Equity, in the Notes to the Consolidated Financial Statements. 
 
Item 13. Certain Relationships and Related Transactions, and Director Independence 
 
We incorporate by reference the information required by this item to the information under the captions “Information 
Regarding the Board and Corporate Governance" and "Certain Relationships and Related Transactions” contained in the Proxy 
Statement. 
 
Item 14. Principal Accountant Fees and Services  
 
We incorporate by reference the information required by this item to the information under the caption “Ratification of 
Selection of Independent Auditors” contained in the Proxy Statement. 
 
PART IV 
  
Item 15. Exhibits, Financial Statement Schedules 
  
(a)(1) Index to Financial Statements 
  
We submitted the consolidated financial statements required by this item in a separate section beginning on page F-1 of this 
Report. 
  
(a)(2) Index to Financial Statement Schedules 
  
We omitted these schedules because they are not required, or are not applicable, or the required information is shown in the 
consolidated financial statements or notes thereto. 
  
(a)(3) Index to Exhibits 
 
 
 
75

 
INDEX TO EXHIBITS 
 
Exhibit 
Number 
  Description of Document 
2.1 
  Agreement and Plan of Merger, dated as of August 30, 2020, among Akcea Therapeutics, Inc., Ionis Pharmaceuticals, 
Inc. and Avalanche Merger Sub, Inc., filed as an exhibit to the Registrant’s Current Report on Form 8-K filed August 
31, 2020 and incorporated herein by reference. 
3.1 
Amended and Restated Certificate of Incorporation filed June 19, 1991, filed as an exhibit to the Registrant’s Annual 
Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference. 
3.2 
  Certificate of Amendment to Restated Certificate of Incorporation, filed as an appendix to the Registrant’s Notice of 
2014 Annual Meeting of Stockholders and Proxy Statement filed on April 25, 2014 and incorporated herein by 
reference. 
3.3 
 
Certificate of Amendment to Restated Certificate of Incorporation, filed as an exhibit to the Registrant’s Current 
Report on Form 8-K filed December 18, 2015 and incorporated herein by reference. 
3.4 
  Amended and Restated Bylaws, filed as an exhibit to the Registrant’s Current Report on Form 8-K filed March 29, 
2021 and incorporated herein by reference. 
4.1 
  Description of the Registrant’s Securities, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the 
year ended December 31, 2021 and incorporated herein by reference.  
4.2 
 
Certificate of Designation of the Series C Junior Participating Preferred Stock, filed as an exhibit to Registrant’s 
Current Report on Form 8-K filed December 13, 2000 and incorporated herein by reference. 
4.3 
  Specimen Common Stock Certificate, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year 
ended December 31, 2017 and incorporated herein by reference.  
4.4 
 
Form of Warrant Transactions Confirmation for Convertible Senior Notes due 2024, filed as an exhibit to the 
Registrant’s Current Report on Form 8-K filed December 12, 2019 and incorporated herein by reference. 
4.5 
 
Indenture, dated as of April 12, 2021, by and between the Registrant and U.S. Bank National Association, as trustee, 
including Form of 0 percent Convertible Senior Note due 2026, filed as an exhibit to the Registrant’s Current Report 
on Form 8-K filed April 13, 2021 and incorporated herein by reference. 
4.6 
 
Form of Warrant Confirmation for Convertible Senior Notes due 2026, filed as an exhibit to the Registrant’s Current 
Report on Form 8-K filed April 13, 2021 and incorporated herein by reference. 
4.7 
 
Form of Convertible Note Hedge Confirmation for Convertible Senior Notes due 2026, filed as an exhibit to the 
Registrant’s Current Report on Form 8-K filed April 13, 2021 and incorporated herein by reference. 
4.8 
 
Indenture, dated as of June 12, 2023, by and between the Registrant and U.S. Bank Trust Company, a National 
Association, as trustee, including Form of 1.75 percent Global Note due in 2028, filed as an exhibit to the 
Registrant’s Current Report on Form 8-K filed June 12, 2023 and incorporated herein by reference. 
10.1* 
 
Advisory Services Agreement by and between the Registrant and Onaiza Cadoret-Manier dated March 15, 2024, filed 
as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2024 and 
incorporated herein by reference. 
10.2* 
  Second Amended Non-Employee Director Compensation Policy, filed as an exhibit to the Registrant’s Quarterly 
Report on Form 10-Q for the quarter ended March 31, 2023 and incorporated herein by reference. 
10.3* 
 
Registrant’s Amended and Restated Severance Benefit Plan dated March 17, 2022, filed as an exhibit to the 
Registrant’s Quarterly Report on form 10-Q for the quarter ended March 31, 2022 and incorporated herein by 
reference. 
10.4 
Form of Indemnity Agreement entered into between the Registrant and its Directors and Executive Officers with 
related schedule, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 
2023 and incorporated herein by reference. 
10.5 
  Form of Employee Confidential Information and Inventions Agreement, filed as an exhibit to the Registrant’s Annual 
Report on Form 10-K for the year ended December 31, 2017 and incorporated herein by reference.  
10.6* 
 
Registrant’s Amended and Restated 2000 Employee Stock Purchase Plan, filed as an exhibit to Registrant’s Current 
Report on Form 8-K filed on March 26, 2019 and incorporated herein by reference. 
10.7* 
 
Registrant’s Amended and Restated 2002 Non-Employee Directors’ Stock Option Plan, filed as an exhibit to the 
Registrant’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2023 and incorporated herein by 
reference. 
10.8* 
 
Form of Option Agreement for Options granted under the Ionis Pharmaceuticals, Inc. Amended and Restated 2002 
Non-Employee Directors’ Stock Option Plan, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for 
the year ended December 31, 2022 and incorporated herein by reference. 
 
 
76

10.9* 
 
Forms of Restricted Stock Unit Grant Notice and Restricted Stock Unit Agreement for Restricted Stock Units granted 
under the Ionis Pharmaceuticals, Inc. Amended and Restated 2002 Non-Employee Directors’ Stock Option Plan,  
filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2023 and 
incorporated herein by reference. 
10.10* 
  Amended and Restated Ionis Pharmaceuticals, Inc. 2011 Equity Incentive Plan, filed as an appendix to the 
Registrant’s Notice of 2024 Annual Meeting of Stockholders and Proxy Statement filed on April 25, 2024 and 
incorporated herein by reference. 
10.11* 
  Form of Option Agreement under the 2011 Equity Incentive Plan, filed as an exhibit to the Registrant’s Annual 
Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference. 
10.12* 
Form of Time-Vested Restricted Stock Unit Agreement for Restricted Stock Units granted under the 2011 Equity 
Incentive Plan, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 
2022 and incorporated herein by reference. 
10.13* 
 
Forms of Performance Based Restricted Stock Unit Grant Notice and Performance Based Restricted Stock Unit 
Agreement for Performance Based Restricted Stock Units granted prior to January 1, 2023 under the 2011 Equity 
Incentive Plan, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 
2021 and incorporated herein by reference. 
10.14* 
Forms of Performance Based Restricted Stock Unit Grant Notice and Performance Based Restricted Stock Unit 
Agreement for Performance Based Restricted Stock Units granted beginning January 1, 2023 under the 2011 Equity 
Incentive Plan, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 
2022 and incorporated herein by reference. 
10.15* 
Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, filed as an exhibit to the Registrant’s Registration Statement 
on Form S-8 filed on December 31, 2020 and incorporated herein by reference. 
10.16* 
Form of Global Option Agreement for options granted under the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive 
Plan, filed as an exhibit to the Registrant’s Registration Statement on Form S-8 filed on December 31, 2020 and 
incorporated herein by reference. 
10.17* 
Form of Global Restricted Stock Unit Agreement for restricted stock units granted under the Ionis Pharmaceuticals, 
Inc. 2020 Equity Incentive Plan, filed as an exhibit to the Registrant’s Registration Statement on Form S-8 filed on 
December 31, 2020 and incorporated herein by reference. 
10.18* 
Forms of Restricted Stock Unit Grant Notice, Stock Option Grant Notice and Stock Option Exercise Notice for 
options granted under the Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, filed as an exhibit to the 
Registrant’s Registration Statement on Form S-8 filed on December 31, 2020 and incorporated herein by reference. 
10.19 
 
Loan Agreement between Ionis Faraday, LLC and UBS AG dated July 18, 2017, filed as an exhibit to the 
Registrant’s Current Report on Form 8-K filed July 21, 2017 and incorporated herein by reference. 
10.20 
 
Guaranty between the Registrant and UBS AG dated July 18, 2017, filed as an exhibit to the Registrant’s Current 
Report on Form 8-K filed July 21, 2017 and incorporated herein by reference. 
10.21 
 
Purchase and Sale Agreement between Ionis Gazelle, LLC and 2850 2855 & 2859 Gazelle Owner (DE) LLC dated as 
of October 20, 2022, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended 
December 31, 2022 and incorporated herein by reference. Portions of this exhibit have been omitted because they are 
both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.22 
 
Purchase and Sale Agreement between the Registrant and Oxford I Asset Management USA Inc. dated as of October 
20, 2022, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 2022 
and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material 
and (ii) the type that the Registrant treats as private or confidential. 
10.23 
 
First Amendment dated June 15, 2023 to the Purchase and Sale Agreement by and between the Registrant and Oxford 
I Asset Management USA Inc. dated as of October 20, 2022, filed as an exhibit to the Registrant’s Quarterly Report 
on Form 10-Q for the quarter ended June 30, 2023 and incorporated herein by reference. 
10.24 
 
Lease Agreement dated October 20, 2022 between the Registrant and 2850 2855 & 2859 Gazelle Owner (DE) LLC, 
filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 2022 and 
incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and 
(ii) the type that the Registrant treats as private or confidential. 
10.25 
 
Amended and Restated Lease Agreement between the Registrant and Lots 21 & 22 Owner (DE) LLC dated as of 
August 21, 2023, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended 
September 30, 2023 and incorporated herein by reference. Portions of this exhibit have been omitted because they are 
both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
 
 
77

10.26 
 
First Amendment dated as of November 6, 2023 to Amended and Restated Lease Agreement between the 
Registrant and Lots 21 & 22 Owner (DE) LLC dated as of August 21, 2023, filed as an exhibit to the Registrant’s 
Annual Report on Form 10-K for the year ended December 31, 2023 and incorporated herein by reference.  
10.27 
 
Second Amendment dated as of June 11, 2024 to the Amended and Restated Lease Agreement by and between the 
Registrant and Lots 21 and 22 Owner (DE) LLC dated as of August 21, 2023, filed as an exhibit to the Registrant’s 
Quarterly Report on Form 10-Q for the quarter ended June 30, 2024 and incorporated herein by reference. 
10.28 
 
Defeasance Pledge and Security Agreement dated as of October 20, 2022 by and among Ionis Gazelle, LLC, Wells 
Fargo Bank, National Association, as Trustee for the Benefit of the Registered Holders of UBS Commercial 
Mortgage Trust 2017-C3, Commercial Mortgage Pass-Through Certificates, Series 2017-C3, and U.S. Bank Trust 
Company, National Association, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year 
ended December 31, 2022 and incorporated herein by reference. Portions of this exhibit have been omitted because 
they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.29 
 
Defeasance Assignment, Assumption and Release Agreement dated as of October 20, 2022 by and among Ionis 
Gazelle, LLC, DHC UBSCM 17 C3 Successor Borrower-R, LLC, Wells Fargo Bank, National Association, as 
Trustee for the Benefit of the Registered Holders of UBS Commercial Mortgage Trust 2017-C3, Commercial 
Mortgage Pass-Through Certificates, Series 2017-C3, Midland Loan Services, a division of PNC Bank, National 
Association, and U.S. Bank Trust Company, National Association, filed as an exhibit to the Registrant’s Annual 
Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by reference. 
10.30 
 
Defeasance Account Agreement dated as of October 20, 2022 by and among Ionis Gazelle, LLC, U.S. Bank Trust 
Company, National Association, U.S. Bank National Association, as Trustee for the Benefit of the Registered 
Holders of UBS Commercial Mortgage Trust 2017-C3, Commercial Mortgage Pass-Through Certificates, Series 
2017-C3, and Midland Loan Services, a division of PNC Bank, National Association, filed as an exhibit to the 
Registrant’s Annual Report on Form 10-K for the year ended December 31, 2022 and incorporated herein by 
reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the 
Registrant treats as private or confidential. 
10.31 
 
Exclusive License Agreement between the Registrant and the University of Massachusetts dated January 14, 2010, 
filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2014 and 
incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and 
(ii) the type that the Registrant treats as private or confidential. 
10.32 
 
Research, Development and License Agreement between the Registrant and Glaxo Group Limited dated March 30, 
2010, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2010 and 
incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a 
request for confidential treatment. 
10.33 
 
Amendment #1 to the Research, Development and License Agreement dated May 11, 2011 by and between the 
Registrant and Glaxo Group Limited, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the 
quarter ended June 30, 2011 and incorporated herein by reference. Portions of this exhibit have been omitted and 
separately filed with the SEC with a request for confidential treatment. 
10.34 
 
Amendment #2 to the Research, Development and License Agreement by and between the Registrant and Glaxo 
Group Limited dated October 30, 2012, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the 
year ended December 31, 2012 and incorporated herein by reference. Portions of this exhibit have been omitted and 
separately filed with the SEC with a request for confidential treatment. 
10.35 
 
Amendment No. 3 to the Research, Development and License Agreement by and between the Registrant and Glaxo 
Group Limited dated July 10, 2013, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the 
quarter ended June 30, 2014 and incorporated herein by reference. Portions of this exhibit have been omitted and 
separately filed with the SEC with a request for confidential treatment. 
10.36 
 
Amendment #4 to the Research, Development and License Agreement by and between the Registrant and Glaxo 
Group Limited dated April 10, 2014, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the 
quarter ended June 30, 2014 and incorporated herein by reference. Portions of this exhibit have been omitted and 
separately filed with the SEC with a request for confidential treatment. 
10.37 
 
Amendment #5 to the Research, Development and License Agreement by and between the Registrant, Glaxo Group 
Limited and GlaxoSmithKline Intellectual Property Development Limited dated June 27, 2014, filed as an exhibit to 
the Registrant’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2014 and incorporated herein by 
reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential 
treatment. 
10.38 
 
Amendment #6 to Research, Development and License Agreement by and between the Registrant, Glaxo Group 
Limited and GlaxoSmithKline Intellectual Property Development Limited dated September 2, 2015, filed as an 
exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and 
incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and 
(ii) the type that the Registrant treats as private or confidential. 
 
 
78

10.39 
 
Amendment #7 to the Research, Development and License Agreement by and between the Registrant, Glaxo Group 
Limited and GlaxoSmithKline Intellectual Property Development Limited dated March 4, 2016, filed as an exhibit to 
the Registrant’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2016 and incorporated herein by 
reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential 
treatment. 
10.40 
 
Amendment #8 to the Research, Development and License Agreement by and between the Registrant, Glaxo Group 
Limited and Glaxosmithkline Intellectual Property Development Limited, dated July 29, 2019, filed as an exhibit to 
the Registrant’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and incorporated herein by 
reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the 
Registrant treats as private or confidential. 
10.41 
 
Amended and Restated Collaboration and License Agreement between the Registrant and Cold Spring Harbor 
Laboratory dated October 26, 2011, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the 
quarter ended September 30, 2014 and incorporated herein by reference. Portions of this exhibit have been omitted 
because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.42 
 
Amendment to Amended and Restated Collaboration and License Agreement between the Registrant and Cold Spring 
Harbor Laboratory dated March 14, 2014, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for 
the quarter ended September 30, 2014 and incorporated herein by reference. Portions of this exhibit have been 
omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.43 
 
Development, Option and License Agreement between the Registrant and Biogen Idec International Holding Ltd. 
dated January 3, 2012, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended 
March 31, 2012 and incorporated herein by reference. Portions of this exhibit have been omitted because they are 
both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.44 
  Amendment #1 to the Development, Option and License Agreement between the Registrant and Biogen Idec 
International Holding Ltd. dated December 15, 2014, filed as an exhibit to the Registrant’s Annual Report on Form 
10-K for the year ended December 31, 2014 and incorporated herein by reference. Portions of this exhibit have been 
omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.45 
  Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB dated December 7, 
2012, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 2012 and 
incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a 
request for confidential treatment. 
10.46 
 
Amendment #1 to Collaboration, License and Development Agreement between the Registrant and AstraZeneca AB 
dated August 13, 2013, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended 
September 30, 2013 and incorporated herein by reference. Portions of this exhibit have been omitted and separately 
filed with the SEC with a request for confidential treatment. 
10.47 
 
Amendment No.2 to the Collaboration, License and Development Agreement between the Registrant and 
AstraZeneca AB dated October 15, 2014, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the 
year ended December 31, 2014 and incorporated herein by reference. Portions of this exhibit have been omitted and 
separately filed with the SEC with a request for confidential treatment. 
10.48 
 
Amendment No.3 to the Collaboration, License and Development Agreement between the Registrant and 
AstraZeneca AB dated January 18, 2016, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for 
the quarter ended March 31, 2016 and incorporated herein by reference. Portions of this exhibit have been omitted 
and separately filed with the SEC with a request for confidential treatment. 
10.49 
 
Amendment No. 4 to the Collaboration, License and Development Agreement by and between the Registrant and 
AstraZeneca AB dated October 18, 2018, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the 
year ended December 31, 2018 and incorporated herein by reference. Portions of this exhibit have been omitted and 
separately filed with the SEC with a request for confidential treatment. 
10.50 
  HTT Research, Development, Option and License Agreement among the Registrant, F. Hoffmann-La Roche Ltd and 
Hoffman-La Roche Inc. dated April 8, 2013, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q 
for the quarter ended March 31, 2023 and incorporated herein by reference. Portions of this exhibit have been omitted 
because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.51 
  Amendment #1 to HTT Research, Development, Option and License Agreement between the Registrant, F. 
Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. dated January 9, 2015, filed as an exhibit to the Registrant’s 
Quarterly Report on Form 10-Q for the quarter ended March 31, 2015 and incorporated herein by reference. Portions 
of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as 
private or confidential. 
 
 
79

10.52 
 
Second Amended and Restated Strategic Collaboration and License Agreement between the Registrant and Alnylam 
Pharmaceuticals, Inc. dated January 8, 2015, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q 
for the quarter ended March 31, 2015 and incorporated herein by reference. Portions of this exhibit have been omitted 
because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.53 
 
Amendment Number One to the Second Amended and Restated Strategic Collaboration and License Agreement 
between the Registrant and Alnylam Pharmaceuticals, Inc. dated July 13, 2015, filed as an exhibit to the Registrant’s 
Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and incorporated herein by reference. 
Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential treatment. 
10.54 
 
Strategic Collaboration Agreement between the Registrant and AstraZeneca AB dated July 31, 2015, filed as an 
exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2015 and 
incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a 
request for confidential treatment. 
10.55 
 
Amendment No. 1 to the Strategic Collaboration Agreement by and between the Registrant and AstraZeneca AB, 
dated October 18, 2018, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended 
December 31, 2018 and incorporated herein by reference. Portions of this exhibit have been omitted and separately 
filed with the SEC with a request for confidential treatment. 
10.56 
 
Amendment No. 2 dated April 30, 2020 to the Strategic Collaboration Agreement by and between the Registrant and 
AstraZeneca AB dated July 31, 2015, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the 
quarter ended June 30, 2020 and incorporated herein by reference. Portions of this exhibit have been omitted because 
they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.57 
 
Amendment No. 3 dated December 17, 2020 to the Strategic Collaboration Agreement by and between the Registrant 
and AstraZeneca AB dated July 31, 2015, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the 
year ended December 31, 2020 and incorporated herein by reference. Portions of this exhibit have been omitted 
because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.58 
 
Amendment No. 4 dated December 23, 2024 to the Strategic Collaboration Agreement by and between the Registrant 
and AstraZeneca AB dated July 31, 2015. Portions of this exhibit have been omitted because they are both (i) not 
material and (ii) the type that the Registrant treats as private or confidential. 
10.59 
 
Strategic Collaboration, Option and License Agreement by and among Akcea Therapeutics, Inc. and Novartis Pharma 
AG, dated January 5, 2017, filed as an exhibit to Akcea Therapeutics, Inc.’s Form S-1 filed March 27, 2017 and 
incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC with a 
request for confidential treatment. 
10.60 
 
Amendment No. 1 to the Strategic Collaboration, Option and License Agreement between Akcea Therapeutics, Inc. 
and Novartis Pharma AG dated February 22, 2019, filed as an exhibit to Akcea Therapeutics, Inc.’s Quarterly Report 
on Form 10-Q for the quarter ended March 30, 2019 and incorporated herein by reference. Portions of this exhibit 
have been omitted and separately filed with the SEC with a request for confidential treatment. 
10.61 
 
Stock Purchase Agreement among the Registrant, Akcea Therapeutics, Inc. and Novartis Pharma AG dated January 
5, 2017, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended March 31, 2017 
and incorporated herein by reference. 
10.62 
 
Research Collaboration, Option and License Agreement between the Registrant and Biogen MA Inc. dated December 
19, 2017, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 2017 
and incorporated herein by reference. Portions of this exhibit have been omitted and separately filed with the SEC 
with a request for confidential treatment. 
10.63 
 
New Strategic Neurology Drug Discovery and Development Collaboration, Option and License Agreement by and 
between the Registrant and Biogen MA Inc., dated April 19, 2018, filed as an exhibit to the Registrant’s Quarterly 
Report on Form 10-Q for the quarter ended June 30, 2018 and incorporated herein by reference. Portions of this 
exhibit have been omitted and separately filed with the SEC with a request for confidential treatment. 
10.64 
 
Amendment No. 1 to the New Strategic Neurology Drug Discovery and Development Collaboration, Option and 
License Agreement between the Registrant and Biogen MA Inc., dated August 16, 2019, filed as an exhibit to the 
Registrant’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2019 and incorporated herein by 
reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the 
Registrant treats as private or confidential. 
 
 
80

10.65 
 
Side Letter dated December 31, 2020 to the New Strategic Neurology Drug Discovery and Development 
Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc. dated April 19, 
2018, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 2020 and 
incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and 
(ii) the type that the Registrant treats as private or confidential. 
10.66 
 
Factor B Development Collaboration, Option and License Agreement by and among the Registrant, F. Hoffmann-La 
Roche Ltd and Hoffmann-La Roche Inc., dated October 9, 2018, filed as an exhibit to the Registrant’s Annual Report 
on Form 10-K for the year ended December 31, 2018 and incorporated herein by reference. Portions of this exhibit 
have been omitted and separately filed with the SEC with a request for confidential treatment.  
10.67 
 
First Amendment dated July 8, 2022 to Factor B Development, Collaboration, Option and License Agreement by and 
between the Registrant, F. Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc., dated October 9, 2018, filed as an 
exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2022. Portions of this 
exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private 
or confidential. 
10.68 
 
Second Amended and Restated Strategic Neurology Drug Discovery and Development Collaboration, Option and 
License Agreement by and between the Registrant and Biogen MA Inc., dated October 17, 2018, filed as an exhibit to 
the Registrant’s Annual Report on Form 10-K for the year ended December 31, 2018 and incorporated herein by 
reference. Portions of this exhibit have been omitted and separately filed with the SEC with a request for confidential 
treatment. 
10.69 
 
Letter Agreement between the Registrant and Biogen MA Inc. dated October 28, 2016, filed as an exhibit to the 
Registrant’s Annual Report on Form 10-K for the year ended December 31, 2016 and incorporated herein by 
reference. Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the 
Registrant treats as private or confidential. 
10.70 
 
Amendment No. 1 to Second Amended and Restated Strategic Neurology Drug Discovery and Development 
Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc., dated May 2, 
2019, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended June 30, 2019 and 
incorporated herein by reference. 
10.71 
 
Collaboration and License Agreement by and between the Registrant and Novartis Pharma AG dated as of August 2, 
2023, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2023 
and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material 
and (ii) the type that the Registrant treats as private or confidential. 
10.72 
 
Research, Development, and License Agreement by and among the Registrant, F. Hoffmann-La Roche Ltd., and 
Hoffmann-La Roche Inc. dated as of September 26, 2023, filed as an exhibit to the Registrant’s Quarterly Report on 
Form 10-Q for the quarter ended September 30, 2023 and incorporated herein by reference. Portions of this exhibit 
have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or 
confidential. 
10.73 
 
Side Letter dated June 11, 2020 to the Second Amended and Restated Strategic Neurology Drug Discovery and 
Development Collaboration, Option and License Agreement by and between the Registrant and Biogen MA Inc. 
dated October 17, 2018, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended 
June 30, 2020 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both 
(i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.74 
 
Collaboration and License Agreement by and between the Registrant and BicycleTX Limited dated July 9, 2021, 
filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 and 
incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and 
(ii) the type that the Registrant treats as private or confidential. 
10.75 
 
Amendment No. 1 dated December 17, 2021 to the Collaboration and License Agreement by and between the 
Registrant and BicycleTX Limited dated July 9, 2021, filed as an exhibit to the Registrant’s Annual Report on Form 
10-K for the year ended December 31, 2021 and incorporated herein by reference. Portions of this exhibit have been 
omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.76 
 
Amendment No. 2 dated July 28, 2022 to the Collaboration and License Agreement by and between the Registrant 
and BicycleTx Limited dated July 9, 2021, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for 
the quarter ended September 30, 2022 and incorporated herein by reference. Portions of this exhibit have been 
omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.77 
 
Amendment No. 3 dated April 27, 2023 to the Collaboration and License Agreement by and between the Registrant 
and BicycleTx Limited dated July 9, 2021, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for 
the quarter ended June 30, 2023 and incorporated herein by reference. Portions of this exhibit have been omitted 
because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
 
 
81

10.78 
 
Amended and Restated Neurology Drug Discovery and Development Collaboration, Option and License Agreement 
by and between the Registrant and Biogen MA Inc. dated July 12, 2021, filed as an exhibit to the Registrant’s 
Quarterly Report on Form 10-Q for the quarter ended September 30, 2021 and incorporated herein by reference. 
Portions of this exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant 
treats as private or confidential. 
10.79 
 
Collaboration and License Agreement by and between Akcea Therapeutics, Inc. and AstraZeneca AB dated 
December 6, 2021, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 
31, 2021 and incorporated herein by reference.  Portions of this exhibit have been omitted because they are both (i) 
not material and (ii) the type that the Registrant treats as private or confidential. 
10.80 
 
Letter Agreement dated June 29, 2023 in reference to the Collaboration and License Agreement dated December 6, 
2021 by and between Akcea Therapeutics, Inc. and AstraZeneca AB, filed as an exhibit to the Registrant’s Quarterly 
Report on Form 10-Q for the quarter ended June 30, 2023 and incorporated herein by reference. Portions of this 
exhibit have been omitted because they are both (i) not material and (ii) the type that the Registrant treats as private 
or confidential. 
10.81 
 
Collaboration and License Agreement between the Registrant and Metagenomi, Inc. dated November 10, 2022, filed 
as an exhibit to the Registrant’s Annual Report on Form 10-K for the year ended December 31, 2022 and 
incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not material and 
(ii) the type that the Registrant treats as private or confidential. 
10.82 
 
Royalty Purchase Agreement by and between the Registrant, Akcea Therapeutics, Inc. and Royalty Pharma 
Investments 2019 ICAV dated as of January 9, 2023, filed as an exhibit to the Registrant’s Annual Report on Form 
10-K for the year ended December 31, 2022 and incorporated herein by reference. Portions of this exhibit have been 
omitted because they are both (i) not material and (ii) the type that the Registrant treats as private or confidential. 
10.83 
 
Amended and Restated License Agreement by and between the Registrant and Otsuka Pharmaceutical Co., Ltd. dated 
June 18, 2024, filed as an exhibit to the Registrant’s Quarterly Report on Form 10-Q for the quarter ended June 30, 
2024 and incorporated herein by reference. Portions of this exhibit have been omitted because they are both (i) not 
material and (ii) the type that the Registrant treats as private or confidential. 
19 
 
Registrant’s Insider Trading Policy. 
21.1 
 
List of Subsidiaries for the Registrant, filed as an exhibit to the Registrant’s Annual Report on Form 10-K for the 
year ended December 31, 2023 and incorporated herein by reference.  
23.1 
  Consent of Independent Registered Public Accounting Firm. 
24.1 
  Power of Attorney – Included on the signature page of this Annual Report on Form 10-K. 
31.1 
  Certification by Chief Executive Officer Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 302 of 
the Sarbanes-Oxley Act of 2002. 
31.2 
  Certification by Chief Financial Officer Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 302 of 
the Sarbanes-Oxley Act of 2002. 
32.1+ 
  Certification Pursuant to 18 U.S.C. Section 1350 as Adopted Pursuant to Section 906 of the Sarbanes-Oxley Act of 
2002. 
97 
 
Registrant’s Amended and Restated Clawback Policy, filed as an exhibit to the Registrant’s Annual Report on Form 
10-K for the year ended December 31, 2023 and incorporated herein by reference.  
101 
The following financial statements from the Ionis Pharmaceuticals, Inc. Annual Report on Form 10-K for the year 
ended December 31, 2024, formatted in Extensive Business Reporting Language (XBRL): (i) consolidated balance 
sheets, (ii) consolidated statements of operations, (iii) consolidated statements of comprehensive income (loss), (iv) 
consolidated statements of stockholders’ equity (v) consolidated statements of cash flows, and (vi) notes to 
consolidated financial statements (detail tagged). 
104 
Cover Page Interactive Data File (formatted in iXBRL and included in exhibit 101). 
 
* 
Indicates management compensatory plans and arrangements as required to be filed as exhibits to this Report pursuant to Item 
14(c). 
+ 
This certification is deemed not filed for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise 
subject to the liability of that section, nor shall it be deemed incorporated by reference into any filing under the Securities Act of 
133, as amended, or the Securities Exchange Act of 1934, as amended. 
 
 
 
 
82

SIGNATURES 
  
Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the Registrant has duly caused 
this report on Form 10-K to be signed on its behalf by the undersigned, thereunto duly authorized on the 19th day of February, 2025. 
  
  
IONIS PHARMACEUTICALS, INC. 
  
 
 
  
By: /s/ BRETT P. MONIA 
  
 
Brett P. Monia, Ph.D. 
  
 
Chief Executive Officer (Principal executive officer) 
  
POWER OF ATTORNEY 
  
KNOW ALL MEN BY THESE PRESENTS, that each person whose signature appears below constitutes and appoints Brett 
P. Monia and Elizabeth L. Hougen, or any of them, his or her attorney-in-fact, each with the power of substitution, for him or her in 
any and all capacities, to sign any amendments to this Report, and to file the same, with exhibits thereto and other documents in 
connection therewith, with the Securities and Exchange Commission, hereby ratifying and confirming all that each of said attorneys-
in-fact, or his or her substitute or substitutes, may do or cause to be done by virtue hereof. 
 
Pursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following 
persons on behalf of the Registrant and in the capacities and on the dates indicated. 
  
Signatures 
  
Title 
  
Date 
  
 
 
 
 
/s/ BRETT P. MONIA 
 Director and Chief Executive Officer 
 
February 19, 2025 
Brett P. Monia, Ph.D. 
 (Principal executive officer) 
 
  
  
 
 
 
  
/s/ ELIZABETH L. HOUGEN 
 Executive Vice President, Finance and Chief Financial Officer 
 
February 19, 2025 
Elizabeth L. Hougen 
 (Principal financial and accounting officer) 
 
  
 
 
/s/ JOSEPH LOSCALZO 
 Chairman of the Board 
 
February 19, 2025 
Joseph Loscalzo, M.D., Ph.D. 
 
 
  
 
 
/s/ SPENCER R. BERTHELSEN 
 Director 
 
February 19, 2025 
Spencer R. Berthelsen, M.D. 
 
 
 
  
  
 
 
 
  
/s/ ALLENE M. DIAZ 
 Director 
 
February 19, 2025 
Allene M. Diaz 
 
 
 
  
 
 
/s/ MICHAEL HAYDEN  
 Director 
 
February 19, 2025 
Michael Hayden, CM OBC MB ChB 
PhD FRCP(C) FRSC  
 
 
 
 
  
/s/ JOAN E. HERMAN 
 Director 
 
February 19, 2025 
Joan E. Herman 
 
 
 
  
  
 
 
 
  
/s/ JOSEPH KLEIN 
 Director 
 
February 19, 2025 
Joseph Klein, III 
 
 
 
  
  
 
 
 
  
/s/ B. LYNNE PARSHALL 
 Director 
 
February 19, 2025 
B. Lynne Parshall, J.D. 
 
 
 
 
 
/s/ JOSEPH H. WENDER 
 Director 
 
February 19, 2025 
Joseph H. Wender 
 
 
 
  
 
/s/ MICHAEL YANG 
 Director 
 
February 19, 2025 
Michael Yang 
 
 
 
  
 
83

F-1 
IONIS PHARMACEUTICALS, INC. 
 
INDEX TO CONSOLIDATED FINANCIAL STATEMENTS 
  
  
Page 
Report of Independent Registered Public Accounting Firm (PCAOB ID 42) 
F-2 
Consolidated Balance Sheets at December 31, 2024 and 2023  
F-4 
Consolidated Statements of Operations for the years ended December 31, 2024, 2023 and 2022  
F-5 
Consolidated Statements of Comprehensive Loss for the years ended December 31, 2024, 2023 and 2022  
F-6 
Consolidated Statements of Stockholders’ Equity for the years ended December 31, 2024, 2023 and 2022  
F-7 
Consolidated Statements of Cash Flows for the years ended December 31, 2024, 2023 and 2022  
F-8 
Notes to the Consolidated Financial Statements 
F-9 
 
 
 

F-2 
REPORT OF INDEPENDENT REGISTERED PUBLIC ACCOUNTING FIRM 
 
  
To the Stockholders and the Board of Directors of Ionis Pharmaceuticals, Inc.  
 
Opinion on the Financial Statements 
 
We have audited the accompanying consolidated balance sheets of Ionis Pharmaceuticals, Inc. (the Company) as of December 31, 
2024 and 2023, the related consolidated statements of operations, comprehensive loss, stockholders’ equity and cash flows for each of 
the three years in the period ended December 31, 2024, 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, 2024 and 2023, and the results of its operations and its cash flows for each of the three years in the period 
ended December 31, 2024, in conformity with U.S. generally accepted accounting principles. 
 
We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) 
(PCAOB), the Company’s internal control over financial reporting as of December 31, 2024, based on criteria established in Internal 
Control—Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 
framework), and our report dated February 19, 2025 expressed an unqualified opinion thereon. 
 
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 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. 
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. 
 
Critical Audit Matters 
 
The critical audit matter communicated below is a matter arising from the current period audit of the financial statements that was 
communicated or required to be communicated to the audit committee and that: (1) relates to accounts or disclosures that are material 
to the financial statements and (2) involved our especially challenging, subjective or complex judgments. The communication of the 
critical audit matter does not alter in any way our opinion on the consolidated financial statements, taken as a whole, and we are not, 
by communicating the critical audit matter below, providing a separate opinion on the critical audit matter or on the accounts or 
disclosures to which it relates. 
 
 

F-3 
 
 
 
Estimated Liability for Clinical Development Costs 
 
Description of the 
Matter 
 
As of December 31, 2024, the Company accrued $77.4 million for clinical development expenses. As 
discussed in Note 1 to the consolidated financial statements, the Company records costs for clinical trial 
activities based upon estimates of costs incurred through the balance sheet date that have yet to be invoiced 
related to third-party clinical management costs, laboratory and analysis costs, toxicology studies and 
investigator grants. The Company estimates its liability using assumptions about study and patient activities 
and the related expected expenses for those activities based on the contracted fees with service providers. 
 
Auditing the Company’s accruals for clinical and contract research organization costs is especially complex as 
the information necessary to estimate the accruals is accumulated from multiple sources. In addition, in certain 
circumstances, the determination of the nature and level of services that have been received during the 
reporting period requires judgment because the timing and pattern of vendor invoicing does not correspond to 
the level of services provided and there may be delays in invoicing from vendors. 
 
How We 
Addressed the 
Matter in Our 
Audit 
 
We obtained an understanding and evaluated the design and tested the operating effectiveness of controls 
over the accounting for accrued clinical development expenses. This included controls over management's 
assessment of the assumptions and accuracy of data underlying the accrued clinical development expenses 
estimate. 
 
To test the accuracy of the Company’s accrued clinical development expenses, we performed audit 
procedures that included, among other procedures, obtaining supporting evidence of the research and 
development activities performed for significant clinical trials and confirming with a sample of vendors the 
progress of activities under research and development contracts at period end. We corroborated the status of 
significant clinical development expenses through meetings with accounting and clinical project managers. 
We compared the costs for a sample of transactions against the related invoices and contracts, and examined 
a sample of subsequent payments to evaluate the accuracy of the accrued clinical development expenses and 
compared the results to the current year accrual. 
 
/s/ Ernst & Young LLP 
 
We have served as the Company’s auditor since 1989. 
 
San Diego, California 
February 19, 2025 
 
 

F-4 
IONIS PHARMACEUTICALS, INC. 
CONSOLIDATED BALANCE SHEETS 
(In thousands, except share and par value data) 
 
  
December 31, 
 
2024 
2023 
 
 
 
ASSETS 
 
 
 
Current assets: 
 
  
Cash and cash equivalents 
$ 
242,077  $ 
399,266
Short-term investments 
 
2,055,579
 
1,931,935
Contracts receivable 
 
92,188
 
97,778
Inventories 
 
12,512
 
7,441
Other current assets 
 
217,934
 
205,433
Total current assets 
 
2,620,290
 
2,641,853
Property, plant and equipment, net 
 
94,251
 
71,043
Right-of-use assets 
 
161,856
 
171,896
Deposits and other assets 
 
127,278
 
105,280
Total assets 
$ 3,003,675  $ 2,990,072
LIABILITIES AND STOCKHOLDERS’ EQUITY 
 
  
Current liabilities: 
 
  
Accounts payable 
$ 
42,964  $ 
26,027
Accrued compensation 
 
69,614
 
67,727
Accrued liabilities 
 
108,438
 
147,894
Income taxes payable 
34
2,151
0.125 percent convertible senior notes, net 
—
44,332
Current portion of deferred contract revenue 
 
78,989
151,128
Other current liabilities 
 
9,279
8,831
Total current liabilities 
 
309,318
 
448,090
Long-term deferred contract revenue 
 
156,504
 
241,184
1.75 percent convertible senior notes, net 
565,026
562,285
0 percent convertible senior notes, net 
628,535
625,380
Liability related to sale of future royalties, net 
542,212
513,736
Long-term lease liabilities 
161,805
170,875
Long-term obligations  
51,924
41,836
Total liabilities 
 
2,415,324
 
2,603,386
Stockholders’ equity: 
 
Common stock, $0.001 par value; 300,000,000 shares authorized, 157,908,815 and 144,340,526 shares 
issued and outstanding at December 31, 2024 and December 31, 2023, respectively 
 
158
 
144
Additional paid-in capital 
 
2,868,812
 
2,215,098
Accumulated other comprehensive loss 
 
(30,811)
 
(32,645)
Accumulated deficit 
 (2,249,808)
 (1,795,911)
Total stockholders’ equity 
 
588,351
 
386,686
Total liabilities and stockholders’ equity 
$ 3,003,675  $ 2,990,072
 
 
See accompanying notes. 
 

F-5 
IONIS PHARMACEUTICALS, INC. 
CONSOLIDATED STATEMENTS OF OPERATIONS 
(In thousands, except for per share amounts) 
 
  
Year Ended December 31, 
  
2024 
 
2023 
 
2022 
 
 
 
 
Revenue: 
 
 
 
 
 
Commercial revenue:  
SPINRAZA royalties 
$ 
216,090
$ 
240,379 $ 
242,314
WAINUA royalties 
20,207
—
—
Other commercial revenue 
56,779
68,212
61,044
Total commercial revenue 
293,076
308,591
303,358
Research and development revenue: 
Collaborative agreement revenue 
332,647  
352,657  
207,222
WAINUA joint development revenue 
79,415
126,399
76,787
Total research and development revenue 
412,062
479,056
284,009
Total revenue 
 
705,138
 
787,647  
587,367
  
 
  
  
Expenses: 
 
  
  
Cost of sales 
11,215
9,133
14,116
Research, development and patent 
 
901,530
 
899,625  
833,147
Selling, general and administrative 
 
267,474
 
232,619  
150,295
Total operating expenses 
 1,180,219
 
1,141,377  
997,558
  
 
  
  
Loss from operations 
 
(475,081)
 
(353,730)  
(410,191)
  
 
  
  
Other income (expense): 
 
  
  
Investment income 
 
107,022
 
89,041  
25,331
Interest expense 
 
(16,994)
 
(12,660)  
(8,122)
Interest expense related to sale of future royalties 
(73,457)
(68,797)
—
Loss on investments 
(2,889)
(1,914)
(7,333)
Gain (loss) on sale of real estate assets 
 
(12)
 
(161)  
149,604
Other income (expense) 
1,343
14,256
(7,274)
  
 
  
  
Loss before income tax benefit (expense) 
 
(460,068)
 
(333,965)  
(257,985)
  
 
  
  
Income tax benefit (expense) 
 
6,171
 
(32,321)  
(11,737)
  
 
  
  
Net loss 
$ (453,897)  $ 
(366,286)  $ 
(269,722)
  
 
  
  
Basic and diluted net loss per share 
$ 
(3.04)  $ 
(2.56)  $ 
(1.90)
Shares used in computing basic and diluted net loss per share 
 
149,514
 
143,190  
141,848
 
 
See accompanying notes. 
 

F-6 
IONIS PHARMACEUTICALS, INC. 
CONSOLIDATED STATEMENTS OF COMPREHENSIVE LOSS 
(In thousands) 
 
  
Year Ended December 31, 
  
2024 
 
2023 
2022 
 
 
 
 
Net loss 
$ (453,897) $ (366,286) $ 
(269,722) 
Unrealized gains (losses) on investments, net of tax 
 
2,107  
24,484
 
(24,395) 
Currency translation adjustment 
(273) 
351
(417) 
Comprehensive loss 
$ (452,063) $ (341,451) $ 
(294,534) 
 
 
See accompanying notes. 
 

F-7 
IONIS PHARMACEUTICALS, INC. 
CONSOLIDATED STATEMENTS OF STOCKHOLDERS’ EQUITY 
(In thousands) 
 
 
 
Common Stock 
 Additional   
Accumulated 
Other 
 Accumulated  
Total Ionis 
Stockholders’ 
Description 
 
Shares  Amount  
Paid in 
Capital 
 
Comprehensive 
Loss 
 
Deficit 
 
Equity 
Balance at December 31, 2021 
141,210 $ 
141 $ 
1,964,167 $ 
(32,668) $ (1,159,903) $ 
771,737
Net loss 
—
—
—
—
(269,722) 
(269,722)
Change in unrealized losses, net of tax 
—
—
—
(24,395)
— 
(24,395)
Foreign currency translation 
—
—
—
(417)
— 
(417)
Issuance of common stock in connection with employee 
stock plans, net 
1,194
1
6,372
—
— 
6,373
Stock-based compensation expense 
—
—
100,264
—
— 
100,264
Payments of tax withholdings related to vesting of 
employee stock awards and exercise of employee 
stock options 
(346)
—
(10,953)
—
— 
(10,953)
Balance at December 31, 2022  
142,058 $ 
142 $ 
2,059,850 $ 
(57,480) $ (1,429,625) $ 
572,887
Net loss 
—
—
—
—
(366,286) 
(366,286)
Change in unrealized gains, net of tax 
—
—
—
24,484
— 
24,484
Foreign currency translation 
—
—
—
351
— 
351
Issuance of common stock in connection with employee 
stock plans, net 
2,283
2
49,439
—
— 
49,441
Stock-based compensation expense 
—
—
105,809
—
— 
105,809
Balance at December 31, 2023  
144,341 $ 
144 $ 
2,215,098 $ 
(32,645) $ (1,795,911) $ 
386,686
Net loss 
—
—
—
—
(453,897) 
(453,897)
Change in unrealized gains, net of tax 
—
—
—
2,107
— 
2,107
Foreign currency translation 
—
—
—
(273)
— 
(273)
Issuance of common stock in connection with employee 
stock plans, net 
2,068
2
33,607
—
— 
33,609
Issuance of public common stock, net 
11,500
12
489,108
—
— 
489,120
Stock-based compensation expense 
—
—
130,999
—
— 
130,999
Balance at December 31, 2024 
157,909 $ 
158 $ 
2,868,812 $ 
(30,811) $ (2,249,808) $ 
588,351
 
 
See accompanying notes. 
 

F-8 
IONIS PHARMACEUTICALS, INC. 
CONSOLIDATED STATEMENTS OF CASH FLOWS 
(In thousands) 
 
  
Year Ended December 31, 
  
2024 
 
2023  
  
2022 
 
 
 
  
 
Operating activities: 
 
Net loss 
$ 
(453,897)  $ 
(366,286)  $ 
(269,722)
Adjustments to reconcile net loss to net cash used in operating activities: 
 
  
   
Depreciation 
 
9,614
 
10,292 
 
14,328
Amortization of right-of-use operating lease assets 
10,040
9,647 
5,362
Amortization of other assets 
 
2,336
 
2,559 
 
2,415
Amortization of premium (discount) on investments, net 
 
(37,733)
 
(28,885) 
 
7,389
Amortization of debt issuance costs 
 
6,690
 
6,330 
 
5,373
Non-cash royalty revenue related to sale of royalties 
(44,981)
(44,628) 
—
Non-cash interest related to sale of future royalties 
72,846
68,238 
—
Stock-based compensation expense 
 
130,200
 
105,809 
 
100,264
Gain on early retirement of debt 
 
—
 
(13,389) 
 
—
Non-cash losses related to disposal of property, plant and equipment 
7,404
16,649 
531
Loss (gain) on sale of real estate assets 
—
161 
(150,135)
Loss on investments 
2,892
1,589 
224
Non-cash losses related to other assets 
 
3,032
 
1,661 
 
2,030
Changes in operating assets and liabilities: 
 
  
   
Contracts receivable 
 
5,590
 
(72,059) 
 
36,358
Inventories 
 
(5,071)
 
(2,469) 
 
5,326
Other current and long-term assets 
 
(25,857)
 
(33,763) 
 
(27,235)
Accounts payable 
 
15,990
 
8,119 
 
1,094
Income taxes 
(2,117)
(4,098) 
6,213
Accrued compensation 
 
1,887
 
18,549 
 
10,368
Accrued liabilities and other current liabilities 
 
(42,993)
 
(5,506) 
 
46,695
Deferred contract revenue 
 
(156,819)
 
13,967 
 
(71,248)
Net cash used in operating activities 
 
(500,947)
 
(307,513) 
 
(274,370)
Investing activities: 
 
  
   
Purchases of short-term investments 
 
(1,852,858)
 (1,770,814) 
 (1,485,772)
Proceeds from sale of short-term investments 
 
1,769,172
 
1,584,676 
 
989,152
Purchases of property, plant and equipment 
 
(45,280)
 
(23,805) 
 
(15,721)
Proceeds from sale of real estate assets 
—
22 
254,083
Acquisition of licenses and other assets, net 
 
(5,061)
 
(4,206) 
 
(4,378)
Net cash used in investing activities 
 
(134,027)
 
(214,127) 
 
(262,636)
Financing activities: 
 
  
   
Proceeds from issuance of common stock through equity plans, net 
 
33,609
 
49,442 
 
6,373
Proceeds from issuance of common stock in public offering, net 
489,120
— 
—
Repayment of 0.125 percent convertible senior notes 
(44,504)
(487,943) 
—
Proceeds from issuance of 1.75 percent convertible senior notes 
—
575,000 
—
1.75 percent convertible senior notes issuance costs 
—
(14,175) 
—
Proceeds from sale of future royalties 
—
500,000 
—
Payments of transaction costs related to sale of future royalties 
—
(10,434) 
(29)
Proceeds from real estate transaction 
—
32,352 
—
Principal payments on mortgage debt 
(167)
(160) 
(50,686)
Payments of tax withholdings related to vesting of employee stock awards and 
exercise of employee stock options 
—
— 
(10,953)
Net cash provided by (used in) financing activities 
 
478,058
 
644,082 
 
(55,295)
Effects of exchange rates on cash 
(273)
352 
(418)
Net increase (decrease) in cash and cash equivalents 
 
(157,189)
 
122,794 
 
(592,719)
Cash and cash equivalents at beginning of year 
 
399,266
 
276,472 
 
869,191
Cash and cash equivalents at end of year 
$ 
242,077  $ 
399,266  $ 
276,472
 
Supplemental disclosures of cash flow information: 
Interest paid 
$ 
10,869  $ 
6,512  $ 
2,898

F-9 
Income taxes paid (refunds received) 
$ 
(5,620)
$ 
48,334
$ 
5,010
Supplemental disclosures of non-cash investing and financing activities: 
  
  
Right-of-use assets obtained in exchange for lease liabilities 
$ 
—
$ 
—
$ 
168,931
Amounts accrued for capital and patent expenditures 
$ 
947  $ 
172  $ 
4,767
 
 
See accompanying notes. 
 

F-10 
IONIS PHARMACEUTICALS, INC. 
NOTES TO CONSOLIDATED FINANCIAL STATEMENTS 
 
1. Organization and Significant Accounting Policies 
 
Basis of Presentation 
 
In our consolidated financial statements we included the accounts of Ionis Pharmaceuticals, Inc. and the consolidated results 
of our wholly owned subsidiary, Akcea Therapeutics, Inc. and its wholly owned subsidiaries (“we”, “us” or “our”). 
 
Organization and Business Activity 
  
We incorporated in California on January 10, 1989. In conjunction with our IPO, we reorganized as a Delaware corporation 
in April 1991. We were organized principally to develop human therapeutic medicines using antisense technology. In December 2015, 
we changed our name from Isis Pharmaceuticals, Inc. to Ionis Pharmaceuticals, Inc. 
 
We operate as a single segment, Ionis operations, because our chief operating decision maker, or CODM, reviews operating 
results on an aggregate basis and manages our operations as a single operating segment. Refer to Note 12, Segment Information, for 
further details on our segment information. 
 
Use of Estimates 
 
We prepare our consolidated financial statements in conformity with accounting principles generally accepted in the United 
States, or U.S., that require us to make estimates and assumptions that affect the amounts reported in our consolidated financial 
statements and accompanying notes. Actual results could differ from our estimates. 
 
Revenue Recognition 
 
We generally recognize revenue when we have satisfied all contractual obligations and are reasonably assured of collecting 
the resulting receivable. We are often entitled to bill our customers and receive payment from our customers in advance of recognizing 
the revenue. In the instances in which we have received payment from our customers in advance of recognizing revenue, we include 
the amounts within deferred revenue in our consolidated balance sheets. 
 
At contract inception, we analyze our collaboration arrangements to assess whether such arrangements involve joint 
operating activities performed by parties that are both active participants in the activities and exposed to significant risks and rewards 
dependent on the commercial success of such activities and therefore within the scope of ASC Topic 808, Collaborative 
Arrangements, or ASC 808. ASC 808 does not address the recognition and measurement of collaborative arrangements and instead 
refers companies to use other authoritative accounting literature. For collaboration arrangements within the scope of ASC 808 that 
contain multiple elements, we first determine which elements of the collaboration reflect a vendor-customer relationship and therefore 
are within the scope of ASC 606, Revenue from Contracts with Customers. When we determine elements of a collaboration do not 
reflect a vendor-customer relationship, we consistently apply the reasonable and rational policy election we made by analogizing to 
authoritative accounting literature.   
 
We evaluate the income statement classification for presentation of amounts due from or owed to other participants 
associated with multiple activities in a collaboration arrangement based on the nature of each separate activity. For example, in our 
WAINUA collaboration with AstraZeneca, we recognize funding received from AstraZeneca for co-development activities as 
revenue; while we recognize cost sharing payments to and from AstraZeneca associated with co-commercialization activities and co-
medical affairs activities as selling, general and administrative, or SG&A, expense and research and development, or R&D, expense, 
respectively.  
 
Steps to Recognize Revenue  
 
For elements of our contractual relationships that we account for under ASC 606, we use a five-step process to determine the 
amount of revenue we should recognize and when we should recognize it. The five-step process is as follows: 
 
1. Identify the contract 
 
Accounting rules require us to first determine if we have a contract with our partner or customer. 
 

F-11 
2. Identify the performance obligations 
 
We next identify our performance obligations, which represent the distinct goods and services we are required to provide 
under the contract.  
 
3. Determine the transaction price 
 
We then determine the transaction price by reviewing the amount of consideration we are eligible to earn under the 
collaboration agreement, including any variable consideration.  
 
4. Allocate the transaction price 
 
Next, we allocate the transaction price to each of our performance obligations. When we have to allocate the transaction price 
to more than one performance obligation, we make estimates of the relative stand-alone selling price of each performance obligation 
because we do not typically sell our goods or services on a stand-alone basis. We then allocate the transaction price to each 
performance obligation based on the relative stand-alone selling price. We do not reallocate the transaction price after the start of an 
agreement to reflect subsequent changes in stand-alone selling prices. 
 
5. Recognize revenue 
 
We recognize revenue in one of two ways, over time or at a point in time. We recognize revenue over time when we are 
executing on our performance obligation over time and our partner receives benefit over time. For example, we recognize revenue 
over time when we provide R&D services. We recognize revenue at a point in time when our partner receives full use of an item at a 
specific point in time. For example, we recognize revenue at a point in time when we deliver a license or API to a partner. 
 
We recognize royalty revenue in the period in which the counterparty sells the related product and recognizes the related 
revenue, which in certain cases may require us to estimate our royalty revenue. 
 
Amendments to Agreements  
 
From time to time we amend our collaboration agreements. When this occurs, we are required to assess the following items 
to determine the accounting for the amendment:  
 
1) If the additional goods and/or services are distinct from the other performance obligations in the original agreement; and 
2) If the goods and/or services are sold at a stand-alone selling price.  
 
If we conclude the goods and/or services in the amendment are distinct from the performance obligations in the original 
agreement and at a stand-alone selling price, we account for the amendment as a separate agreement. If we conclude the goods and/or 
services are not distinct and are sold at a stand-alone selling price, we then assess whether the remaining goods or services are distinct 
from those already provided. If the goods and/or services are distinct from what we have already provided, then we allocate the 
remaining transaction price from the original agreement and the additional transaction price from the amendment to the remaining 
goods and/or services. If the goods and/or services are not distinct from what we have already provided, we update the transaction 
price for our single performance obligation and recognize any change in our estimated revenue as a cumulative-effect adjustment. 
 
Multiple agreements 
 
From time to time, we may enter into separate agreements at or near the same time with the same partner. We evaluate such 
agreements to determine whether we should account for them individually as distinct arrangements or whether the separate 
agreements should be combined and accounted for together. We evaluate the following to determine the accounting for the 
agreements: 
 
● 
Whether the agreements were negotiated together with a single objective; 
● 
Whether the amount of consideration in one contract depends on the price or performance of the other agreement; or 
● 
Whether the goods and/or services promised under the agreements are a single performance obligation.  
 
Our evaluation involves significant judgment to determine whether a group of agreements might be so closely related that 
accounting guidance requires us to account for them as a combined arrangement. 
 

F-12 
Refer to Note 4, Collaborative Arrangements and Licensing Agreements, for further discussion of our 2018 neurology 
collaboration with Biogen that included multiple agreements which we negotiated concurrently and in contemplation of one another. 
 
Contracts Receivable 
 
Our contracts receivable balance represents the amounts we have billed our partners or customers and that are due to us 
unconditionally for goods we have delivered or services we have performed. When we bill our partners or customers with payment 
terms based on the passage of time, we consider the contracts receivable to be unconditional. We typically receive payment within one 
quarter of billing our partner or customer.  
 
As of December 31, 2024, approximately 95.6 percent of our contracts receivables were from three significant customers. As 
of December 31, 2023, approximately 87.8 percent of our contracts receivables were from one significant customer. 
 
Unbilled Royalties 
 
Our unbilled royalties represent our right to receive consideration from our partners in advance of when we are eligible to bill 
them for royalties. We include these unbilled amounts in other current assets in our consolidated balance sheets. 
 
Deferred Revenue 
 
We are often entitled to bill our customers and receive payment from our customers in advance of our obligation to provide 
services or transfer goods to our partners. In these instances, we include the amounts in deferred revenue in our consolidated balance 
sheets. During the years ended December 31, 2024 and 2023, we recognized $166.1 million and $78.2 million of revenue from 
amounts that were in our beginning deferred revenue balance for each respective period. For further discussion, refer to our revenue 
recognition policy above. 
 
Cost of Sales 
 
Our cost of sales is comprised of costs related to our commercial revenue, including manufacturing costs, transportation and 
freight costs and indirect overhead costs associated with the manufacturing and distribution of our products. We also may include 
certain period costs related to manufacturing services and inventory adjustments in cost of sales.  
 
Research, Development and Patent Expenses 
 
Our research, development and patent expenses include wages, benefits, facilities, supplies, external services, clinical trial 
and manufacturing costs, patents and other expenses that are directly related to our R&D operations. We expense R&D costs as we 
incur them. When we make payments for R&D services prior to the services being rendered, we record those amounts as prepaid 
assets in our consolidated balance sheets and we expense them as the services are provided. A portion of the costs included in R&D 
expenses are costs associated with our partner agreements. In 2024, 2023 and 2022, patent expenses were $5.3 million, $4.3 million 
and $4.7 million, respectively. 
 
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 our financial statements or tax returns. In 
addition, deferred tax assets are recorded for the future benefit of utilizing net operating losses and research and development credit 
carryforwards. We record a valuation allowance when necessary to reduce our net deferred tax assets to the amount expected to be 
realized. 
 
We apply the authoritative accounting guidance prescribing a threshold and measurement attribute for the financial 
recognition and measurement of a tax position taken or expected to be taken in a tax return. We recognize liabilities for uncertain tax 
positions based on a two-step process. The first step is to evaluate the tax position for recognition by determining if the weight of 
available evidence indicates that it is more likely than not that the position will be sustained on audit, including resolution of related 
appeals or litigation processes, if any. The second step requires us to estimate and measure the tax benefit as the largest amount that is 
more than 50 percent likely to be realized upon ultimate settlement. 
 

F-13 
We are required to use significant judgment in evaluating our uncertain tax positions and determining our provision for 
income taxes. Although we believe our reserves are reasonable, we can provide no assurance that the final tax outcome of these 
matters will not be different from that which we have reflected in our historical income tax provisions and accruals. We adjust these 
reserves for changing facts and circumstances, such as the closing of a tax audit or the refinement of an estimate. To the extent that the 
final tax outcome of these matters is different than the amounts recorded, such differences may impact the provision for income taxes 
in the period in which we make such determination. 
 
We are also required to use significant judgment in determining any valuation allowance recorded against our deferred tax 
assets. In assessing the need for a valuation allowance, we consider all available evidence, including scheduled reversal of deferred tax 
liabilities, past operating results, the feasibility of tax planning strategies and estimates of future taxable income. We base our 
estimates of future taxable income on assumptions that are consistent with our plans. The assumptions we use represent our best 
estimates and involve inherent uncertainties and the application of our judgment. Should actual amounts differ from our estimates, the 
amount of our tax expense and liabilities we recognize could be materially impacted. We record a valuation allowance to reduce the 
balance of our net deferred tax assets to the amount we believe is more-likely-than-not to be realized.  
 
Basic and Diluted Net Loss per Share  
 
Basic net loss per share 
 
We compute basic net loss per share by dividing our net loss by our weighted-average number of common shares outstanding 
during the period.  
 
Diluted net loss per share 
 
For the years ended December 31, 2024, 2023 and 2022, we incurred a net loss; therefore, we did not include dilutive 
common equivalent shares in the computation of diluted net loss per share because the effect would have been anti-dilutive. Common 
stock from the following would have had an anti-dilutive effect on net loss per share: 
 
● 
0 percent convertible senior notes, or 0% Notes; 
● 
Note hedges related to the 0% Notes; 
● 
0.125 percent convertible senior notes, or 0.125% Notes; 
● 
Note hedges related to the 0.125% Notes; 
● 
Dilutive stock options; 
● 
Unvested restricted stock units, or RSUs; 
● 
Unvested performance restricted stock units, or PRSUs; and 
● 
Employee Stock Purchase Plan, or ESPP. 
 
For the years ended December 31, 2024 and 2023, common stock underlying the 1.75 percent convertible senior notes, or 
1.75% Notes, would also have had an anti-dilutive effect on net loss per share. 
 
As of December 31, 2024, 2023 and 2022, we had outstanding warrants related to our 0% Notes and 0.125% Notes. We will 
include the shares issuable under these warrants in our calculation of diluted earnings per share when the average market price per 
share of our common stock for the reporting period exceeds the strike price of the warrants. During 2024, 2023 and 2022, the market 
price of our common stock did not exceed the strike price of the warrants. 
 
Stock-Based Compensation Expense 
 
We measure stock-based compensation expense for equity-classified awards, principally related to stock options, RSUs, 
PRSUs and stock purchase rights under our ESPP based on the estimated fair value of the award on the date of grant. We recognize 
the value of the portion of the award that we ultimately expect to vest as stock-based compensation expense over the requisite service 
period in our consolidated statements of operations. We reduce stock-based compensation expense for estimated forfeitures at the time 
of grant and revise in subsequent periods if actual forfeitures differ from those estimates. 
 
We recognize compensation expense for stock options granted, RSUs, PRSUs and stock purchase rights under the ESPP 
using the accelerated multiple-option approach. Under the accelerated multiple-option approach (also known as the graded-vesting 
method), we recognize compensation expense over the requisite service period for each separately vesting tranche of the award as 
though the award were in substance multiple awards, which results in the expense being front-loaded over the vesting period.  
 

F-14 
Stock Options and Stock Purchase Rights: 
 
We use the Black-Scholes model to estimate the fair value of stock options granted and stock purchase rights under our 
ESPP. On the grant date, we use our stock price and assumptions regarding a number of variables to determine the estimated fair value 
of stock-based payment awards. These variables include, but are not limited to, our expected stock price volatility over the term of the 
awards, and actual and projected employee stock option exercise behaviors. The expected term of stock options granted represents the 
period of time that we expect them to be outstanding. Historically, we estimated the expected term of options granted based on 
historical exercise patterns. In 2021, our Compensation Committee approved an amendment to the 2011 Equity Incentive Plan, or 
2011 Plan, and the 2020 Equity Incentive Plan, or 2020 Plan, that increased the contractual term of stock options granted under these 
plans from seven years to ten years for stock options granted on January 1, 2022 and thereafter. We determined that we are unable to 
rely on our historical exercise data as a basis for estimating the expected life of stock options granted to employees following this 
change because the contractual term changed and we have no other means to reasonably estimate future exercise behavior. We 
therefore used the simplified method for determining the expected life of stock options granted to employees in the years ended 
December 31, 2024, 2023 and 2022. Under the simplified method, we calculate the expected term as the average of the time-to-vesting 
and the contractual life of the options. As we gain additional historical information, we will transition to calculating our expected term 
based on our historical exercise patterns. 
 
RSU’s: 
 
The fair value of RSUs is based on the market price of our common stock on the date of grant. The RSUs we have granted to 
employees vest annually over a four-year period. The RSUs we granted to our board of directors prior to June 2020 vest annually over 
a four-year period. The annual RSUs we granted to our board of directors after June 2020 fully vest after one year. The RSUs we 
granted to board members at their initial appointment to the board of directors vest annually over a three-year period.  
 
PRSU’s: 
 
Beginning in 2020, we added PRSU awards to the compensation for our Chief Executive Officer, Dr. Brett Monia. Beginning 
in 2022, we added PRSU awards to the compensation for our other Section 16 officers. Under the terms of the PRSUs we granted in 
2020 through 2022, one third of the PRSUs may vest at the end of three separate performance periods spread over the three years 
following the date of grant (i.e., the one-year period commencing on the date of grant and ending on the first anniversary of the date of 
grant; the two-year period commencing on the date of grant and ending on the second anniversary of the date of grant; and the three-
year period commencing on the date of grant and ending on the third anniversary of the date of grant) based on our relative total 
shareholder return, or TSR, as compared to a peer group of companies, and as measured, in each case, at the end of the applicable 
performance period. Under the terms of the grants no number of PRSUs is guaranteed to vest and the actual number of PRSUs that 
will vest at the end of each performance period may be anywhere from zero to 150 percent of the target number depending on our 
relative TSR. These PRSU awards also included an alternative three-year payout mechanism, or the Alternative Calculation, under 
which we must calculate an alternative payout at the end of the final three-year measurement period assuming the only measurement 
period for all shares under the award was the three-year period. If the Alternative Calculation is greater than payouts under the sum of 
the three years, then such PRSU award will pay out to achieve the number of shares payable under the Alternative Calculation. 
 
Under the terms of the PRSUs we granted in 2024 and 2023, 100 percent of the PRSUs may vest at the end of the three-year 
performance period based on our relative TSR as compared to a peer group of companies and as measured at the end of the 
performance period. Under the terms of the grants, no number of PRSUs is guaranteed to vest and the actual number of PRSUs that 
will vest at the end of each performance period may be anywhere from zero to 200 percent of the target number depending on our 
relative TSR. 
 
We determine the fair value of the PRSUs using a Monte Carlo model because the performance target is based on our relative 
TSR, which represents a market condition. We are recognizing the grant date fair value of these awards as stock-based compensation 
expense using the accelerated multiple-option approach over the vesting period. 
 
Refer to Note 8, Stockholders’ Equity, for additional information regarding our stock-based compensation plans. 
 

F-15 
Concentration of Credit Risk 
 
Financial instruments that potentially subject us to concentrations of credit risk consist primarily of cash equivalents, short-
term investments and receivables. We place our cash equivalents and short-term investments with reputable financial institutions. We 
primarily invest our excess cash in commercial paper and debt instruments of the U.S. Treasury, financial institutions, corporations, 
and U.S. government agencies with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Moody’s, 
Standard & Poor’s, or S&P, or Fitch, respectively. We have established guidelines relative to diversification and maturities that 
maintain safety and liquidity. We periodically review and modify these guidelines to maximize trends in yields and interest rates 
without compromising safety and liquidity. 
 
Fair Value Measurements 
 
We have estimated the fair value of our financial instruments. The amounts reported for cash, accounts receivable, accounts 
payable and accrued expenses approximate the fair value because of their short maturities. We report our investment securities at their 
estimated fair value based on quoted market prices for identical or similar instruments. 
 
We use a three-tier fair value hierarchy to prioritize the inputs used in our fair value measurements. These tiers include: Level 
1, defined as observable inputs such as quoted prices in active markets for identical assets, which includes our money market funds 
and treasury securities classified as available-for-sale securities and our investment in equity securities in publicly traded 
biotechnology companies; Level 2, defined as inputs other than quoted prices in active markets that are either directly or indirectly 
observable, which includes our fixed income securities and commercial paper classified as available-for-sale securities; and Level 3, 
defined as unobservable inputs in which little or no market data exists, therefore requiring us to develop our own assumptions. We 
classify most of our securities as Level 2. We obtain the fair value of our Level 2 investments from our custodian bank or from a 
professional pricing service. We validate the fair value of our Level 2 investments by understanding the pricing model used by the 
custodian banks or professional pricing service provider and comparing that fair value to the fair value based on observable market 
prices. 
 
Cash, Cash Equivalents and Investments 
 
We consider all liquid investments with maturities of three months or less when we purchase them to be cash equivalents. 
Our short-term investments have initial maturities of greater than three months from date of purchase. We classify our short-term debt 
investments as “available-for-sale” and carry them at fair market value based upon prices on the last day of the fiscal period for 
identical or similar items. We record unrealized gains and losses on debt securities as a separate component of comprehensive income 
(loss) and include net realized gains and losses in gain (loss) on investments in our consolidated statements of operations. We use the 
specific identification method to determine the cost of securities sold. 
 
We also have equity investments of less than 20 percent ownership in public and private biotechnology companies that we 
received as part of a technology license or partner agreement. At December 31, 2024, we held equity investments in three publicly 
traded companies and seven privately held companies. 
 
We are required to measure and record our equity investments at fair value and to recognize the changes in fair value in our 
consolidated statements of operations. We account for our equity investments in publicly traded companies at their listed stock price. 
We account for our equity investments in privately held companies at their cost minus impairments, plus or minus changes resulting 
from observable price changes in orderly transactions for the identical or similar investment of the same issuer. 
 
Inventories 
 
We reflect our inventory in our consolidated balance sheets at the lower of cost or net realizable value under the first-in, first-
out method, or FIFO. Our inventory costs include material, labor and overhead costs. Our raw materials include active pharmaceutical 
ingredient, or API, for commercial medicines. We capitalize inventory costs related to drug products when we consider future 
commercialization to be probable and expect to realize future economic benefit. When evaluating whether to capitalize inventory 
costs, we consider various factors, including the likelihood of receiving required regulatory approvals, communications from 
regulatory agencies such as safety or efficacy concerns, underlying manufacturing processes and supply chain matters, shelf life of the 
inventory, market trends such as competition and pricing, potential legal matters and potential reimbursement strategies. We record 
inventory costs that do not meet our capitalization requirements as R&D expense in our consolidated statements of operations. 
 
We review our inventory periodically and reduce the carrying value of items we consider to be slow moving or obsolete to 
their estimated net realizable value based on forecasted demand compared to quantities on hand. We consider several factors in 
estimating the net realizable value, including shelf life of our inventory and historical write-offs. 
 
 
 

F-16 
Capitalized Materials 
 
We capitalize the costs of certain materials that we purchase for use in manufacturing our medicines in our clinical 
development programs because until we use these materials, they have alternative future uses. We can use these materials in multiple 
products and, as a result, each material has future economic value independent of the development status of any single medicine. We 
include capitalized materials in other current assets in our consolidated balance sheets and expense these costs as R&D expenses when 
the materials are used. We review our capitalized materials periodically for continued alternative future use and reduce the carrying 
value of items in the period in which an impairment is identified. 
 
In 2024, we reclassified capitalized costs related to materials used in our clinical development programs from inventories to 
other current assets in our consolidated balance sheets. As such, we reclassified the respective prior period amounts to conform with 
the current year presentation. 
 
Property, Plant and Equipment 
 
We carry our property, plant and equipment at cost and depreciate it on the straight-line method over its estimated useful life, 
which we determine as the following (in years):  
 
 
Estimated 
 
Useful Lives 
Computer software, laboratory, manufacturing and other equipment 
3 to 10 
Building, building improvements and building systems 
15 to 40 
Land improvements 
20 
Leasehold improvements 
5 to 15 
Furniture and fixtures 
5 to 10 
 
We depreciate our leasehold improvements using the shorter of the estimated useful life or remaining lease term. We evaluate 
long-lived assets, which include property, plant and equipment, for impairment whenever events or changes in circumstances indicate 
that we may not be able to recover the carrying amount of such assets. 
 
Accrued Liabilities 
 
We have numerous medicines in preclinical studies and/or clinical trials at clinical sites throughout the world. We estimate 
our liability for preclinical and clinical development costs we have incurred and services that we have received but for which we have 
not yet been billed and maintain an accrual to cover these costs. These costs primarily relate to third-party clinical management costs, 
laboratory and analysis costs, toxicology studies and investigator grants. We estimate our liability using assumptions about study and 
patient activities and the related expected expenses for those activities determined based on the contracted fees with our service 
providers. The assumptions we use represent our best estimates of the activity and expenses at the time of our accrual and involve 
inherent uncertainties and the application of our judgment. Upon settlement, these costs may differ materially from the amounts 
accrued in our consolidated financial statements. Our historical accrual estimates have not been materially different from our actual 
amounts. 
 
Convertible Debt 
 
We account for each of our convertible debt instruments as a single unit of accounting, a liability, because we concluded that 
the conversion features do not require bifurcation as a derivative under ASC 815-15 and we did not issue our convertible debt 
instruments at a substantial premium. We record debt issuance costs as contra-liabilities in our consolidated balance sheets at issuance 
and amortize them over the contractual term of the convertible debt instrument using the effective interest rate. The balances of our 
convertible senior notes presented in our consolidated balance sheets represent the principal balance of each convertible debt 
instrument less debt issuance costs. 
 
As of December 31, 2024, we had two outstanding convertible senior notes, our 1.75% Notes, which mature in June 2028, 
and our 0% Notes, which mature in April 2026. Our 0.125% Notes matured in December 2024. Refer to Note 7, Long-Term 
Obligations and Commitments, for further details on our convertible senior notes. 
 

F-17 
Call Spread 
 
In conjunction with the issuance of our 0% Notes and 0.125% Notes in April 2021 and December 2019, respectively, we 
entered into call spread transactions, which were comprised of purchasing note hedges and selling warrants. We account for the note 
hedges and warrants as separate freestanding financial instruments and treat each instrument as a separate unit of accounting. We 
determined that the note hedges and warrants do not meet the definition of a liability using the guidance contained in ASC Topic 480; 
therefore, we account for the note hedges and warrants using the Derivatives and Hedging – Contracts in Entity’s Own Equity 
accounting guidance contained in ASC Topic 815. We determined that the note hedges and warrants meet the definition of a 
derivative, are indexed to our stock and meet the criteria to be classified in shareholders’ equity. We recorded the aggregate amount 
paid for the note hedges and the aggregate amount received for the warrants as additional paid-in capital in our consolidated balance 
sheets. We reassess our ability to continue to classify any outstanding note hedges and warrants in shareholders’ equity at each 
reporting period. Refer to Note 7, Long-Term Obligations and Commitments, for further details on the call spread transactions.  
 
Liability Related to Sale of Future Royalties 
 
In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to 
monetize a portion of our future SPINRAZA and pelacarsen royalties we are entitled to under our arrangements with Biogen and 
Novartis, respectively. Under our agreement with Royalty Pharma, we record upfront payments and milestone payments we receive 
from the sale of future royalties as a liability, net of transaction costs. Refer to Note 7, Long-Term Obligations and Commitments, for 
further details on the agreement. 
 
We record royalty payments made to Royalty Pharma as a reduction of the liability or accrued interest and amortize the 
transaction costs over the estimated life of the royalty stream. We account for the associated interest expense under the effective 
interest rate method, while continuing to recognize the full amount of royalty revenue in the period in which the counterparty sells the 
related product and recognizes the related revenue. 
 
We calculate the liability related to the sale of future royalties, effective interest rate and the related interest expense using 
our current estimate of anticipated future royalty payments under the arrangement, which we periodically reassess based on internal 
projections and information from our partners who are responsible for commercializing the medicines. If there is a material change in 
our estimate, we will prospectively adjust the effective interest rate and the related interest expense. 
 
Leases 
 
We determine if an arrangement contains a lease at inception. We currently only have operating leases. We recognize a right-
of-use operating lease asset and associated short- and long-term operating lease liability in our consolidated balance sheets for 
operating leases greater than one year. Our right-of-use assets represent our right to use an underlying asset for the lease term and our 
lease liabilities represent our obligation to make lease payments arising from the lease arrangement. We recognize our right-of-use 
operating lease assets and lease liabilities based on the present value of the future minimum lease payments we will pay over the lease 
term. We determine the lease term at the inception of each lease, and in certain cases our lease term could include renewal options if 
we conclude we are reasonably certain to exercise the renewal option. When we exercise a lease option that was not previously 
included in the initial lease term, we reassess our right-of-use asset and lease liabilities for the new lease term.  
 
As our leases do not provide an interest rate implicit in the lease, we use our incremental borrowing rate, based on the 
information available as of the lease inception date or at the lease option extension date in determining the present value of future 
payments. We recognize rent expense for our minimum lease payments on a straight-line basis over the expected term of our lease. 
Our leases do not include material variable or contingent lease payments. We recognize period expenses, such as common area 
maintenance expenses, in the period we incur the expense. 
 

F-18 
Recent Accounting Standards 
 
In November 2023, the Financial Accounting Standards Board, or FASB, issued Accounting Standard Update, or ASU, 
2023-07, which provides updated guidance on segment reporting. The guidance requires public companies to disclose significant 
expenses that are regularly provided to the chief operating decision maker, or CODM, other segment items for each reportable 
segment and measures of segment profit or loss used by the CODM for allocating resources. In addition, the updated guidance 
requires public companies with a single reportable segment to provide all disclosures required under ASC 280, Segment Reporting, 
and public companies to include in interim reports all disclosures related to a reportable segment's profit or loss and assets that are 
currently required in annual reports. This update is effective for annual periods beginning after December 15, 2023 and interim 
periods beginning after December 15, 2024. The guidance is applied on a retrospective basis for all periods presented in the financial 
statements, unless it is impracticable. We adopted the annual reporting requirements in our 2024 Annual Report on Form 10-K. We 
expect to adopt the interim reporting requirements in our Quarterly Report on Form 10-Q in the first quarter of 2025. Refer to Note 12, 
Segment Information, for further details on our segment information. 
 
In December 2023, the FASB issued ASU 2023-09, which provides updated guidance on income tax disclosures. The new 
guidance requires companies to provide additional disaggregation of information related to the income tax rate reconciliation and 
income tax payments. In addition, the guidance eliminates certain existing disclosure requirements related to uncertain tax positions 
and unrecognized deferred tax liabilities. This update is effective for annual periods beginning after December 15, 2024. Early 
adoption of this guidance is permitted. The guidance may be applied on a prospective or retrospective basis. We currently plan to 
adopt this guidance in our 2025 Annual Report on Form 10-K. 
 
In November 2024, the FASB issued ASU 2024-03, which requires public companies to disclose disaggregated expenses for 
certain expenses in the income statement. This update is effective for annual periods beginning after December 15, 2026 and interim 
periods within annual periods beginning after December 15, 2027. Early adoption of this guidance is permitted. The guidance may be 
applied on a prospective or retrospective basis. We are currently assessing the impact and timing of adopting this update. 
 
In November 2024, the FASB issued ASU 2024-04 to clarify the guidance for determining whether to account for early 
settlements of convertible debt as induced conversions or extinguishments. This update is effective for annual periods beginning after 
December 15, 2025 and interim periods within those annual periods. Early adoption of this guidance is permitted. The guidance may 
be applied on a prospective or retrospective basis. We are currently assessing the impact and timing of adopting this update. 
 
We do not expect any other recently issued accounting standards to have a material impact to our financial statements or 
disclosures. 
 
2. Supplemental Financial Data 
 
Inventories 
 
Our inventory consisted of the following (in thousands): 
 
  
December 31, 
  
2024 
  
2023 
Raw materials 
$ 
5,557
$  
1,810
Work in process 
6,679
5,477
Finished goods 
 
276
 
154
Total inventories 
$ 
12,512
$ 
7,441
 
 

F-19 
Property, Plant and Equipment 
 
Our property, plant and equipment consisted of the following (in thousands): 
 
  
 
December 31, 
  
 
2024 
  
2023 
Computer software, laboratory, manufacturing and other equipment 
$ 
86,540
$ 
79,885
Building, building improvements and building systems 
 
41,228
 
41,228
Leasehold improvements 
 
54,375
 
28,276
Furniture and fixtures 
 
9,855
 
9,844
  
 
191,998
 
159,233
Less: Accumulated depreciation 
 
(106,316)
 
(96,759)
  
 
85,682
 
62,474
Land 
 
8,569
 
8,569
 Total 
$ 
94,251
$ 
71,043
 
Accrued Liabilities 
 
Our accrued liabilities consisted of the following (in thousands):  
 
 
December 31, 
  
2024 
  
2023 
Clinical expenses 
$ 
77,436 $ 
105,967
In-licensing expenses 
 
7,951
 
7,454
Commercial expenses 
3,589
4,875
Other miscellaneous expenses 
19,462
29,598
Total accrued liabilities 
$ 
108,438 $ 
147,894
 
3. Revenues 
 
During the years ended December 31, 2024, 2023 and 2022, our revenues were comprised of the following (in thousands): 
 
 
Year Ended December 31, 
   
2024 
2023 
2022 
Revenue: 
 
 
Commercial revenue:  
 
 
SPINRAZA royalties 
$ 
216,090  $ 
240,379 $ 
242,314 
WAINUA royalties 
20,207  
—
— 
Other commercial revenue: 
 
 
TEGSEDI and WAYLIVRA revenue, net 
34,189  
34,913
30,051 
Other revenue 
22,590  
33,299
30,993 
Total other commercial revenue 
56,779  
68,212
61,044 
Total commercial revenue 
293,076  
308,591
303,358 
Research and development revenue: 
 
 
Collaborative agreement revenue 
 
332,647   
352,657
 
207,222 
WAINUA joint development revenue 
79,415  
126,399
76,787 
Total research and development revenue 
 
412,062   
479,056
 
284,009 
Total revenue 
$ 
705,138  $ 
787,647 $ 
587,367 
 
Revenue Sources   
 
The following are sources of revenue and when we typically recognize revenue.  
 
Commercial Revenue 
 
We earn commercial revenue primarily in the form of royalty payments on net sales of SPINRAZA and WAINUA. In 2024, 
we began earning royalties on net sales of WAINUA. 
 

F-20 
We earn commercial revenue from TEGSEDI and WAYLIVRA sales under our distribution agreements with Sobi. In 
addition, we receive royalties from PTC Therapeutics International Limited, or PTC, for TEGSEDI and WAYLIVRA sales. Refer to 
Note 4, Collaborative Arrangements and Licensing Agreements, for details on our commercialization partnerships with Sobi and PTC. 
 
We also recognize as commercial revenue sales milestone payments and royalties we earn under our other collaborations.  
 
In December 2024, the FDA approved TRYNGOLZA (olezarsen) in the U.S. for the treatment of familial chylomicronemia 
syndrome, or FCS. Our launch of TRYNGOLZA is currently underway. 
 
Research and development revenue under collaboration agreements  
 
We enter into collaboration agreements to license and sell our technology on an exclusive or non-exclusive basis. Our 
collaboration agreements typically contain multiple elements, or performance obligations, including technology licenses or options to 
obtain technology licenses, R&D services and manufacturing services. 
 
For R&D services that we recognize over time, we measure our progress using an input method. The input methods we use 
are based on the effort we expend or costs we incur toward the satisfaction of our performance obligation. We estimate the amount of 
effort we expend, including the time we estimate it will take us to complete the activities, or costs we incur in a given period, relative 
to the estimated total effort or costs to satisfy the performance obligation. This results in a percentage that we multiply by the 
transaction price to determine the amount of revenue we recognize each period. This approach requires us to make numerous estimates 
and may use judgement. If our estimates or judgements change over the course of the collaboration, they may affect the timing and 
amount of revenue that we recognize in the current and future periods. 
 
Upfront payments: When we enter into a collaboration agreement and receive an upfront payment, we record the entire 
upfront payment as deferred revenue if our only performance obligation is for R&D services we will provide in the future. We 
amortize the upfront payment into revenue as we perform the R&D services. If part or all of the upfront payment is a license fee, we 
recognize as revenue the portion related to the license when we deliver the license to our partner because our partner has full use of the 
license and we do not have any additional performance obligations related to the license after delivery. 
 
Milestone payments: We include variable consideration in the transaction price when it is probable. We typically include 
milestone payments for R&D services in the transaction price when they are achieved. We include these milestone payments when 
they are achieved because there is considerable uncertainty in the research and development processes that trigger these payments. 
Similarly, we include regulatory milestone payments in the transaction price once the medicine is approved by the applicable 
regulatory agency. We will recognize sales-based milestone payments in the period in which we achieve the milestone under the sales-
based royalty exception allowed under accounting rules. 
 
We recognize milestone payments that relate to an ongoing performance obligation over our period of performance. For 
example, when we achieve a milestone payment from a partner for advancing a clinical study under a collaboration agreement, we add 
the milestone payment to the transaction price if the milestone relates to an ongoing R&D services performance obligation and 
recognize revenue related to the milestone payment over our estimated period of performance. If we have partially completed our 
performance obligation, then we record a cumulative-effect adjustment in the period we add the milestone payment to the transaction 
price.  
 
Conversely, we recognize in full those milestone payments that we earn based on our partners’ activities when our partner 
achieves the milestone event and we do not have a remaining performance obligation. For example, in 2024, we earned a $10 million 
milestone payment from Biogen when the Ministry of Health, Labour and Welfare of Japan approved Biogen’s Japanese New Drug 
Application filing of QALSODY, which we recognized in full because we did not have any remaining performance obligations related 
to this milestone payment. 
 
License fees: We recognize as revenue the total amount we determine to be the relative stand-alone selling price of a license 
when we deliver the license to our partner because our partner has full use of the license and we do not have any additional 
performance obligations related to the license after delivery.  
 
WAINUA (Eplontersen) Collaboration with AstraZeneca 
 
In 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and 
commercialize WAINUA for the treatment of transthyretin amyloidosis, or ATTR. Under the terms of the agreement, we received a 
$200 million upfront payment in 2021. Refer to Note 4, Collaborative Arrangements and Licensing Agreements, for further details on 
this collaboration. 
 

F-21 
We evaluated our WAINUA collaboration under ASC 808 and identified four material components: (i) the license we granted 
to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca are performing, (iii) the co-commercialization 
activities that we and AstraZeneca are performing and (iv) the co-medical affairs activities that we and AstraZeneca are performing. 
 
We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to 
AstraZeneca and as a result we had one performance obligation. For our sole performance obligation, we determined the transaction 
price was the $200 million upfront payment we received. We recognized the upfront payment in full in 2021 because we did not have 
any remaining performance obligations after we delivered the license to AstraZeneca. 
 
We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs 
activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the 
activities under the collaboration and therefore do not have a vendor-customer relationship. AstraZeneca is currently responsible for 
55 percent of the costs associated with the ongoing global Phase 3 development program. Because we are leading the Phase 3 
development program, we made an accounting policy election to recognize as non-customer revenue the cost-share funding from 
AstraZeneca, net of our share of AstraZeneca’s development expenses, in the same period we incur the related development expenses. 
As AstraZeneca is responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with 
bringing WAINUA to market outside the U.S., we made an accounting policy election to recognize cost-share funding we receive 
from AstraZeneca related to commercial and medical affairs activities as reductions of our SG&A expense and R&D expense, 
respectively. 
 
Swedish Orphan Biovitrum AB (Sobi) 
 
Under our distribution agreements with Swedish Orphan Biovitrum AB, or Sobi, we concluded that our performance 
obligation is to provide services to Sobi over the term of the agreement, which includes supplying finished goods inventory to Sobi. 
We are also responsible for maintaining the marketing authorization for TEGSEDI and WAYLIVRA in major markets and for leading 
the global commercial strategy for each medicine. We view this performance obligation as a series of distinct activities that are 
substantially the same. Therefore, we recognize as revenue the price Sobi pays us for the inventory when we deliver the finished 
goods inventory to Sobi. We also recognize distribution fee revenue based on Sobi’s net sales of TEGSEDI and WAYLIVRA. Under 
our agreements with Sobi, Sobi does not generally have a right of return. 
 
4. Collaborative Arrangements and Licensing Agreements 
 
AstraZeneca 
 
WAINUA (Eplontersen) Collaboration 
 
In 2021, we entered into a joint development and commercialization agreement with AstraZeneca to develop and 
commercialize eplontersen for the treatment of ATTR. The FDA and Health Canada approved eplontersen with the brand name, 
WAINUA, for hereditary ATTR, or ATTRv-PN, while the Medicines and Healthcare products Regulatory Agency, or MHRA, 
approved WAINUA for ATTRv-PN in the United Kingdom, or UK, as WAINZUA. Under the agreement, we are jointly developing 
WAINUA with AstraZeneca worldwide for ATTRv-PN and ATTR cardiomyopathy, or ATTR-CM. We are jointly commercializing 
WAINUA with AstraZeneca in the U.S. We granted AstraZeneca exclusive rights to commercialize WAINUA outside the U.S.  
 
Over the term of the collaboration, we are eligible to receive up to $3.6 billion, which is comprised of a $200 million upfront 
payment, up to $485 million in development and approval milestone payments and up to $2.9 billion in sales milestone payments. The 
agreement includes territory-specific development, commercial and medical affairs cost-sharing provisions. In addition, we are 
eligible to receive up to mid-20 percent royalties for sales in the U.S. and tiered royalties up to the high teens for sales outside the U.S. 
From inception through December 31, 2024, we have received more than $465 million in payments under this collaboration. We will 
achieve the next payment of $200 million or $115 million upon regulatory approval of WAINUA for ATTR-CM in the U.S. or 
Europe, respectively, under this collaboration. 
 
In January 2024, we and AstraZeneca launched WAINUA in the U.S. for the treatment of adults with ATTRv-PN. As a 
result, we began earning royalties from WAINUA sales, which we recognize as commercial revenue in our consolidated statements of 
operations. 
 
We evaluated our WAINUA collaboration under ASC 808 and identified four material components: (i) the license we granted 
to AstraZeneca in 2021, (ii) the co-development activities that we and AstraZeneca will perform, (iii) the co-commercialization 
activities that we and AstraZeneca will perform and (iv) the co-medical affairs activities that we and AstraZeneca will perform. 
 

F-22 
We determined that we had a vendor-customer relationship within the scope of ASC 606 for the license we granted to 
AstraZeneca and as a result we had one performance obligation. For our sole performance obligation, we determined the transaction 
price was the $200 million upfront payment we received in 2021. In 2023, we earned a $20 million license fee payment when we 
licensed rights to Latin America for WAINUA to AstraZeneca. We recognized these payments in full because we did not have any 
remaining performance obligations after we delivered the licenses to AstraZeneca.  
 
We also concluded that the co-development activities, the co-commercialization activities and the co-medical affairs 
activities are within the scope of ASC 808 because we and AstraZeneca are active participants exposed to the risks and benefits of the 
activities under the collaboration. AstraZeneca is currently responsible for 55 percent of the costs associated with the ongoing global 
Phase 3 development program. Because we are leading the Phase 3 development program, we recognize as revenue the 55 percent of 
cost-share funding AstraZeneca is responsible for in the same period we incur the related development expenses. As AstraZeneca is 
responsible for the majority of the commercial and medical affairs costs in the U.S. and all costs associated with bringing WAINUA to 
market outside the U.S., we recognize cost-share funding we receive from AstraZeneca related to these activities as a reduction of our 
commercial and medical affairs expenses. In the fourth quarter of 2024, we earned a $30 million milestone payment from AstraZeneca 
when the MHRA approved WAINZUA for ATTRv-PN in the UK. We recognized this milestone payment in full as joint development 
revenue because we did not have any remaining performance obligations related to the milestone payment. 
 
Cardiovascular, Renal and Metabolic Collaboration 
 
In addition to our collaboration for WAINUA, we have a collaboration with AstraZeneca focused on discovering and 
developing treatments for cardiovascular, renal and metabolic diseases, which we formed in 2015. In December 2024, we amended 
this collaboration agreement with AstraZeneca. The amendment changed future potential milestone payments and royalties we could 
receive under the collaboration. We determined there were no changes that would require adjustments to revenue we previously 
recognized because we had no ongoing performance obligations under the agreement. Under our collaboration, AstraZeneca has 
licensed multiple medicines from us. AstraZeneca is responsible for global development, regulatory and commercialization activities 
and costs for each of the medicines it has licensed from us. 
 
Over the term of the collaboration, we are eligible to receive up to $4.3 billion, which is comprised of a $65 million upfront 
payment, up to $175 million in license fees, up to $514 million in development milestone payments, up to $863 million in regulatory 
milestone payments and up to $2.8 billion in sales milestone payments. In addition, we are eligible to receive tiered royalties up to 10 
percent on net sales from any product that AstraZeneca successfully commercializes under this collaboration agreement. From 
inception through December 31, 2024, we have received more than $340 million in payments under this collaboration. We will 
achieve the next payment of up to $30 million if AstraZeneca advances a medicine under this collaboration. 
 
At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services 
for AstraZeneca. We determined the transaction price to be the $65 million upfront payment we received and we allocated it to our 
single performance obligation. We recognized revenue for our R&D services performance obligation as we performed services based 
on our effort to satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We 
completed our performance obligation in 2021. As we achieved milestone payments for our R&D services, we included these amounts 
in our transaction price for our R&D services performance obligation. From inception through the completion of our performance 
obligation, we have included $90 million in payments in the transaction price for our R&D services performance obligation.  
 
Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services 
performance obligation. We recognized each of these payments in full in the respective period we generated the payment because the 
payments were distinct and we did not have any performance obligations for the respective payment. For example, in the fourth 
quarter of 2024, we earned a $25 million payment when AstraZeneca licensed a compound from us. We recognized this payment in 
full in 2024 because we did not have any remaining performance obligations after we delivered the license to AstraZeneca. 
 
During the years ended December 31, 2024, 2023 and 2022, we earned the following revenue from our relationship with 
AstraZeneca (in thousands, except percentage amounts): 
 
 
Year Ended December 31, 
 
2024 
 
2023 
 
2022 
Revenue from our relationship with AstraZeneca 
$ 
129,759 $ 
202,236  $ 
79,160
Percentage of total revenue 
18%
26%  
13%
 
We did not have any deferred revenue from our relationship with AstraZeneca at December 31, 2024 and 2023. 
 

F-23 
Biogen 
 
Marketed Medicines 
 
SPINRAZA 
 
In 2012, we entered into a collaboration agreement with Biogen to develop and commercialize SPINRAZA, our approved 
medicine to treat people with spinal muscular atrophy, or SMA. From inception through December 31, 2024, we received more than 
$2.2 billion in total payments under this collaboration, including approximately $1.8 billion from SPINRAZA royalties and more than 
$425 million from R&D revenue. We are receiving tiered royalties ranging from 11 percent to 15 percent on net sales of SPINRAZA. 
We have exclusive in-licensed patents related to SPINRAZA from Cold Spring Harbor Laboratory and the University of 
Massachusetts. We pay Cold Spring Harbor Laboratory and the University of Massachusetts a low single digit royalty on net sales of 
SPINRAZA. Biogen is responsible for all global development, regulatory and commercialization activities and costs for SPINRAZA. 
We completed our performance obligations under this collaboration in 2016. 
 
In 2023, we entered into a royalty purchase agreement with Royalty Pharma in which Royalty Pharma receives 25 percent of 
our SPINRAZA royalty payments from 2023 through 2027, increasing to 45 percent of royalty payments in 2028, on up to $1.5 billion 
in annual sales. Royalty Pharma’s royalty interest in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty 
Pharma reach either $475 million or $550 million, depending on the timing and occurrence of the U.S. Food and Drug Administration, 
or FDA, approval of pelacarsen, which Novartis is developing. Refer to Note 7, Long-Term Obligations and Commitments, for further 
discussion of this agreement.  
 
QALSODY 
 
In 2018, Biogen exercised its option to license QALSODY, our medicine that received accelerated approval from the FDA in 
April 2023 and marketing authorization under exceptional circumstances from the European Medicines Agency, or EMA, in May 
2024 for the treatment of adult patients with superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS. As a result, Biogen 
is responsible for global development, regulatory and commercialization activities and costs for QALSODY. Biogen is also evaluating 
QALSODY as a potential treatment for presymptomatic SOD1-ALS patients in the ongoing ATLAS study. From inception through 
December 31, 2024, we received more than $110 million in total payments under this collaboration, including approximately $3 
million from QALSODY royalties and $108 million from R&D revenue. We are receiving tiered royalties ranging from 11 percent to 
15 percent on net sales of QALSODY. We completed our performance obligations under this collaboration in 2020. 
 
New Antisense Medicines for the Treatment of SMA 
 
In 2017, we entered into a collaboration agreement with Biogen to identify new antisense medicines for the treatment of 
SMA. At the commencement of this collaboration, we received a $25 million upfront payment from Biogen. In 2021, Biogen 
exercised its option to license ION306, a drug we discovered under this collaboration, for which we earned a $60 million license fee 
payment. We recognized this payment as revenue in full because Biogen had full use of the license without any continuing 
involvement from us. Biogen is solely responsible for the costs and expenses related to the development, manufacturing and potential 
future commercialization of ION306 following the option exercise. We do not have any remaining performance obligations under this 
collaboration. We will receive development and regulatory milestone payments from Biogen if new medicines, including ION306, 
advance towards marketing approval. 
 
Over the term of the collaboration, we are eligible to receive up to $555 million if Biogen advances ION306, which is 
comprised of up to $45 million in development milestone payments, up to $110 million in regulatory milestone payments and up to 
$400 million in sales milestone payments. In addition, we are eligible to receive tiered royalties from the mid-teens to mid-20 percent 
range on net sales from any product that Biogen successfully commercializes under this collaboration. From inception through 
December 31, 2024, we received $85 million in payments under this collaboration. We will achieve the next payment of up to $45 
million if Biogen initiates a Phase 3 trial under this collaboration. 
 
Neurology Collaborations 
 
We have multiple collaborations with Biogen focused on using antisense technology to advance the treatment of neurological 
disorders, including our 2018 and 2012 neurology collaborations. Under these collaborations, Biogen gained exclusive rights to the 
use of our antisense technology to develop therapies for certain neurological diseases and the option to license certain medicines 
resulting from these collaborations. If Biogen exercises its option to license a medicine, it will assume global development, regulatory 
and commercialization responsibilities and costs for that medicine.  
 

F-24 
Under our 2018 neurology collaboration, we are currently advancing multiple programs. For each medicine under this 
collaboration, we are eligible to receive up to $270 million, which is comprised of a $15 million license fee, up to $105 million in 
development milestone payments and up to $150 million in regulatory milestone payments. In addition, we are eligible to receive 
tiered royalties up to the 20 percent range on net sales from any product that Biogen successfully commercializes under this 
collaboration. From inception through December 31, 2024, we have received nearly $1.1 billion in payments under this collaboration, 
including payments to purchase our stock. We will achieve the next payment of up to $15 million if Biogen licenses a medicine under 
this collaboration. 
 
At the commencement of our 2018 neurology collaboration, we determined our transaction price to be $552 million, 
comprised of $375 million from the upfront payment and $177 million for the premium paid by Biogen for its purchase of our 
common stock. We allocated the transaction price to our single performance obligation, which was to perform R&D services for 
Biogen. From inception through December 31, 2024, we have included $623 million in upfront and milestone payments in the 
transaction price for our R&D services performance obligation. We recognize revenue for our R&D services performance obligation 
as we perform services based on our effort to satisfy our performance obligation relative to our total effort expected to satisfy our 
performance obligation. We currently estimate we will satisfy our performance obligation at the end of the contractual term in June 
2028. 
 
Under our 2012 neurology collaboration, Biogen exercised its option to license IONIS-MAPTRx, an investigational RNA-
targeted medicine for the potential treatment of Alzheimer’s disease, or AD, in 2019. As a result, Biogen is responsible for global 
development, regulatory and commercialization activities and costs for IONIS-MAPTRx. We are eligible to receive up to $185 million 
for the IONIS-MAPTRx program, which is comprised of a license fee of $45 million, up to $10 million in development milestone 
payments and up to $130 million in regulatory milestone payments, plus a mark-up on the cost estimate of the Phase 1 and 2 studies. 
In addition, we are eligible to receive tiered royalties up to the mid-teens on net sales of any medicines resulting from the IONIS-
MAPTRx program. From inception through December 31, 2024, we have received more than $230 million in payments under this 
collaboration. We will achieve the next payment of $25 million if Biogen advances MAPTRx into Phase 3 development under this 
collaboration. 
 
At the commencement of our 2012 neurology collaboration, we identified two separate performance obligations as our 
development work for IONIS-MAPTRx and ION582. We completed our R&D services performance obligations for IONIS-MAPTRx 
and ION582 in 2022 and 2024, respectively. From inception through the completion of our performance obligations, we have included 
$57 million in the transaction price for our IONIS-MAPTRx development performance obligation. From inception through the 
completion of our performance obligations, we have included $68 million in milestone payments in the transaction price for our 
ION582 development performance obligation. We recognized revenue for our R&D services performance obligations as we 
performed services based on our effort to satisfy our performance obligations relative to our total effort expected to satisfy our 
performance obligations. 
 
In the second quarter of 2024, Biogen’s option to license ION582, an investigational antisense medicine for the potential 
treatment of Angelman syndrome, or AS, expired unexercised. As a result, we recognized $30 million of R&D revenue from 
previously deferred milestone payments related to the ION582 study because we did not have any remaining performance obligations. 
 
During the years ended December 31, 2024, 2023 and 2022, we earned the following revenue from our relationship with 
Biogen (in thousands, except percentage amounts): 
 
 
Year Ended December 31, 
 
2024 
 
2023 
 
2022 
Revenue from our relationship with Biogen 
$ 
368,058  $ 
350,146  $ 
366,696
Percentage of total revenue 
52%  
44%  
62%
 
Our consolidated balance sheets at December 31, 2024 and 2023 included deferred revenue of $211.0 million and $307.4 
million, respectively, from our relationship with Biogen. 
 
GSK  
 
In 2010, we entered into a collaboration with GSK using our antisense drug discovery platform to discover and develop new 
medicines against targets for serious and rare diseases, including infectious diseases. Upon initiating the collaboration, we received an 
upfront payment of $35 million. Under our collaboration, GSK is developing bepirovirsen for the treatment of chronic hepatitis B 
virus infection, or HBV, infection. In 2019, following positive Phase 2 results, GSK licensed our HBV program. GSK is responsible 
for all global development, regulatory and commercialization activities and costs for the HBV program. 
 

F-25 
Over the term of the collaboration, we are eligible to receive nearly $260 million, which is comprised of a $25 million license 
fee, up to $42.5 million in development milestone payments, up to $120 million in regulatory milestone payments and up to $70 
million in sales milestone payments if GSK successfully develops and commercializes bepirovirsen. In addition, we are eligible to 
receive tiered royalties up to the low-teens on net sales of bepirovirsen. From inception through December 31, 2024, we have received 
more than $105 million in an upfront payment and payments related to the HBV program.  
 
We completed our R&D services performance obligations in 2015. Therefore, we do not have any remaining performance 
obligations under our collaboration with GSK. However, we can still earn additional payments and royalties as GSK advances the 
HBV program. In 2023, we earned a $15 million milestone payment when GSK initiated a Phase 3 program of bepirovirsen. We 
recognized this milestone payment as R&D revenue in full in 2023 because we did not have any remaining performance obligations 
related to the milestone payment. We will achieve the next payment of $15 million if the FDA accepts an NDA filing of bepirovirsen 
for review.  
 
During the years ended December 31, 2024, 2023 and 2022, we earned the following revenue from our relationship with 
GSK (in thousands, except percentage amounts): 
 
 
Year Ended December 31, 
 
2024 
 
2023 
 
2022 
Revenue from our relationship with GSK 
$ 
— $ 
15,000  $ 
—
Percentage of total revenue 
0%
2%  
0%
 
We did not have any deferred revenue from our relationship with GSK at December 31, 2024 and 2023. 
 
Novartis 
 
Pelacarsen Collaboration 
 
In 2017, we initiated a collaboration with Novartis to develop and commercialize pelacarsen. Novartis is responsible for 
conducting and funding development and regulatory activities for pelacarsen, including a global Phase 3 cardiovascular outcomes 
study that Novartis initiated in 2019. 
 
Over the term of the collaboration, we are eligible to receive up to $900 million, which is comprised of a $75 million upfront 
payment, a $150 million license fee, a $25 million development milestone payment, up to $290 million in regulatory milestone 
payments and up to $360 million in sales milestone payments. We are also eligible to receive tiered royalties in the mid-teens to low 
20 percent range on net sales of pelacarsen. From inception through December 31, 2024, we have received more than $275 million in 
payments under this collaboration. We will achieve the next payment of $50 million if the FDA accepts an NDA filing for pelacarsen. 
 
At the commencement of this collaboration, we determined our transaction price to be $108.4 million, comprised of the $75 
million from the upfront payment, $28.4 million for the premium paid by Novartis for its purchase of our common stock and $5.0 
million for the potential premium Novartis would have paid if they purchased our common stock in the future. We identified four 
separate performance obligations as the R&D services and API for pelacarsen and olezarsen. We recognized revenue for our R&D 
services performance obligations as we performed services based on our effort to satisfy our performance obligations relative to our 
total effort expected to satisfy our performance obligations. We completed our R&D services performance obligations for olezarsen 
and pelacarsen in 2019. As such, we recognized all revenue we allocated to the olezarsen and pelacarsen R&D services as of the end of 
2019. From inception through the completion of our performance obligations, we have included $104 million in payments in the 
transaction price for our R&D services performance obligations under this collaboration. 
 
As described in the Biogen SPINRAZA section above, in 2023, we entered into a royalty purchase agreement with Royalty 
Pharma. Under the agreement, in addition to a minority interest in SPINRAZA royalties, Royalty Pharma will receive 25 percent of 
any future royalty payments on pelacarsen. Refer to Note 7, Long-Term Obligations and Commitments, for further discussion of this 
agreement. 
 
New Medicine for the Treatment of Lp(a)-Driven Cardiovascular Disease 
 
In August 2023, we entered into a collaboration and license agreement with Novartis for the discovery, development and 
commercialization of a novel medicine for patients with Lp(a)-driven cardiovascular disease, or lipoprotein(a)-driven CVD. Novartis 
is solely responsible for the development, manufacturing and potential commercialization of the next generation Lp(a) therapy.  
 

F-26 
Over the term of the collaboration, we are eligible to receive up to $730 million, which is comprised of a $60 million upfront 
payment, up to $155 million in development milestone payments, up to $105 million in regulatory milestone payments and up to $410 
million in sales milestone payments. In addition, we are eligible to receive tiered royalties ranging from 10 percent to 20 percent on 
net sales. From inception through December 31, 2024, we have received more than $65 million from payments under this 
collaboration. We will achieve the next payment of $10 million if Novartis advances a medicine under this collaboration. 
 
At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services 
for Novartis. We recognized revenue for our R&D services performance obligation as we performed services based on our effort to 
satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our 
performance obligation in the third quarter of 2024. As we achieved milestone payments for our R&D services, we included these 
amounts in our transaction price for our R&D services performance obligation. From inception through the completion of our 
performance obligation, we have included $65 million in upfront and milestone payments in the transaction price for our R&D 
services performance obligation under this collaboration. 
 
During the years ended December 31, 2024, 2023 and 2022, we earned the following revenue from our relationship with 
Novartis (in thousands, except percentage amounts): 
 
 
Year Ended December 31, 
 
2024 
 
2023 
 
2022 
Revenue from our relationship with Novartis 
$ 
37,762 $ 
30,194  $ 
237
Percentage of total revenue 
5%
4%  Less than 1%
 
Our consolidated balance sheets at December 31, 2024 and 2023 included deferred revenue of $4.2 million and $30.0 million, 
respectively, from our relationship with Novartis. 
 
Roche 
 
Sefaxersen (IONIS-FB-LRx) for Complement-Mediated Diseases 
 
In 2018, we entered into a collaboration agreement with Roche to develop sefaxersen (IONIS-FB-LRx) for the treatment of 
complement-mediated diseases, including immunoglobulin A nephropathy, or IgAN, and geographic atrophy, or GA. In April 2023, 
Roche initiated a Phase 3 study of sefaxersen in patients with IgAN. 
 
After positive data from a Phase 2 clinical study in patients with IgAN, Roche licensed sefaxersen in 2022 for $35 million. 
As a result, Roche is responsible for global development, regulatory and commercialization activities, and costs for sefaxersen. In 
2022, we amended our sefaxersen collaboration agreement with Roche. The amendment changed future potential milestone payments 
we could receive under the collaboration. We determined there were no changes that would require adjustments to revenue we 
previously recognized. 
 
In July 2024, Roche discontinued development of sefaxersen for the treatment of GA, following the completion of the Phase 
2 study, which showed a favorable safety profile and target engagement, but insufficient efficacy to advance into Phase 3 
development.  
 
Over the term of the sefaxersen collaboration for the treatment of IgAN, we are eligible to receive up to $430 million, which 
is comprised of a $35 million license fee, up to $25 million in development milestone payments, up to $90 million in regulatory 
milestone payments and up to $280 million in sales milestone payments. In addition, we are also eligible to receive tiered royalties 
from the high teens to 20 percent on net sales. From inception through December 31, 2024, we have received more than $140 million 
in payments under this collaboration. We will achieve the next payment of $23.5 million if Roche advances sefaxersen for the 
treatment of IgAN under this collaboration. 
 
At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services 
for Roche. We recognized revenue for our R&D services performance obligation as we performed services based on our effort to 
satisfy this performance obligation relative to our total effort expected to satisfy our performance obligation. We completed our 
performance obligation in the fourth quarter of 2024. As we achieved milestone payments for our R&D services, we included these 
amounts in our transaction price for our R&D services performance obligation. From inception through the completion of our 
performance obligation, we have included $97 million in upfront and milestone payments in the transaction price for our R&D 
services performance obligation under this collaboration.  
 

F-27 
Huntington’s Disease  
 
In 2013, we entered into an agreement with Hoffmann-La Roche Inc and F. Hoffmann-La Roche Ltd, collectively Roche, to 
develop treatments for Huntington’s disease, or HD, based on our antisense technology. Under the agreement, we discovered and 
developed tominersen, an investigational medicine targeting HTT protein. We developed tominersen through completion of our Phase 
1/2 clinical study in people with early-stage HD. In 2017, upon completion of the Phase 1/2 study, Roche exercised its option to 
license tominersen. As a result, Roche is responsible for all global development, regulatory and commercialization activities and costs 
for tominersen.  
 
Over the term of the collaboration, we are eligible to receive up to $395 million, which is comprised of a $30 million upfront 
payment, a $45 million license fee, up to $70 million in development milestone payments, up to $170 million in regulatory milestone 
payments and up to $80 million in sales milestone payments as tominersen advances. In addition, we are eligible to receive up to 
$136.5 million in milestone payments for each additional medicine successfully developed. We are also eligible to receive tiered 
royalties up to the mid-teens on net sales of any product resulting from this collaboration. From inception through December 31, 2024, 
we have received more than $150 million in payments under this collaboration. We will achieve the next payment of $17.5 million if 
Roche advances a medicine under this collaboration. 
 
At the commencement of this collaboration, we identified one performance obligation, which was to perform R&D services 
for Roche. We determined the transaction price to be the $30 million upfront payment we received and allocated it to our single 
performance obligation. As we achieved milestone payments for our R&D services, we included these amounts in our transaction 
price for our R&D services performance obligation. We recognized revenue for our R&D services performance obligation over our 
period of performance, which ended in 2017.  
 
Under this collaboration, we have also generated additional payments that we concluded were not part of our R&D services 
performance obligation. We recognized each of these payments in full in the respective period in which we generated the payment 
because the payments were distinct and we did not have any performance obligations for the respective payment. In 2021, Roche 
decided to discontinue dosing in the Phase 3 GENERATION HD1 study of tominersen in patients with manifest HD based on the 
results of a pre-planned review of data from the Phase 3 study conducted by an unblinded independent data monitoring committee, or 
iDMC. 
 
In 2023, Roche initiated the Phase 2, GENERATION HD2, study of tominersen in patients with prodromal or early manifest 
HD. Roche is focusing on early-stage and younger patients based on the post-hoc analyses from the GENERATION HD1 study that 
suggested tominersen may benefit these patient groups. We do not have any remaining performance obligations related to tominersen 
under this collaboration with Roche; however, we can still earn additional payments and royalties as Roche advances tominersen. 
 
RNA-Targeting Medicines for Alzheimer's Disease and Huntington's Disease 
 
In September 2023, we entered into an agreement with Roche to develop two undisclosed early-stage programs for RNA-
targeting investigational medicines for the treatment of AD and HD. Under the agreement, we are responsible for advancing the two 
programs through preclinical studies and Roche is responsible for clinical development, manufacturing and commercialization of the 
medicines if they receive regulatory approval. 
 
Over the term of the collaboration, we are eligible to receive up to $625 million, which is comprised of a $60 million upfront 
payment, up to $167 million in development milestone payments and up to $398 million in sales milestone payments. In addition, we 
are eligible to receive tiered royalties up to the mid-teens on net sales. From inception through December 31, 2024, we have received 
more than $60 million in payments under this collaboration. We will achieve the next payment of $7.5 million if we advance a 
medicine under this collaboration. 
 
We identified two performance obligations under this new agreement, comprised of R&D services for each of the two 
separate programs. We determined the transaction price to be the $60 million upfront payment we received in the fourth quarter 2023. 
We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows: 
 
● 
$45 million for the R&D services for the investigational medicine for AD; and 
● 
$15 million for the R&D services for the investigational medicine for HD. 
 

F-28 
We are recognizing revenue for our R&D services performance obligations as we perform services based on our effort to 
satisfy our performance obligations relative to our total effort expected to satisfy our performance obligations. We completed our 
performance obligation for the investigational medicine for AD in June 2024. We currently estimate we will satisfy our performance 
obligation for the investigational medicine HD at the end of the research term of July 2025. 
 
During the years ended December 31, 2024, 2023 and 2022, we earned the following revenue from our relationship with 
Roche (in thousands, except percentage amounts): 
 
 
Year Ended December 31, 
 
2024 
 
2023 
 
2022 
Revenue from our relationship with Roche 
$ 
39,871 $ 
48,838  $ 
67,202
Percentage of total revenue 
6%
6%  
11%
 
Our consolidated balance sheets at December 31, 2024 and 2023 included deferred revenue of $7.7 million and $36.7 million, 
respectively, from our relationship with Roche.  
 
Commercialization Partnerships 
 
Otsuka 
 
In December 2023, we entered into an agreement with Otsuka Pharmaceutical Co., Ltd., or Otsuka, to commercialize 
donidalorsen in Europe. In the second quarter of 2024, we expanded the agreement to include commercialization rights for 
donidalorsen in the Asia-Pacific region. As a result, we received a $20 million upfront payment from Otsuka. We are responsible for 
the ongoing development of donidalorsen. We retained the rights to commercialize donidalorsen in the U.S. and in the rest of the 
world, assuming regulatory approval. 
 
Over the term of this collaboration, we are eligible to receive up to $290 million, which is comprised of $85 million in 
upfront payments, up to $65 million in regulatory milestone payments and up to $140 million in sales milestone payments. In addition, 
we are eligible to receive tiered royalties up to 30 percent on net sales. In the fourth quarter of 2024, we earned a $15 million 
milestone payment from Otsuka when the EMA accepted our Marketing Authorization Application, or MAA, filing for donidalorsen 
in the European Union, or EU. We will achieve the next payment of $15 million if the European Commission approves donidalorsen 
under this collaboration. 
 
We identified two performance obligations under this agreement, comprised of our license of donidalorsen to Otsuka and 
R&D services for donidalorsen. We determined the transaction price to be $85 million, comprised of the following: 
 
● 
$65 million from the upfront payment we received in 2023; and 
● 
$20 million from the upfront payment we received in 2024. 
 
We allocated the transaction price based on the estimated stand-alone selling price of each performance obligation as follows: 
 
● 
$73.5 million for the license of donidalorsen; and 
● 
$11.5 million for the R&D services for donidalorsen. 
 
We are recognizing revenue for our R&D services performance obligation as we perform services based on our effort to 
satisfy our performance obligation relative to our total effort expected to satisfy our performance obligation. We currently estimate we 
will satisfy our performance obligations in March 2026. 
 
In November 2024, we entered into an agreement with Otsuka to commercialize ulefnersen worldwide. We are responsible 
for the ongoing development of ulefnersen. 
 
From inception through December 31, 2024, we have received more than $95 million in payments under these collaborations. 
 

F-29 
During the year ended December 31, 2024, we earned the following revenue from our relationship with Otsuka (in thousands, 
except percentage amount): 
 
 
Year Ended December 31, 
 
2024 
 
2023 
Revenue from our relationship with Otsuka 
$ 
46,856 $ 
56,480
Percentage of total revenue 
7%
7%
 
Our consolidated balance sheets at December 31, 2024 and 2023 included deferred revenue of $6.7 million and $8.5 million, 
respectively, from our relationship with Otsuka. 
 
PTC Therapeutics 
 
In 2018, we entered into an exclusive license agreement with PTC Therapeutics to commercialize TEGSEDI and 
WAYLIVRA in Latin America and certain Caribbean countries. Under the license agreement, we are eligible to receive royalties from 
PTC in the mid-20 percent range on net sales for each medicine. In December 2021 and September 2023, we started receiving 
royalties from PTC for TEGSEDI and WAYLIVRA sales, respectively.  
 
Swedish Orphan Biovitrum AB (Sobi) 
 
In 2021, we began commercializing TEGSEDI and WAYLIVRA in Europe and TEGSEDI in North America through 
distribution agreements with Sobi. Under our distribution agreements, Sobi is responsible for commercializing TEGSEDI and 
WAYLIVRA in Europe and TEGSEDI in North America, respectively. We are responsible for supplying finished goods inventory to 
Sobi and Sobi is responsible for selling each medicine to the end customer. Under our agreements with Sobi, Sobi does not generally 
have a right of return. We recognize as revenue the price Sobi pays us for the inventory when we deliver the finished goods inventory 
to Sobi. In addition, we earn a distribution fee on net sales from Sobi for each medicine.  
 
In October 2023, our distribution agreement for TEGSEDI in North America was terminated and Sobi began transitioning 
responsibilities to us. Following the transition, we discontinued TEGSEDI in North America in 2024. During the years ended 
December 31, 2024, 2023 and 2022, we earned nominal revenue from our distribution agreement with Sobi for TEGSEDI in North 
America. 
 
Technology Enhancement Collaborations 
 
Bicycle Therapeutics 
 
In 2020, we entered into a collaboration agreement with Bicycle and obtained an option to license its peptide technology that 
we expect can expand our LICA platform to target both skeletal and cardiac muscle, and potentially deliver medicines across the 
blood brain barrier. In 2021, we paid $42 million when we exercised our option to license Bicycle’s technology, which included an 
equity investment in Bicycle. As part of our stock purchase, we entered into a lockup agreement with Bicycle that restricted our ability 
to trade our Bicycle shares for one year. In 2021, we recorded a $7.2 million equity investment for the shares we received in Bicycle. 
We recognized the remaining $34.8 million as R&D expense in 2021. We will pay Bicycle milestone payments and royalties that are 
contingent on the achievement of certain development, regulatory and sales events. 
 
Metagenomi 
 
In 2022, we entered into a collaboration and license agreement with Metagenomi to research, develop and commercialize 
investigational medicines for up to four initial genetic targets, and, upon the achievement of certain development milestones, four 
additional genetic targets using gene editing technologies. As a result, we paid $80 million to license Metagenomi’s technologies and 
will pay Metagenomi certain fees for the selection of genetic targets. We recorded the $80 million payment as R&D expense in 2022 
upon receiving a license from Metagenomi for intellectual property that is in research with no current alternate use. In addition, we 
will pay Metagenomi milestone payments and royalties that are contingent on the achievement of certain development, regulatory and 
sales events. We will also reimburse Metagenomi for certain of its costs in conducting its research and drug discovery activities under 
the collaboration.  
 

F-30 
Other Agreements 
 
Alnylam Pharmaceuticals, Inc. 
 
Under the terms of our agreement with Alnylam, we co-exclusively (with ourselves) licensed to Alnylam our patent estate 
relating to antisense motifs and mechanisms and oligonucleotide chemistry for double-stranded RNAi therapeutics, with Alnylam 
having the exclusive right to grant platform sublicenses for double-stranded RNAi. In exchange for such rights, we are eligible to earn 
a technology access fee, participate in fees from Alnylam’s partnering programs and earn future milestone and royalty payments from 
Alnylam. We retained exclusive rights to our patents for single-stranded antisense therapeutics and for a limited number of double-
stranded RNAi therapeutic targets and all rights to single-stranded RNAi, or ssRNAi, therapeutics. In turn, Alnylam nonexclusively 
licensed to us its patent estate relating to antisense motifs and mechanisms and oligonucleotide chemistry to research, develop and 
commercialize single-stranded antisense therapeutics, ssRNAi therapeutics, and to research double-stranded RNAi compounds. We 
also received a license to develop and commercialize double-stranded RNAi therapeutics targeting a limited number of therapeutic 
targets on a nonexclusive basis. Additionally, in 2015, we and Alnylam entered into an alliance in which we cross-licensed intellectual 
property. Under this alliance, we and Alnylam each obtained exclusive license rights to four therapeutic programs. Alnylam granted us 
an exclusive, royalty-bearing license to its chemistry, RNA targeting mechanism and target-specific intellectual property for 
oligonucleotides against four targets, including FXI and Apo(a) and two other targets. In exchange, we granted Alnylam an exclusive, 
royalty-bearing license to our chemistry, RNA targeting mechanism and target-specific intellectual property for oligonucleotides 
against four other targets. Alnylam also granted us a royalty-bearing, non-exclusive license to new platform technology arising from 
May 2014 through April 2019 for single-stranded antisense therapeutics. In turn, we granted Alnylam a royalty-bearing, non-exclusive 
license to new platform technology arising from May 2014 through April 2019 for double-stranded RNAi therapeutics. 
 
During the years ended December 31, 2024, 2023 and 2022, we earned the following revenue from our relationship with 
Alnylam (in thousands, except percentage amounts): 
 
 
Year Ended December 31, 
 
2024 
 
2023 
 
2022 
Revenue from our relationship with Alnylam 
$ 
8,110 $ 
28,426  $ 
21,389
Percentage of total revenue 
1%
4%  
4%
 
We did not have any deferred revenue from our relationship with Alnylam at December 31, 2024 and 2023. 
 
5. Investments 
 
The following table summarizes the contract maturity of the available-for-sale securities we held as of December 31, 2024: 
 
One year or less 
 
69%
After one year but within two years 
 
24%
After two years but within three and a half years 
 
7%
Total 
 
100%
 
As illustrated above, at December 31, 2024, 93 percent of our available-for-sale securities had a maturity of less than two 
years. 
 
All of our available-for-sale securities are available to us for use in our current operations. As a result, we categorize all of 
these securities as current assets even though the stated maturity of some individual securities may be one year or more beyond the 
balance sheet date. 
 
We invest in debt securities with strong credit ratings and an investment grade rating at or above A-1, P-1 or F-1 by Standard 
& Poor’s, Moody’s or Fitch, respectively. 
 
At December 31, 2024, we had an ownership interest of less than 20 percent in seven private companies and three public 
companies with which we conduct business. 
 

F-31 
The following is a summary of our investments (in thousands): 
 
 
 Amortized 
Gross Unrealized 
Estimated 
December 31, 2024 
 
 Cost 
 
Gains 
 
Losses 
 
Fair Value 
Available-for-sale securities: 
 
  
  
  
Corporate debt securities (1) 
$ 
593,810  $ 
487  $ 
(240)  $ 
594,057
Debt securities issued by U.S. government agencies 
 
143,647   
287   
(39)   
143,895
Debt securities issued by the U.S. Treasury (1) 
 
657,285 
825 
(120) 
657,990
Debt securities issued by states of the U.S. and political subdivisions of 
the states 
 
7,516   
8   
—   
7,524
Total securities with a maturity of one year or less 
 
1,402,258   
1,607   
(399)   
1,403,466
Corporate debt securities 
 
439,561   
723   
(2,275)   
438,009
Debt securities issued by U.S. government agencies 
 
65,255   
137   
(289)   
65,103
Debt securities issued by the U.S. Treasury 
149,086 
124 
(476) 
148,734
Other municipal debt securities 
698 
— 
(2) 
696
Total securities with a maturity of more than one year 
 
654,600   
984   
(3,042)   
652,542
Total available-for-sale securities 
$ 
2,056,858  $ 
2,591  $ 
(3,441)  $ 
2,056,008
Equity securities: 
 
 
 
Publicly traded equity securities included in other current assets (2) 
$ 
11,897 $ 
26 $ 
(6,660) $ 
5,263
Privately held equity securities included in deposits and other assets (3) 
23,115 
25,001 
(7,093) 
41,023
Total equity securities  
$ 
35,012 $ 
25,027 $ (13,753) $ 
46,286
Total available-for-sale and equity securities 
$ 
2,091,870  $ 
27,618  $ (17,194)  $ 
2,102,294
 
 
 Amortized  
Gross Unrealized 
 
Estimated  
December 31, 2023 
 
 Cost 
 
Gains 
 
Losses 
 
Fair Value 
Available-for-sale securities: 
 
  
  
  
Corporate debt securities (1) 
$ 
559,967  $ 
157  $ 
(2,625)  $ 
557,499
Debt securities issued by U.S. government agencies 
 
224,711   
64   
(611)   
224,164
Debt securities issued by the U.S. Treasury (1) 
 
513,784   
152   
(1,889)   
512,047
Debt securities issued by states of the U.S. and political subdivisions of 
the states 
 
17,757   
42   
(113)   
17,686
Total securities with a maturity of one year or less 
 
1,316,219   
415   
(5,238)   
1,311,396
Corporate debt securities 
 
243,151   
1,270   
(692)   
243,729
Debt securities issued by U.S. government agencies 
 
110,138   
547   
(21)   
110,664
Debt securities issued by the U.S. Treasury 
294,873 
1,239 
(480) 
295,632
Debt securities issued by states of the U.S. and political subdivisions of 
the states 
 
3,466   
7   
(4)   
3,469
Total securities with a maturity of more than one year 
 
651,628   
3,063   
(1,197)   
653,494
Total available-for-sale securities 
$ 
1,967,847  $ 
3,478  $ 
(6,435)  $ 
1,964,890
Equity securities: 
 
 
 
Publicly traded equity securities included in other current assets (2) 
$ 
11,897 $ 
236 $ 
(5,832) $ 
6,301
Privately held equity securities included in deposits and other assets (3) 
23,115 
25,001 
(5,125) 
42,991
Total equity securities 
$ 
35,012 $ 
25,237 $ (10,957) $ 
49,292
Total available-for-sale and equity securities 
$ 
2,002,859 $ 
28,715 $ (17,392) $ 
2,014,182
________________ 
(1) Includes investments classified as cash equivalents in our consolidated balance sheets. 
 
(2) Our publicly traded equity securities are included in other current assets. We recognize publicly traded equity securities at fair 
value. In the year ended December 31, 2024, we recorded a $1.0 million net unrealized loss in our consolidated statement of 
operations related to changes in the fair value of our investments in publicly traded companies.  
 
(3) Our privately held equity securities are included in deposits and other assets. We recognize our privately held equity securities at 
cost minus impairments, plus or minus changes resulting from observable price changes in orderly transactions for the identical or 
similar investment of the same issuer, which are Level 3 inputs. In the year ended December 31, 2024, we recorded a $2.0 million 
net unrealized loss in our consolidated statements of operations related to observable price changes of our investments in privately 
held companies. 
 

F-32 
The following is a summary of our investments we considered to be temporarily impaired at December 31, 2024 (in 
thousands, except for number of investments):  
 
  
 
 
Less than 12 Months of 
Temporary Impairment  
More than 12 Months of 
Temporary Impairment  
Total Temporary 
Impairment 
 
Number of 
Investments  
Estimated 
Fair Value  
Unrealized 
Losses 
 
Estimated 
Fair Value  
Unrealized 
Losses 
 
Estimated 
Fair Value  
Unrealized 
Losses 
Corporate debt securities 
 
274 $ 
488,949 $ 
(2,463) $ 
27,713 $ 
(52) $ 
516,662 $ 
(2,515) 
Debt securities issued by U.S. 
government agencies 
 
30
67,854
(328)
—
—
67,854
(328) 
Debt securities issued by the 
U.S. Treasury   
38
252,926
(503)
24,173
(93)
277,099
(596) 
Debt securities issued by states 
of the U.S. and political 
subdivisions of the states 
 
3
643
—
129
—
772
— 
Other municipal debt securities 
1
696
(2)
—
—
696
(2) 
Total temporarily impaired 
securities 
 
346 $ 
811,068 $ 
(3,296) $ 
52,015 $ 
(145) $ 
863,083 $ 
(3,441) 
 
We believe that the decline in value of these securities is temporary and is primarily related to the change in market interest 
rates since purchase rather than underlying credit deterioration for any of the issuers. We believe it is more likely than not that we will 
be able to hold our debt securities with declines in value to maturity. Therefore, we intend to hold these securities to maturity and 
anticipate full recovery of our debt securities’ amortized cost basis at maturity. 
 
6. Fair Value Measurements 
 
The following tables present the major security types we held at December 31, 2024 and 2023 that we regularly measure and 
carry at fair value. The following tables segregate each security type by the level within the fair value hierarchy of the valuation 
techniques we utilized to determine the respective securities’ fair value (in thousands): 
 
  
At 
December 31, 2024   
Quoted Prices in 
Active Markets 
(Level 1) 
  
Significant Other 
Observable Inputs 
(Level 2) 
Cash equivalents (1) 
$ 
180,445
 $ 
180,445
 $ 
—
Corporate debt securities (2) 
 
1,032,066
  
—
  
1,032,066
Debt securities issued by U.S. government agencies (2) 
 
208,998
  
—
  
208,998
Debt securities issued by the U.S. Treasury (2) 
 
806,724
  
806,724
  
—
Debt securities issued by states of the U.S. and political 
subdivisions of the states (2) 
 
7,524
  
—
  
7,524
Other municipal debt securities (2) 
696
 
—
 
696
Publicly traded equity securities included in other current assets (3) 
5,263
 
5,263
 
—
Total 
$ 
2,241,716
 $ 
992,432
 $ 
1,249,284
 
 
At 
December 31, 2023   
Quoted Prices in 
Active Markets 
(Level 1) 
  
Significant Other 
Observable Inputs 
(Level 2) 
Cash equivalents (1) 
$ 
185,424
$ 
185,424 
$ 
—
Corporate debt securities (4) 
 
801,228
 
— 
 
801,228
Debt securities issued by U.S. government agencies (2) 
 
334,828
 
— 
 
334,828
Debt securities issued by the U.S. Treasury (2) 
 
807,679
 
807,679 
 
—
Debt securities issued by states of the U.S. and political 
subdivisions of the states (2) 
 
21,155
 
— 
 
21,155
Publicly traded equity securities included in other current assets (3) 
6,301
6,301 
 
—
Total 
$ 
2,156,615
$ 
999,404 
$ 
1,157,211
________________ 
(1) Included in cash and cash equivalents in our consolidated balance sheets. 
 
(2) Included in short-term investments in our consolidated balance sheets. 
 

F-33 
(3) Included in other current assets in our consolidated balance sheets. 
 
(4) $33.0 million was included in cash and cash equivalents, with the difference included in short-term investments in our 
consolidated balance sheets. 
 

F-34 
Convertible Notes 
 
Our 1.75% Notes and 0% Notes had a fair value of $569.3 million and $612.8 million at December 31, 2024, respectively. 
Our 1.75% Notes, 0% Notes and 0.125% Notes had a fair value of $661.1 million, $667.8 million and $42.4 million at December 31, 
2023, respectively. We determine the fair value of our notes based on quoted market prices for these notes, which are Level 2 
measurements because the notes do not trade regularly. 
 
7. Long-Term Obligations and Commitments 
 
The carrying value of our long-term obligations was as follows (in thousands): 
 
  
December 31, 
  
2024 
  
2023 
1.75% convertible senior notes 
$ 
565,026 
$ 
562,285
0% convertible senior notes 
628,535 
625,380
Liability related to sale of future royalties 
542,212 
513,736
Lease liabilities 
170,869 
178,969
Mortgage debt 
8,714 
8,859
Other obligations 
 
43,425 
 
33,714
Total 
$ 
1,958,781 
$ 
1,922,943
Less: current portion 
 
(9,279) 
 
(8,831)
Total Long-Term Obligations 
$ 
1,949,502 
$ 
1,914,112
 
As of December 31, 2023, our 0.125% Notes was classified as a current liability because they matured in December 2024. 
 
Convertible Debt and Call Spread 
 
1.75 Percent Convertible Senior Notes 
 
In 2023, we completed a $575.0 million offering of our 0.125% Notes and used $488.2 million of the net proceeds from the 
issuance of the 1.75% Notes to repurchase $504.4 million in principal of our 0.125% Notes. In December 2024, we used $44.5 million 
of the net proceeds to settle the remaining principal balance of our 0.125% Notes upon maturity. 
 
At December 31, 2024, we had the following 1.75% Notes outstanding (in millions, except interest rate and price per share 
data): 
 
 
1.75% Notes 
Outstanding principal balance  
$575.0 
Unamortized debt issuance costs 
$10.0 
Maturity date 
June 2028 
Interest rate 
1.75% 
Effective interest rate 
2.3% 
Conversion price per share 
$53.73 
Total shares of common stock subject to conversion 
10.7 
 
0 Percent Convertible Senior Notes and Call Spread  
 
In 2021, we completed a $632.5 million offering of our 0% Notes. We used $319.0 million of the net proceeds from the 
issuance of our 0% Notes to pay the remaining $309.9 million principal balance of our 1% convertible senior notes, or 1% Notes, in 
2021. 
 

F-35 
At December 31, 2024, we had the following 0% Notes outstanding (in millions, except interest rate and price per share 
data): 
 
 
0% Notes 
Outstanding principal balance  
$632.5 
Unamortized debt issuance costs 
$4.0 
Maturity date 
April 2026 
Interest rate 
0% 
Effective interest rate 
0.5% 
Conversion price per share 
$57.84 
Effective conversion price per share with call spread 
$76.39 
Total shares of common stock subject to conversion 
10.9 
 
In conjunction with the 2021 offering, we entered into a call spread transaction, which was comprised of purchasing note 
hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of our 0% Notes by increasing the 
effective conversion price on our 0% Notes. We increased our effective conversion price to $76.39 with the same number of 
underlying shares as our 0% Notes. The call spread cost us $46.9 million, of which $136.7 million was for the note hedge purchase, 
offset by $89.8 million we received for selling the warrants. Similar to our 0% Notes, our note hedges are subject to adjustment. 
Additionally, our note hedges are exercisable upon conversion of the 0% Notes. The note hedges will expire upon maturity of the 0% 
Notes, or April 2026. The note hedges and warrants are separate transactions and are not part of the terms of our 0% Notes. The 
holders of the 0% Notes do not have any rights with respect to the note hedges and warrants. 
 
We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in 
capital in our consolidated balance sheets. Refer to Note 1, Organization and Significant Accounting Policies, for our Call Spread 
accounting policy. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each 
reporting period. 
 
0.125 Percent Convertible Senior Notes and Call Spread 
 
In 2019, we entered into privately negotiated exchange and/or subscription agreements with certain new investors and certain 
holders of our 1% Notes to exchange $375.6 million of our 1% Notes for $439.3 million of our 0.125% Notes, and to issue $109.5 
million of our 0.125% Notes. 
 
As discussed above, in 2023, we repurchased $504.4 million of our 0.125% Notes. As a result of the repurchase, we 
recognized a $13.4 million gain on the early retirement of debt, which we recorded as other income in our consolidated statement of 
operations for the year ended December 31, 2023. The gain on the early retirement of our debt is the difference between the amounts 
paid to repurchase our 0.125% Notes and the net carrying balance of the liability at the time that we completed the repurchases. We 
paid the remaining principal balance of our 0.125% Notes with $44.5 million of cash at maturity in December 2024. 
 
In conjunction with the issuance of our 0.125% Notes in 2019, we entered into a call spread transaction, which was 
comprised of purchasing note hedges and selling warrants, to minimize the impact of potential economic dilution upon conversion of 
our 0.125% Notes by increasing the effective conversion price on our 0.125% Notes. We increased our effective conversion price 
from $83.28 to $123.38 with the same number of underlying shares as our 0.125% Notes. The call spread cost us $52.6 million, of 
which $108.7 million was for the note hedge purchase, offset by $56.1 million we received for selling the warrants. Similar to our 
0.125% Notes, our note hedges were subject to adjustment. Additionally, our note hedges were exercisable upon conversion of the 
0.125% Notes. The note hedges expired upon maturity of the 0.125% Notes in December 2024. The warrants will expire in March 
2025. The note hedges and warrants were separate transactions and were not part of the terms of our 0.125% Notes. The holders of the 
0.125% Notes did not have any rights with respect to the note hedges and warrants.  
 
We recorded the amount we paid for the note hedges and the amount we received for the warrants in additional paid-in 
capital in our consolidated balance sheets. Refer to Note 1, Organization and Significant Accounting Policies, for our Call Spread 
accounting policy. We reassess our ability to continue to classify the note hedges and warrants in shareholders’ equity at each 
reporting period. 
 

F-36 
Other Terms of Convertible Senior Notes 
 
The 1.75% and 0% Notes are convertible under certain conditions, at the option of the note holders. We can settle 
conversions of the notes, at our election, in cash, shares of our common stock or a combination of both. We may not redeem the notes 
prior to maturity, and we do not have to provide a sinking fund for them. Holders of the notes may require us to purchase some or all 
of their notes upon the occurrence of certain fundamental changes, as set forth in the indentures governing the notes, at a purchase 
price equal to 100 percent of the principal amount of the notes to be purchased, plus any accrued and unpaid interest. The 0.125% 
Notes were subject to similar terms. 
 
Our total interest expense for our outstanding senior convertible notes for the years ended December 31, 2024, 2023 and 
2022 included $6.1 million, $5.9 million and $5.3 million, respectively, of non-cash interest expense related to the amortization of 
debt issuance costs for our convertible notes. 
 
Financing Arrangements 
 
Operating Facilities 
 
In 2017, we purchased the building that houses our primary R&D facility for $79.4 million and our manufacturing facility for 
$14.0 million. We financed the purchase of these two facilities with mortgage debt of $60.4 million in total. Our primary R&D facility 
mortgage had an interest rate of 3.88 percent. Our manufacturing facility mortgage has an interest rate of 4.20 percent. During the first 
five years of both mortgages, we were only required to make interest payments. We began making principal payments in 2022. Our 
manufacturing facility mortgage matures in August 2027. We repaid our primary R&D facility mortgage in 2022 in conjunction with a 
sale and leaseback transaction.  
 
In 2022, we concurrently entered into two purchase and sale agreements with a real estate investor. In the same period, we 
closed the first transaction in which we sold the facilities at our headquarters in Carlsbad, California, which includes our primary R&D 
facility, for a purchase price of $263.4 million. As a result, we de-recognized the related land and improvements, building and 
building improvements, which resulted in a net gain of $150.1 million that we reported in other income in our consolidated statements 
of operations. We used a portion of the sale proceeds to extinguish our outstanding mortgage debt on our primary R&D facility of 
$51.3 million. In connection with this transaction, we leased back our headquarters facilities for an initial lease term of 15 years with 
options to extend the lease for two additional terms of five years each. 
 
In August 2023, we closed the second transaction and transferred legal ownership of two lots of undeveloped land adjacent to 
our headquarters to the real estate investor for a purchase price of $33 million. In connection with this transaction, we entered into a 
build-to-suit lease agreement with the same real estate investor to lease a new R&D facility. The lessor will develop and construct a 
new building composed of R&D and office space. We will design and construct tenant improvements to customize the facility’s 
interior space. We will lease the facility for an initial term of 15 years with options to extend the lease for two additional terms of five 
years each. The lease will commence once the structure of this new facility is completed. 
 
Since the building is under construction and unavailable to lease, we are unable to complete the sale-leaseback evaluation 
under ASC 842, Leases. As a result, the land remains in our consolidated balance sheets and we accounted for the proceeds as a 
financial liability. We will reassess the transaction under the sale-leaseback accounting guidance when the facilities are available for 
lease commencement.  
 
Debt Maturity Schedules 
 
Annual convertible and mortgage debt maturities, including fixed and determinable interest, at December 31, 2024 are as 
follows (in thousands): 
 
2025 
$ 
10,657
2026 
 
643,157
2027 
 
18,737
2028 
 
580,091
2029 
 
60
Thereafter 
 
360
Total debt and mortgage maturities 
$ 
1,253,062
Less: Current portion included in other current liabilities 
 
(165)
Less: Fixed and determinable interest 
 
(36,511)
Less: Debt issuance costs 
(13,981)
Total debt  
$ 
1,202,405
 

F-37 
Operating Leases 
 
Carlsbad Leases 
 
We lease a facility adjacent to our manufacturing facility that has laboratory and office space that we use to support our 
manufacturing facility. We lease this space under a non-cancelable operating lease. In 2020, we exercised our option to extend our 
lease, extending our lease term from June 2021 to August 2026. We have one remaining option to extend the lease for an additional 
five-year period. 
 
We also lease an additional office space and warehouse space in Carlsbad. We lease these spaces under non-cancelable 
operating leases. In 2022, we exercised our option to extend the office space lease, extending our term from January 2023 to May 
2027. We have no remaining options to extend this lease. Our warehouse space lease in Carlsbad has an initial term ending in 2028 
with no options to extend the lease. 
 
As discussed above in the section titled, Financing Arrangements, we lease our headquarters, which includes our primary 
R&D facility, as part of a sale and leaseback transaction that closed in 2022. The initial lease term for our headquarters facilities is 15 
years with options to extend the lease for two additional terms of five years each. We determined at lease inception that it was not 
reasonably certain that we would exercise any of the options to extend the lease. We expect our lease payments over the initial term to 
total approximately $280 million. In connection with the transfer of legal ownership of the two lots of undeveloped land to the real 
estate investor, we entered into a build-to-suit lease agreement with the same real estate investor who will build a new R&D facility 
for us on those lots. The lease will commence once the structure of this new facility is completed. 
 
Oceanside Lease 
 
In 2022, we entered into a build-to-suit lease agreement to lease a development chemistry and manufacturing facility to be 
constructed by the lessor in Oceanside, California. We capitalized costs that we incurred related to the design and development of 
tenant improvements as construction-in-progress in our consolidated balance sheets. In 2023, we reached a mutual agreement with the 
lessor to terminate the lease agreement. As a result, we recorded a charge of $20 million, primarily associated with the impairment of 
construction-in-progress assets, within SG&A expense in our consolidated statements of operations. 
 
Boston Leases 
 
We entered into an operating lease agreement for office space located in Boston, Massachusetts which commenced in August 
2018. We are leasing this space under a non-cancelable operating lease with an initial term ending after 123 months and an option to 
extend the lease for an additional five-year term. Under the lease agreement, we received a three-month free rent period. 
 
In 2022, we entered into a sublease agreement for our office space located in Boston, Massachusetts. The sublease 
commencement date was in January 2022 when the office space was ready for our tenant’s occupancy. We are subleasing this space 
under a non-cancelable operating sublease with a sublease term ending 83 months following the sublease commencement date with no 
option to extend the sublease. Under the sublease agreement we provided a seven-month free rent period, which commenced in 
January 2022. We will receive lease payments over the sublease term totaling $9.6 million. 
 
We entered into an operating lease agreement for another office space located in Boston, Massachusetts which commenced in 
2021. We are leasing this space under a non-cancelable operating lease with an initial term ending 91 months following the lease 
commencement date and an option to extend the lease for an additional five-year term. Under the lease agreement, we received a 
seven-month free rent period, which commenced in November 2021. Our lease payments over the initial term total $6.8 million.  
 
When we determined our lease term for our operating lease right-of-use assets and lease liabilities for these leases, we did not 
include the extension options for these leases in the original lease term because it was not reasonably certain we would exercise those 
extension options.  
 
Amounts related to our operating leases were as follows (dollar amounts in millions): 
 
At December 31, 2024 
Right-of-use operating lease assets 
$ 
161.9
Operating lease liabilities 
$ 
170.9
Weighted average remaining lease term  
12.1 years
Weighted average discount rate  
6.9%
 

F-38 
During the years ended December 31, 2024, 2023, and 2022 we paid $20.5 million, $20.1 million and $4.0 million of lease 
payments, which were included in operating activities in our consolidated statements of cash flows. 
 
As of December 31, 2024, the future payments for our operating lease liabilities are as follows (in thousands): 
 
Operating Leases 
Year ending December 31,  
2025 
$  
20,870
2026 
 
21,032
2027 
 
21,054
2028 
20,973
2029 
18,687
Thereafter 
157,622
Total minimum lease payments 
260,238
Less: Imputed interest 
(89,369)
Less: Current portion (included in other current liabilities) 
(9,064)
Total long-term lease liabilities  
$ 
161,805
 
Rent expense was $23.2 million, $23.1 million and $8.3 million for the years ended December 31, 2024, 2023 and 2022, 
respectively.  
 
Royalty Revenue Monetization 
 
In January 2023, we entered into a royalty purchase agreement with Royalty Pharma Investments, or Royalty Pharma, to 
monetize a portion of our future SPINRAZA and pelacarsen royalties we are entitled to under our agreements with Biogen and 
Novartis, respectively. As a result, we received an upfront payment of $500 million and we are eligible to receive up to $625 million 
in additional milestone payments. Under the terms of the agreement, Royalty Pharma will receive 25 percent of our SPINRAZA 
royalty payments from 2023 through 2027, increasing to 45 percent of royalty payments in 2028, on up to $1.5 billion in annual sales. 
In addition, Royalty Pharma will receive 25 percent of any future royalty payments on pelacarsen. Royalty Pharma’s royalty interest 
in SPINRAZA will revert to us after total SPINRAZA royalty payments to Royalty Pharma reach either $475 million or $550 million, 
depending on the timing and occurrence of FDA approval of pelacarsen. 
 
We recorded the upfront payment of $500 million as a liability related to the sale of future royalties, net of transaction costs 
of $10.4 million, which we are amortizing over the estimated life of the arrangement using the effective interest rate method. We 
recognize royalty revenue in the period in which the counterparty sells the related product and recognizes the related revenue. We 
record royalty payments made to Royalty Pharma as a reduction of the liability. 
 
We determine the effective interest rate used to record interest expense under this agreement based on an estimate of future 
royalty payments to Royalty Pharma. As of December 31, 2024 and 2023, the estimated effective interest rate under the agreement 
was 13.5 percent. 
 
The following is a summary of our liability related to sale of future royalties for the year ended December 31, 2024 (in 
thousands): 
 
Proceeds from sale of future royalties in January 2023 
 
$ 
500,000 
Issuance costs related to sale of future royalties 
 
 
(10,434) 
Royalty payments to Royalty Pharma 
 
 
(44,628) 
Interest expense related to sale of future royalties 
 
 
68,238 
Amortization of issuance costs related to sale of future royalties 
 
 
560 
Net liability related to sale of future royalties as of December 31, 2023 
 
 
513,736 
Royalty payments to Royalty Pharma 
 
 
(44,981) 
Interest expense related to sale of future royalties 
 
 
72,846 
Amortization of issuance costs related to sale of future royalties 
 
 
611 
Net liability related to sale of future royalties as of December 31, 2024 
 
$ 
542,212 
 
There are numerous factors, most of which are not within our control, that could materially impact the amount and timing of 
royalty payments from Biogen and Novartis, and result in changes to our estimate of future royalty payments to Royalty Pharma. Such 
factors include, but are not limited to, the commercial sales of SPINRAZA, the regulatory approval and commercial sales of 
pelacarsen, competing products or other significant events. 
 

F-39 
8. Stockholders’ Equity 
 
Preferred Stock 
 
We are authorized to issue up to 15 million shares of “blank check” Preferred Stock. As of December 31, 2024, there were no 
shares of Preferred Stock outstanding. We have designated Series C Junior Participating Preferred Stock but have no issued or 
outstanding shares as of December 31, 2024. 
 
Common Stock 
 
At December 31, 2024 and 2023, we had 300 million shares of common stock authorized, of which 157.9 million and 144.3 
million were issued and outstanding, respectively. As of December 31, 2024, total common shares reserved for future issuance were 
48.0 million.  
 
During the years ended December 31, 2024, 2023 and 2022, we issued 2.1 million, 2.3 million and 1.2 million shares of 
common stock, respectively, for stock option exercises, vesting of restricted stock units, and ESPP purchases. We received net 
proceeds from these transactions of $33.6 million, $49.4 million and $6.4 million in 2024, 2023 and 2022, respectively. 
 
In September 2024, we completed the sale of 11.5 million shares of our common stock through a public offering at a price of 
$43.50 per share. We received net proceeds of $489.1 million from the sale of these shares net of underwriting discounts and 
commissions and other offering expenses of $11.2 million. 
 
Stock Plans 
 
1989 Stock Option Plan 
 
In 1989, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that, as amended, 
provides for the issuance of non-qualified and incentive stock options for the purchase of up to 20.0 million shares of common stock 
to our employees, directors, and consultants. The plan expired in January 2024. The 1989 Stock Option Plan, or 1989 Plan, did not 
allow us to grant stock bonuses or restricted stock awards and prohibited us from repricing any options outstanding under the plan 
unless our stockholders approved the repricing. Options vested over a four-year period, with 25 percent exercisable at the end of one 
year from the date of the grant and the balance vested ratably, on a monthly basis, thereafter and had a term of seven years. At 
December 31, 2024, no options were outstanding and no shares were available for future grant under the 1989 Plan. 
 
2011 Equity Incentive Plan 
 
In 2011, our Board of Directors adopted, and the stockholders subsequently approved, a stock option plan that provides for 
the issuance of stock options, stock appreciation rights, restricted stock awards, restricted stock unit awards, and performance cash 
awards to our employees, directors, and consultants. In June 2015, May 2017 and June 2019, after receiving approval from our 
stockholders, we amended our 2011 Equity Incentive Plan, or 2011 Plan, to increase the total number of shares reserved for issuance. 
We increased the shares available under our 2011 Equity Incentive Plan from 5.5 million to 11.0 million in June 2015, from 11.0 
million to 16.0 million in May 2017 and from 16.0 million to 23.0 million in June 2019. In June 2021, after receiving approval from 
our stockholders, we amended our 2011 Plan. The amendment increased the total number of shares of common stock authorized for 
issuance under the 2011 Plan from 23.0 million to 29.7 million and added a fungible share counting ratio whereby the share reserve 
will be reduced by 1.7 shares for each share of common stock issued pursuant to a full value award (i.e., RSU or PRSU) and increased 
by 1.7 shares for each share of common stock returning from a full value award. In June 2023, after receiving approval from our 
stockholders, we amended our 2011 Plan to increase the total number of shares of common stock authorized for issuance under the 
2011 Plan from 29.7 million to 35.2 million. In June 2024, after receiving approval from our stockholders, we amended our 2011 Plan 
to increase the total number of shares of common stock authorized for issuance under the 2011 Plan from 35.2 million to 38.5 million. 
 
The plan expires in June 2031. The 2011 Plan does not allow us to reduce the exercise price of any outstanding stock options 
or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or strike 
price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our 
stockholders approve such action. Currently we anticipate awarding only stock options, RSU and PRSU awards to our employees, 
directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the 
grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 
31, 2021 have a term of ten years. We have granted restricted stock unit awards to our employees under the 2011 Plan which vest 
annually over a four-year period. At December 31, 2024, a total of 13.3 million options were outstanding, of which 9.0 million were 
exercisable, 3.9 million restricted stock unit awards were outstanding, and 7.3 million shares were available for future grant under the 
2011 Plan. 
 

F-40 
Under the 2011 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a 
change in control. In the absence of such provisions, no such acceleration will occur. In addition, we implemented a change of control 
and severance benefit plan that provides for change of control and severance benefits to our executive officers, including our chief 
executive officer and chief financial officer, and vice presidents. If one of our executive officers or vice presidents is terminated or 
resigns for good reason during the period that begins three months before and ends twelve months following a change in control of the 
company, the impacted employee’s stock options and RSUs vesting will accelerate for options and RSUs outstanding as of the 
termination date.  
 
2020 Equity Incentive Plan  
 
In connection with the Akcea Merger in 2020, we assumed the unallocated portion of the available share reserve under the 
Akcea 2015 Equity Incentive Plan. In 2020, we amended and restated the Akcea 2015 equity plan, including renaming the plan as the 
Ionis Pharmaceuticals, Inc. 2020 Equity Incentive Plan, or 2020 Plan. The 2020 Plan provided for the issuance of up to 2.6 million 
shares of our Common Stock to our employees, directors and consultants who were employees of Akcea prior to the Akcea Merger. In 
the second quarter of 2021, our Compensation Committee approved an amendment to the 2020 Plan. The amendment decreased the 
total number of shares of common stock authorized for issuance under the 2020 Plan from approximately 2.6 million to 1.6 million. 
We assumed the 2020 Plan in connection with Ionis’ reacquisition of all of the outstanding shares of Akcea Therapeutics, Inc. as part 
of the Akcea Merger. 
 
The plan expires in December 2025. The 2020 Plan does not allow us to reduce the exercise price of any outstanding stock 
options or stock appreciation rights or cancel any outstanding stock options or stock appreciation rights that have an exercise price or 
strike price greater than the current fair market value of the common stock in exchange for cash or other stock awards unless our 
stockholders approve such action. Currently we anticipate awarding only stock options and RSU awards to our eligible employees, 
directors and consultants. Options vest over a four-year period, with 25 percent exercisable at the end of one year from the date of the 
grant and the balance vesting ratably, on a monthly basis, thereafter and have a term of seven years. Options granted after December 
31, 2021 have a term of ten years. We have granted restricted stock unit awards to our employees under the 2020 Plan which vest 
annually over a four-year period. At December 31, 2024, a total of 0.5 million options were outstanding, of which 0.2 million were 
exercisable, 0.2 million restricted stock unit awards were outstanding, and 0.8 million shares were available for future grant under the 
2020 Plan. 
 
Under the 2020 Plan, we may issue a stock award with additional acceleration of vesting and exercisability upon or after a 
change in control. In the absence of such provisions, no such acceleration will occur.  
 
Corporate Transactions and Change in Control under 2011 and 2020 Plans 
 
In the event of certain significant corporate transactions, our Board of Directors has the discretion to take one or more of the 
following actions with respect to outstanding stock awards under the 2011 and 2020 Plans: 
 
● 
arrange for assumption, continuation, or substitution of a stock award by a surviving or acquiring entity (or its parent 
company); 
● 
arrange for the assignment of any reacquisition or repurchase rights applicable to any shares of our common stock issued 
pursuant to a stock award to the surviving or acquiring corporation (or its parent company); 
● 
accelerate the vesting and exercisability of a stock award followed by the termination of the stock award; 
● 
arrange for the lapse of any reacquisition or repurchase rights applicable to any shares of our common stock issued 
pursuant to a stock award; 
● 
cancel or arrange for the cancellation of a stock award, to the extent not vested or not exercised prior to the effective date 
of the corporate transaction, in exchange for cash consideration, if any, as the Board, in its sole discretion, may consider 
appropriate; and 
● 
arrange for the surrender of a stock award in exchange for a payment equal to the excess of (a) the value of the property 
the holder of the stock award would have received upon the exercise of the stock award, over (b) any exercise price 
payable by such holder in connection with such exercise. 
 

F-41 
2002 Non-Employee Directors’ Stock Option Plan 
 
In 2001, our Board of Directors adopted, and the stockholders subsequently approved, an amendment and restatement of the 
1992 Non-Employee Directors’ Stock Option Plan, which provides for the issuance of non-qualified stock options and restricted stock 
units to our non-employee directors. The name of the resulting plan is the 2002 Non-Employee Directors’ Stock Option Plan, or the 
2002 Plan. In 2015, after receiving approval from our stockholders, we amended our 2002 Plan to increase the total number of shares 
reserved for issuance from 1.2 million to 2.0 million. In 2020, after receiving approval from our stockholders, we further amended our 
2002 Plan. The amendments included: 
 
● 
An increase to the total number of shares reserved for issuance under the plan from 2.0 million to 2.8 million shares;  
● 
A reduction to the amount of the automatic awards under the plan; 
● 
A revision to the vesting schedule of new awards granted; and 
● 
An extension of the term of the plan. 
 
Options under this plan expire 10 years from the date of grant. At December 31, 2024, a total of 0.9 million options were 
outstanding, of which 0.8 million were exercisable, 52,000 restricted stock unit awards were outstanding, and 0.4 million shares were 
available for future grant under the 2002 Plan. 
 
Employee Stock Purchase Plan 
 
In 2009, our Board of Directors adopted, and the stockholders subsequently approved, the amendment and restatement of the 
ESPP and we reserved an additional 150,000 shares of common stock for issuance thereunder. In each of the subsequent years until 
2019, we reserved an additional 150,000 shares of common stock for the ESPP resulting in a total of 3.2 million shares authorized 
under the plan as of December 31, 2024. The ESPP permits full-time employees to purchase common stock through payroll 
deductions (which cannot exceed 10 percent of each employee’s compensation) at the lower of 85 percent of fair market value at the 
beginning of the purchase period or the end of each purchase period. Under the amended and restated ESPP, employees must hold the 
stock they purchase for a minimum of six months from the date of purchase. During 2024, employees purchased and we issued to 
employees 0.1 million shares under the ESPP at a weighted average price of $35.93 per share. At December 31, 2024, there were 0.3 
million shares available for purchase under the ESPP. 
 
Stock Option Activity 
 
The following table summarizes the stock option activity under our stock plans for the year ended December 31, 2024 (in 
thousands, except per share and contractual life data): 
 
  
Number 
of Shares 
  
Weighted 
Average Exercise 
Price Per Share   
Average 
Remaining 
Contractual 
Term 
(Years) 
  
Aggregate 
Intrinsic 
Value 
Outstanding at December 31, 2023 
 
14,091 $ 
48.43
Granted 
 
2,729 $ 
49.77
Exercised 
 
(399) $ 
39.55
Cancelled/forfeited/expired 
 
(1,704) $ 
54.40
Outstanding at December 31, 2024 
 
14,717 $ 
48.23
 
5.27 
$
4,692
Exercisable at December 31, 2024 
 
10,089 $ 
49.85
 
3.66 
$
3,460
 
The weighted-average estimated fair values of options granted were $24.37, $19.72 and $18.66 for the years ended December 
31, 2024, 2023 and 2022, respectively. The total intrinsic value of options exercised during the years ended December 31, 2024, 2023 
and 2022 were $3.6 million, $6.0 million and $1.4 million, respectively, which we determined as of the date of exercise. The amount 
of cash received from the exercise of stock options was $15.8 million, $65.1 million and $3.6 million for the years ended December 
31, 2024, 2023 and 2022, respectively. For the year ended December 31, 2024, the weighted-average fair value of options exercised 
was $48.59. As of December 31, 2024, total unrecognized compensation cost related to non-vested stock options was $43.7 million. 
We expect to recognize this cost over a weighted average period of 1.1 years. We will adjust the total unrecognized compensation cost 
for future changes in estimated forfeitures.  
 

F-42 
Restricted Stock Unit Activity 
 
The following table summarizes the RSU activity for the year ended December 31, 2024 (in thousands, except per share 
data): 
 
 
Number 
of Shares 
  
Weighted Average 
Grant Date Fair 
Value Per Share 
Non-vested at December 31, 2023 
 
3,239
$ 
43.40
Granted 
 
2,005
$ 
50.92
Vested 
 
(1,185)
$ 
46.88
Cancelled/forfeited 
 
(228)
$ 
46.83
Non-vested at December 31, 2024 
 
3,831
$ 
46.06
 
For the years ended December 31, 2024, 2023 and 2022, the weighted-average grant date fair value of RSUs granted was 
$50.92, $40.51 and $36.14 per RSU, respectively. As of December 31, 2024, total unrecognized compensation cost related to RSUs 
was $72.6 million. We expect to recognize this cost over a weighted average period of 1.3 years. We will adjust the total unrecognized 
compensation cost for future changes in estimated forfeitures. 
 
Performance Restricted Stock Unit Activity 
 
The following table summarizes the PRSU activity for the year ended December 31, 2024 (in thousands, except per share 
data): 
 
 
Number 
of Shares 
  
Weighted Average 
Grant Date Fair 
Value Per Share 
Non-vested at December 31, 2023 
 
226
$ 
56.04
Granted 
 
179
$ 
78.41
Vested 
 
(73)
$ 
53.35
Cancelled/forfeited 
(25)
$ 
68.21
Non-vested at December 31, 2024 
 
307
$ 
66.72
 
For the years ended December 31, 2024, 2023 and 2022, the weighted-average grant date fair value of PRSUs granted was 
$78.41, $57.43 and $42.28 per PRSU, respectively. As of December 31, 2024, total unrecognized compensation cost related to PRSUs 
was $10.4 million. We expect to recognize this cost over a weighted average period of 1.4 years. We will adjust the total unrecognized 
compensation cost for future changes in estimated forfeitures.  
 
Stock-based Compensation Expense and Valuation Information 
 
The following table summarizes stock-based compensation expense for the years ended December 31, 2024, 2023 and 2022 
(in thousands): 
 
 
Year Ended December 31, 
 
2024 
  
2023 
  
2022 
Cost of sales 
$ 
767
$ 
499
$
533 
Research, development and patent 
92,403
 
77,826
73,704 
Selling, general and administrative 
 
37,030
 
27,484
26,027 
Stock-based compensation expense, net of amounts capitalized 
$ 
130,200
$ 
105,809
$
100,264 
Capitalized stock-based compensation expense 
799
 
—
— 
Total stock-based compensation expense 
$ 
130,999
$ 
105,809
$
100,264 
 
Stock-based compensation expense increased in 2024 compared to 2023 due to increased headcount and a higher stock price 
on the grant date of annual equity awards in 2024 compared to 2023. Refer to Note 1, Organization and Significant Accounting 
Policies, for further details on how we determine the fair value of stock options granted, RSUs, PRSUs and stock purchase rights 
under the ESPP. 
 

F-43 
For the years ended December 31, 2024, 2023 and 2022, we used the following weighted-average assumptions in our Black-
Scholes calculations: 
 
Employee Stock Options: 
 
 
Year Ended December 31, 
 
2024 
  
2023 
  
2022 
Risk-free interest rate 
4.1%
3.8%
2.1%
Dividend yield 
0.0%
0.0%
0.0%
Volatility 
43.7%
46.8%
54.5%
Expected life 
6.3 years
6.3 years
6.3 years
 
Board of Director Stock Options: 
 
 
Year Ended December 31, 
 
2024 
  
2023 
  
2022 
Risk-free interest rate 
4.5%
3.8%
2.9%
Dividend yield 
0.0%
0.0%
0.0%
Volatility 
49.8%
52.7%
56.2%
Expected life 
7.5 years
7.7 years
7.4 years
 
ESPP: 
 
 
Year Ended December 31, 
 
2024 
  
2023 
  
2022 
Risk-free interest rate 
5.2%
 
5.3%
 
1.2%
Dividend yield 
0.0%
 
0.0%
 
0.0%
Volatility 
37.8%
 
36.0%
 
50.1%
Expected life 
6 months
 
6 months
 
6 months
 
Risk-Free Interest Rate. We base the risk-free interest rate assumption on observed interest rates appropriate for the term of 
our stock option plans or ESPP. 
 
Dividend Yield. We base the dividend yield assumption on our history and expectation of dividend payouts. We have not paid 
dividends in the past and do not expect to in the future. 
 
Volatility. We use an average of the historical stock price volatility of our stock for the Black-Scholes model. We computed 
the historical stock volatility based on the expected term of the awards. 
 
Expected Life. The expected term of stock options we have granted represents the period of time that we expect them to be 
outstanding. Historically, we estimated the expected term of options we have granted based on actual and projected exercise patterns. 
In 2021, our Compensation Committee approved an amendment to the 2011 Equity Incentive Plan, or 2011 Plan, and the 2020 Equity 
Incentive Plan, or 2020 Plan, that increased the contractual term of stock options granted under these plans from seven to ten years for 
stock options granted on January 1, 2022 and thereafter. We determined that we are unable to rely on our historical exercise data as a 
basis for estimating the expected life of stock options granted to employees following this change because the contractual term 
changed and we have no other means to reasonably estimate future exercise behavior. We therefore used the simplified method for 
determining the expected life of stock options granted to employees in the years ended December 31, 2024, 2023 and 2022. Under the 
simplified method, we calculate the expected term as the average of the time-to-vesting and the contractual life of the options. As we 
gain additional historical information, we will transition to calculating our expected term based on our historical exercise patterns. 
 
Forfeitures. We reduce stock-based compensation expense for estimated forfeitures. We estimate forfeitures at the time of 
grant and revise, if necessary, in subsequent periods if actual forfeitures differ from those estimates. We estimate forfeitures based on 
historical experience.  
 

F-44 
9. Income Taxes 
 
Loss before income taxes is comprised of (in thousands): 
 
Year Ended December 31, 
 
2024 
  
2023 
  
2022 
United States 
$ (460,712)
 $ 
(334,707) $ 
(258,493)
Foreign 
644
  
742 
 
508
Loss before income taxes  
$ (460,068)
 $ 
(333,965) $ 
(257,985)
 
Our income tax expense (benefit) was as follows (in thousands): 
 
 
Year Ended December 31, 
 
2024 
  
2023 
  
2022 
Current: 
 
Federal 
$ 
(5,492)
 $
35,861 
$
10,522 
State 
(848)
 
(3,687) 
1,129 
Foreign 
169
 
147 
86 
Total current income tax expense (benefit) 
(6,171)
 
32,321 
11,737 
 
 
 
Deferred: 
 
 
 
Federal 
—
 
— 
— 
State 
—
 
— 
— 
Total deferred income tax benefit 
—
 
— 
— 
Total income tax expense (benefit)  
$ 
(6,171)
 $
32,321 
$
11,737 
 
Our expense (benefit) for income taxes differs from the amount computed by applying the U.S. federal statutory rate to loss 
before income taxes. The sources and tax effects of the differences are as follows (in thousands): 
 
  
Year Ended December 31, 
  
2024 
  
2023 
  
2022 
Pre-tax loss 
$ (460,068)
$
(333,965)
$
(257,985) 
  
 
 
Statutory rate 
 
(96,614)
21.0%
(70,133)
21.0% 
(54,177) 
21.0%
State income tax net of federal benefit 
 
(11,889)
2.6%
(22,597)
6.8% 
(13,622) 
5.3%
Foreign 
15
0.0%
(22)
0.0% 
(49) 
0.0%
Net change in valuation allowance 
 
152,590
(33.2)%
175,388
(52.5)% 
104,951 
(40.7)%
Tax credits 
 
(53,497)
11.6%
(67,131)
20.1% 
(39,729) 
15.4%
Tax rate change 
10,815
(2.4)%
1,023
(0.3)% 
(3,091) 
1.2%
Non-deductible compensation 
1,895
(0.4)%
3,814
(1.1)% 
3,023 
(1.2)%
Other non-deductible items 
188
0.0%
327
(0.1)% 
57 
0.0%
Foreign-derived intangible income benefit 
(21,071)
4.6%
(7,493)
2.2% 
— 
—
Stock-based compensation 
10,732
(2.3)%
19,546
(5.9)% 
14,030 
(5.4)%
Other 
 
665
(0.2)%
(401)
0.1% 
344 
(0.1)%
Effective rate 
$ 
(6,171)
1.3% $
32,321
(9.7)% $
11,737 
(4.5)%
 
Deferred income taxes reflect the net tax effects of temporary differences between the carrying amounts of assets and 
liabilities for financial reporting purposes and the amounts used for income tax purposes. 
 

F-45 
Significant components of our deferred tax assets and liabilities as of December 31, 2024 and 2023 are as follows (in 
thousands): 
 
 
Year Ended December 31, 
 
2024 
  
2023 
Deferred Tax Assets: 
 
 
 
Net operating loss carryovers 
$
95,851
$ 
77,964
Tax credits 
310,703
 
239,962
Deferred revenue 
54,063
 
71,683
Stock-based compensation 
82,660
 
77,468
Intangible and capital assets 
93,541
 
104,380
Convertible debt 
9,310
 
16,849
Capitalized research and development expenses 
323,560
 
238,738
Long-term lease liabilities 
41,481
 
43,718
Sale of future royalties 
148,918
 
144,608
Other 
14,024
 
10,343
Total deferred tax assets 
$
1,174,111
$ 1,025,713
 
 
Deferred Tax Liabilities: 
 
Fixed assets 
(5,719)
 
(4,166)
Right-of-use assets 
(36,788)
 
(42,007)
Other 
(1,896)
 
(1,910)
Net deferred tax asset 
$
1,129,708
$ 
977,630
Valuation allowance 
(1,129,708)
 (977,630)
Total net deferred tax assets and liabilities 
$
—
$ 
—
 
As of December 31, 2024, we maintained a full valuation allowance on our net deferred tax assets. We determined the 
valuation allowance in accordance with the provisions of ASC 740, Accounting for Income Taxes, which requires an assessment of 
both positive and negative evidence when determining whether it is more likely than not that deferred tax assets are realizable. Our 
recent history of cumulative losses and expected near-term future losses require us to record a full valuation allowance against all net 
deferred tax assets. We will maintain a full valuation allowance on net deferred tax assets until sufficient positive evidence exists to 
support reversal of the valuation allowance. 
 
Our valuation allowance increased by $152 million from December 31, 2023 to December 31, 2024. The increase was 
primarily related to increases in our deferred tax assets for capitalized research and development expenses and tax credits. 
 
At December 31, 2024, we had federal and state, primarily California, tax net operating loss carryforwards of $290.2 million 
and $526.9 million, respectively. Our federal tax loss carryforwards are available indefinitely. Our California tax loss carryforwards 
will begin to expire in 2032. At December 31, 2024, we also had federal and California research and development tax credit 
carryforwards of $234.2 million and $137.6 million, respectively. Our federal research and development tax credit carryforwards will 
begin to expire in 2037. Our California research and development tax credit carryforwards are available indefinitely. 
 
Utilization of the net operating loss and tax credit carryforwards may be subject to an annual limitation due to the ownership 
change limitations provided by the Internal Revenue Code of 1986, as amended, and similar state provisions. The annual limitation 
may result in the expiration of net operating losses and credits before utilization. 
 
We analyze filing positions in all U.S. federal, state and foreign jurisdictions where we file income tax returns, and all open 
tax years in these jurisdictions to determine if we have any uncertain tax positions on any of our income tax returns. We recognize the 
impact of an uncertain tax position on an income tax return at the largest amount that the relevant taxing authority is more-likely-than 
not to sustain upon audit. We do not recognize uncertain income tax positions if they have less than 50 percent likelihood of the 
applicable tax authority sustaining our position. 
 

F-46 
The following table summarizes our gross unrecognized tax benefits (in thousands): 
 
 
Year Ended December 31, 
 
2024 
  
2023 
  
2022 
Beginning balance of unrecognized tax benefits 
$ 
43,298
$
56,567
$
55,085
Decrease for lapse of statute of limitations 
(7,579)
(14,993)
—
Decrease for prior period tax positions 
(110)
(737)
(267)
Increase for prior period tax positions 
 
1,902
429
259
Increase for current period tax positions 
 
3,650
2,032
1,490
Ending balance of unrecognized tax benefits 
$ 
41,161
$
43,298
$
56,567
 
Included in the balance of unrecognized tax benefits at December 31, 2024, 2023 and 2022 was $0.3 million, $0.3 million 
and $6.2 million respectively, that if we recognized, could impact our effective tax rate, subject to our remaining valuation allowance.  
 
We do not expect any material changes to our gross unrecognized tax benefits within the next 12 months.  
 
We recognize interest and/or penalties related to income tax matters in income tax expense. During the years ended 
December 31, 2024, 2023 and 2022, we recognized $0.1 million, $0.1 million and $0.8 million, respectively, of accrued interest and 
penalties related to gross unrecognized tax benefits. 
 
We are subject to taxation in the U.S. and various state and foreign jurisdictions. U.S. tax years 2021 through 2023 remain 
open to examination and tax years 2020 through 2023 remain open to examination by major state taxing jurisdictions, primarily 
California, although net operating loss and credit carryforwards generated prior to these periods may still be adjusted upon 
examination by the Internal Revenue Service or state tax authorities if they have been used in an open period or are used in a future 
period. 
 
Accounting guidance for income taxes requires a deferred tax liability to be established for the tax impact of undistributed 
earnings of foreign subsidiaries unless it can be shown that these earnings will be permanently reinvested outside the U.S. If our 
foreign earnings were to be repatriated in the future, the estimated tax liability would be insignificant. 
 
10. Employment Benefits 
 
We have employee 401(k) salary deferral plans covering all employees. Employees could make contributions by withholding 
a percentage of their salary up to the IRS annual limits of $23,000 and $30,500 in 2024 for employees under 50 years old and 
employees 50 years old or over, respectively. We made approximately $8.6 million, $7.1 million and $5.6 million in matching 
contributions for the years ended December 31, 2024, 2023 and 2022, respectively. 
 
11. Legal Proceedings 
 
From time to time, we are involved in legal proceedings arising in the ordinary course of our business. Periodically, we 
evaluate the status of each legal matter and assess our potential financial exposure. If we consider the potential loss from any legal 
proceeding to be probable and we can reasonably estimate the amount, we accrue a liability for the estimated loss. The outcome of any 
proceeding is not determinable in advance. Therefore, we are required to use significant judgment to determine the probability of a 
loss and whether the amount of the loss is reasonably estimable. Our assessment of a potential liability and the amount of accruals we 
recorded are based only on the information available to us at the time. As additional information becomes available, we reassess the 
potential liability related to the legal proceeding and may revise our estimates. 
 
There are no pending material legal proceedings to which we are a party or of which our property is the subject. 
 

F-47 
12. Segment Information 
 
We operate as a single operating segment, Ionis operations, focused on the research, development and commercialization of 
our RNA-targeted medicines to bring better futures to people with serious diseases. As the Chief Operating Decision Maker, or 
CODM, our Chief Executive Officer manages our company, reviews operating results, assesses performance and allocates resources 
on an aggregate basis using consolidated net income or loss as the key measure of segment profit or loss. As such, results of our 
operations are reported on a consolidated basis for purposes of management and segment reporting. 
 
Ionis operations derives its revenues from commercial and R&D revenue sources. Refer to Note 3, Revenues, for further 
details on our sources of revenue. 
 
The following table sets forth information on segment profit or loss, including significant segment expenses (in thousands): 
 
  
Year Ended December 31, 
  
2024 
 
2023 
 
2022 
 
 
 
 
Revenue 
$ 
705,138
$ 
787,647 $ 
587,367
  
 
  
  
Less: 
 
  
  
Cost of sales 
10,415
8,686
13,447
Drug discovery 
114,350
125,649
181,302
Drug development 
527,259
530,332
426,225
Medical affairs 
 
27,229
19,454
15,948
Manufacturing and development chemistry 
57,729
65,293
76,162
R&D support 
82,559
81,019
59,840
Selling, general and administrative 
230,478
205,135
124,370
Other segment items (1) 
 
109,016
118,365
(40,205)
  
 
  
  
Consolidated net loss 
$ (453,897)  $ 
(366,286)  $ 
(269,722)
 
(1) Other segment items include stock-based compensation expense, investment income, interest expense, gain or loss on 
investments, other income or expense and income tax expense or benefit.  
 
13. Fourth Quarter Financial Data (Unaudited) 
 
The following financial information reflects all normal recurring adjustments, which are, in the opinion of management, 
necessary for a fair statement of the results of the interim periods. Summarized fourth quarter data for 2024 and 2023 are as follows 
(in thousands, except per share data). 
 
Three Months Ended December 31,  
 
2024 
  
2023 
Revenue (1) 
$ 
226,577
$ 
324,505
Operating expenses (2) 
$ 
337,398
$ 
330,627
Loss from operations 
$ 
(110,821)
$ 
(6,122)
Net loss 
$ 
(104,349)
$ 
(9,263)
Basic net loss per share (3) (4) 
$ 
(0.66)
$ 
(0.06)
Diluted net loss per share (3) (5) 
$ 
(0.66)
$ 
(0.06)
________________ 
(1) Revenue was lower in the three months ended December 31, 2024 compared to the same period in 2023 primarily due to 
significant partner payments earned in the fourth quarter of 2023, including the $50 million milestone payment we earned from 
AstraZeneca when the FDA approved WAINUA for ATTRv-PN in the U.S., $36 million payment we earned when AstraZeneca 
licensed ION826 and revenue we recognized in the fourth quarter of 2023 from the upfront payments we received from our new 
collaborations with Otsuka, Roche and Novartis. In addition, WAINUA joint development revenue decreased in the three months 
ended December 31, 2024 compared to the same period in 2023 as development activities relating to ATTRv-PN wound down 
with the launch of WAINUA. 
 
(2) Operating expenses were relatively consistent in the three months ended December 31, 2024 compared to the same period in 
2023. 
 
(3) We compute net loss per share independently for each quarter during the year. 

F-48 
 
(4) As discussed in Note 1, Organization and Significant Accounting Policies, we compute basic net loss per share by dividing the 
total net loss by our weighted-average number of common shares outstanding during the period.  
 
(5) We incurred a net loss for the fourth quarter of 2024 and 2023. As a result, we did not include dilutive common equivalent shares 
in the computation of diluted net loss per share because the effect would have been anti-dilutive. 
 

Front cover: Rick, diagnosed with 
Familial Chylomicronemia Syndrome (FCS)
Back cover: Rick and his wife, Kim
Ionis Pharmaceuticals, Inc.
2855 Gazelle Court
Carlsbad, CA 92010
www.ionis.com