UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, DC 20549
FORM 10-K
For the fiscal year ended December 31, 2024
For the transition period from ___________ to ___________
Commission file number 000-19125
Ionis Pharmaceuticals, Inc.
(Exact name of Registrant as specified in its charter)
(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.
________________
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 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;
● 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 6. Reserved 61
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 71
Item 8. Financial Statements and Supplementary Data 71
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 14. Principal Accountant Fees and Services 75
PART IV
Item 15. Exhibits, Financial Statement Schedules 75
Signatures 83
Table of Contents
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
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.
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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.
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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.
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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.
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.
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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.
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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 bepirovirsenin 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.
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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.
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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.
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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.
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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.
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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.
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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.