NASDAQ: IONS

● WAINUA is approved in the U.S., EU, China and
numerous other countries 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 patients with spinal muscular atrophy, or SMA. Our partner,
Biogen, is responsible for commercializing SPINRAZA worldwide.

● QALSODY is approved in the U.S., 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 U.S. Food and Drug Administration, or 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.

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In addition to our currently marketed medicines, we are also positioned to independently launch two medicines in 2026, assuming regulatory approval. The FDA recently granted priority review of olezarsen for the treatment of severe hypertriglyceridemia, or sHTG, with an action date of June 30, 2026 under the Prescription Drug User Fee Act, or PDUFA. We are on track to launch olezarsen following anticipated approval. We also submitted the NDA for zilganersen in January 2026 and plan to launch zilganersen in the second half of 2026 for the treatment of Alexander disease, or AxD. We also have a rich innovative late- and mid-stage pipeline across our focus areas of neurology, cardiometabolic diseases and select areas of high patient needs. We currently have three wholly owned medicines in late-stage development, including obudanersen (formerly ION582) for Angelman syndrome, or AS, which we advanced into a Phase 3 study in the second quarter of 2025. Additionally, we have six partnered medicines in late-stage development. We also have additional medicines in early and mid-stage development. We delivered multiple positive data readouts in the last year from our late- and mid-stage pipeline, including positive data for olezarsen in sHTG, zilganersen in AxD, bepirovirsen in chronic hepatitis B, or CHB, obudanersen in AS and sapablursen in polycythemia vera, or PV. 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.

We earned revenues of $944 million in 2025 and ended 2025 with a cash, cash equivalents and short-term investment balance of $2.7 billion that enables our continued investments to support ongoing and 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 two 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 was also approved in the EU in September 2025 as an adjunct to diet in adult patients for the treatment of genetically confirmed FCS in September 2025. TRYNGOLA was also approved in Canada in December 2025. Our partner, Sobi, is responsible for commercializing TRYNGOLZA in countries outside of the U.S., Canada and China.

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.

TRYNGOLZA 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, a substantial and clinically meaningful reduction in AP events, and a favorable safety and tolerability profile.

Prior to approval, TRYNGOLZA was granted Priority Review, Fast Track, Orphan Drug and Breakthrough Therapy designations for the treatment of FCS.

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.

DAWNZERA (PKK) – DAWNZERA (donidalorsen) is a prekallikrein, or PKK, -directed antisense oligonucleotide indicated for prophylaxis to prevent attacks of hereditary angioedema, or HAE, in adult and pediatric patients 12 years of age and older. PKK plays an important role in the activation of inflammatory mediators associated with acute attacks of HAE and by reducing the production of PKK, DAWNZERA works to prevent HAE attacks. DAWNZERA was approved in the U.S. in August 2025 and in the EU in January 2026. Our partner, Otsuka Pharmaceutical Co., Ltd., or Otsuka, is responsible for commercializing DAWNZERA in Europe and Asia.

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.

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DAWNZERA approval was based on the positive data from the placebo-controlled Phase 3 OASIS-HAE study, the Phase 3 OASISplus study and the Phase 2 study, including an 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 switch cohort to assess patients switching from currently available long-term prophylactic treatments to DAWNZERA. 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 DAWNZERA. Results showed that patients were able to switch to DAWNZERA from prior prophylactic treatment without an increase in breakthrough attacks. Switching to DAWNZERA also reduced mean HAE attack rate and led to continued improvement in quality-of-life measures compared to baseline with prior prophylactic treatment. The majority of patients surveyed reported a preference for DAWNZERA over their previous treatment. In all of these studies, DAWNZERA demonstrated a favorable safety and tolerability profile.

The FDA and EMA granted Orphan Drug designation to DAWNZERA.

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 in the EU in March 2025. WAINUA is also approved in other markets, including the UK, Canada and China, 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.

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. Higher dose SPINRAZA was approved in EU and Japan in 2025 and is currently under review in the U.S. with a PDUFA action date of April 3, 2026. 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.

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SPINRAZA approval 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 open-label extension, or 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 that 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 EU and Japan approvals and the regulatory submission in the U.S., which has an action date of April 23, 2026.

QALSODY (SOD1) – QALSODY (tofersen) injection for intrathecal use is an antisense medicine indicated for the treatment of ALS, in adults who have SOD1-ALS. QALSODY inhibits the production of SOD1 protein. QALSODY was granted accelerated approval in April 2023 based on reduction in plasma neurofilament light chain protein, 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 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 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.

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.

TEGSEDI approvals were based on efficacy and safety data from the Phase 3 NEURO-TTR study in patients with ATTRv-PN.

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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.

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Ionis is commercializing TRYNGOLZA (olezarsen) for the treatment of FCS in the U.S. Sobi is responsible for commercializing olezarsen in countries outside of the U.S., Canada and China and Theratechnologies is responsible for commercializing olezarsen 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 risk of potentially life-threatening acute pancreatitis, or AP, (a painful inflammation of the pancreas) and atherosclerotic cardiovascular disease, or ASCVD. Reducing the risk of pancreatitis is a critically important reason to treat sHTG. Olezarsen is currently under review by the FDA. The agency has granted olezarsen priority review and set a PDUFA action date of June 30, 2026.

Our regulatory submission is based on the positive data from the broad development program for olezarsen that includes three Phase 3 studies supporting development for the treatment of sHTG: CORE, CORE2 and ESSENCE. The CORE and CORE2 studies met the primary endpoint across doses, with olezarsen demonstrating an up to 72% (p<0.001) placebo-adjusted mean reduction in fasting triglyceride levels at six months. The reductions were sustained through 12 months. Additionally at 12 months, 86% of olezarsen-treated patients achieved triglyceride levels less than 500 mg/dL, below the risk threshold for acute pancreatitis. Olezarsen also demonstrated a highly statistically significant 85% reduction in adjudicated acute pancreatitis events at 12 months (p<0.001). These results were based on a total of 22 events in 17 patients in the placebo group, compared to seven events in five patients in the olezarsen group. In an overall pooled analysis of the number of patients needed to treat, NNT, treating 20 patients with olezarsen is estimated to prevent one acute pancreatitis event over one year. In the highest risk group, patients with triglyceride levels greater than or equal to 880 mg/dL and a history of acute pancreatitis, treating four patients is estimated to prevent one event over one year. Olezarsen demonstrated favorable safety and tolerability at both dose levels in the studies.

The FDA granted Breakthrough Therapy designation to olezarsen as an adjunct to diet to reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia.

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As discussed above under “TRYNGOLZA” in the section titled, Our Marketed Medicines – Bringing Value to Patients Today, olezarsen is approved for the treatment of FCS.

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 often 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 the symptoms of AxD. In January 2026, we submitted the zilganersen New Drug Application, or NDA, to the U.S. FDA. Additionally, we established an expanded access program, or EAP, for zilganersen in the U.S. for individuals aged two and older living with AxD, subject to certain inclusion and exclusion criteria.

Our regulatory submission of zilganersen is based on the positive data from the pivotal Phase 1-3 study we conducted in patients with AxD. Zilganersen 50 mg demonstrated statistically significant and clinically meaningful stabilization on the primary endpoint of gait speed as assessed by the 10-Meter Walk Test, or 10MWT, compared to control at week 61 (mean difference 33.3%, p=0.0412). Zilganersen also demonstrated consistent benefit in key secondary endpoints. In addition to achieving the primary endpoint, zilganersen demonstrated consistent favorable trends across key secondary endpoints, indicating evidence of slowed disease progression, stabilization or improvement. Key secondary endpoints include change from baseline in patients' self-identified Most Bothersome Symptom, or MBS, Score, Patient Global Impression of Severity, or PGIS, Score, Patient Global Impression of Change, or PGIC, Score and Clinician Global Impression of Change, or CGIC, Score. Zilganersen demonstrated favorable safety and tolerability in the study.

The FDA and EMA granted Orphan Drug designation to zilganersen. Additionally, the FDA granted Breakthrough Therapy, Fast Track and Rare Pediatric designations to zilganersen.

Obudanersen (UBE3A) – Obudanersen (formerly 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.

We are conducting the ongoing placebo-controlled Phase 3 REVEAL study of obudanersen designed to assess the efficacy, safety and tolerability of obudanersen administered intrathecally in children and adults with AS who have a maternal UBE3A gene deletion or mutation. We are also conducting the ongoing open label Phase 1/2 study, HALOS, of obudanersen in patients with AS. In 2024, we presented positive results from the completed multiple ascending dose, or MAD, portion of the HALOS study in people with AS demonstrating consistent and encouraging clinical improvement on measures assessing all functional domains including communication, cognition and motor function. Obudanersen showed favorable safety and tolerability at all dose levels in the study. In 2025, we also presented positive 12- and 18-month long-term extension data from the HALOS study, which supports continued development.

The FDA and EMA granted Orphan Drug designations to obudanersen. Additionally, the FDA granted Breakthrough Therapy, Fast Track and Rare Pediatric designations to obudanersen.

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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.

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 that can lead to CHB, potentially allowing a person’s immune system to regain control. Bepirovirsen inhibits the replication of viral DNA in the body, suppresses the level of hepatitis B surface antigen, or HBsAg, in the blood and stimulates the immune system to increase the chances of a durable and sustained response. CHB is a viral infection that can cause both acute and chronic liver disease. CHB occurs when the immune system is unable to clear the virus, resulting in long-lasting infection. It affects more than 250 million people and causes approximately 1.1 million deaths each year, largely due to complications such as cirrhosis and liver cancer. Many patients often require lifelong antiviral therapy for viral suppression; making functional cure a critical goal in disease management. Our partner, GSK, is responsible for ongoing development and commercialization of bepirovirsen worldwide.

In January 2026, we and GSK announced positive topline results from the B-Well 1 and B-Well 2 pivotal Phase 3 studies of bepirovirsen in patients with CHB. The B-Well studies met their primary endpoint of a statistically significant and clinically meaningful functional cure rate. Functional cure rates were significantly higher with bepirovirsen plus standard of care compared with standard of care alone. Results were statistically significant across all ranked endpoints, including in patients with baseline surface antigen (HBsAg) ≤1000 IU/ml where an even greater effect was demonstrated. The studies demonstrated an acceptable safety and tolerability profile consistent with what was reported in other studies.

The FDA, Center for Drug Evaluation, or CDE, of National Medical Products Administration, or NMPA, of China and Japanese Ministry of Health, Labour and Welfare, or MHLW, granted bepirovirsen Fast Track designation, Breakthrough Therapy designation and SENKU (formerly known as SAKIGAKE) designation, respectively, for the treatment of patients with CHB.

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 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 CDE of NMPA of China granted pelacarsen Fast Track designation and Breakthrough Therapy, respectively, for the treatment of patients with elevated Lp(a) and established CVD.

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, Hoffmann-La Roche Inc. and F. Hoffmann-La Roche Ltd, collectively 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.

Tofersen (SOD1) – As discussed above under “QALSODY” in the section titled, Our Marketed Medicines – Bringing Value to Patients Today, tofersen is being evaluated for treatment of presymptomatic individuals who have a SOD1 genetic mutation

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 the Phase 3 FUSION 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. The FDA also granted Fast Track designation to ulefnersen.

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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

We have a rich history of discovering and developing life-changing medicines that target RNA – a molecule that carries out the genetic instructions encoded in people's DNA. Today, we are focused on harnessing advanced technology to create medicines that target and interact with both RNA and DNA to treat a variety of conditions, including prevalent cardiometabolic diseases, neurological conditions and rare diseases with few or no effective treatment options. 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.

Overview of Ionis’ Technology

The advanced technology behind our medicines leverages oligonucleotides – small sequences of modified RNA – to precisely target and interact with RNA and DNA. We achieve this precision by tapping into the same biology used to store and process information in the genetic code – our genes. Our technology enables us to change the function or expression of a gene in a highly specific and directed manner, which, in turn, can help address the root cause of a disease.

For example, a gene called TTR contains instructions to make TTR protein, which can accumulate in tissues and cause disease. We have designed eplontersen, an RNA medicine that seeks out, binds to and destroys TTR RNA, which significantly reduces the levels of the disease-causing TTR protein. Our technology can also increase or change the expression of a gene. For example, in SMA we have mitigated the deficiency in a critical protein called SMN with a medicine that changes the “instructions” in RNA. This modulation enabled the production of the SMN protein, thereby counteracting the root, genetic cause of the disease.

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 MsPA backbone chemistry, Bicycle technology and Vect-Horus technology. And we now have 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.

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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). Our first program utilizing Bicycle technology, ION826 (AZD4063), is being advanced by AstraZeneca and is currently in Phase 1 development.

Vect-Horus License Agreement

In 2023, we exclusively licensed Vect-Horus’ platform technology for systemic delivery of RNA-targeted therapeutics to potentially cross the blood-brain barrier and address targets in the central nervous system for a specified number of targets. This technology is derived from antibodies made by certain camelid species, which are smaller than normal human antibodies. We advanced our first program that utilizes this technology into preclinical development in 2025.

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.

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, Ono, Otsuka and Roche. Through our partnerships, we have earned both commercial revenue in the form of royalties and sales milestones and a broad and sustaining base of R&D revenue in the form of license fees, upfront payments and milestone payments. 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 approved eplontersen with the brand name, WAINUA, for ATTRv-PN, while the EC approved WAINUA for ATTRv-PN in the EU as WAINZUA. WAINUA is also approved in other markets, including the UK, Canada and China, with additional regulatory reviews underway. 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. From inception through December 31, 2025, AstraZeneca was responsible for 55 percent of the costs associated with the ongoing global Phase 3 development program. After December 31, 2025, AstraZeneca is responsible for 75 percent and 87.5 percent of development costs in the U.S. and the rest of the world, respectively. 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.

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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.

We recognize royalties that we earn from WAINUA sales within commercial revenue in our consolidated statements of operations.

From inception through December 31, 2025, we have generated more than $615 million in payments under this collaboration, including regulatory milestone payments and 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, 2025, we have generated more than $420 million in payments under this collaboration.

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, 2025, we recognized more than $2.5 billion in total revenue under this collaboration, including more than $2.0 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, 2025, we recognized more than $120 million in total revenue under this collaboration, including approximately $14 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 salanersen (formerly ION306). Biogen is solely responsible for the costs and expenses related to the development, manufacturing and potential future commercialization of salanersen. We will receive development and regulatory milestone payments from Biogen if salanersen advances 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, 2025, we have generated $85 million in payments under this collaboration.

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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, 2025, 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.

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 ranging from 10 to 12 percent on net sales of bepirovirsen. From inception through December 31, 2025, 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 cardiovascular disease, or 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, 2025, 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 CVD. In 2025, Novartis terminated this collaboration and license agreement. Prior to this, Novartis was solely responsible for the development, manufacturing and potential commercialization of the next generation Lp(a) medicine. From inception through December 31, 2025, we have generated more than $65 million in payments under this collaboration.

Ono

In March 2025, we entered
into an agreement with Ono Pharmaceutical Co., Ltd., or Ono, to develop and
commercialize sapablursen, an investigational RNA-targeted medicine for the
potential treatment of polycythemia vera, a rare and potentially life-threatening
hematologic disease. We are responsible for completing the Phase 2
IMPRSSION study of sapablursen, including the ongoing extension period. Ono is solely responsible for subsequent
development, regulatory filings and commercialization of sapablursen.

Over the term of the collaboration, we are eligible to receive an upfront payment, development milestone payments, regulatory milestone payments and sales milestone payments. We are also eligible to receive royalties in the mid-teen percentage range on net sales. From inception through December 31, 2025, we have generated more than $285 million in payments under this collaboration.

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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, 2025, we have generated approximately $140 million in payments under this collaboration.

Huntington’s Disease

In 2013, we entered into an agreement with 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.

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, 2025, 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 if they receive regulatory approval.

In January 2026, Roche initiated a Phase 1 trial for an investigational medicine for the treatment of AD.

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, 2025, we have generated more than $65 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 DAWNZERA in Europe. In the second quarter of 2024, we expanded the agreement to include commercialization rights for DAWNZERA in the Asia-Pacific region. We are responsible for the ongoing development of DAWNZERA.

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, 2025, we have generated more than $125 million in payments under these collaborations.

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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, 2025, we have generated more than $70 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. In March 2025, we entered into an agreement with Sobi to commercialize TRYNGOLZA in countries outside of the U.S., Canada and China. From inception through December 31, 2025, we have generated more than $145 million in payments under this collaboration.

Theratechnologies

In December 2024, we entered into an agreement with Theratechnologies, Inc. to commercialize DAWNZERA and olezarsen in Canada. We are responsible for the ongoing development of DAWNZERA and olezarsen.

Technology Enhancement Collaborations

Bicycle Therapeutics

In 2020, we entered into a collaboration agreement with Bicycle Therapeutics 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' technology 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, each party licensed to the other party its early patent estate relating to oligonucleotide chemistry for specified uses (generally, single-stranded ASOs for us and siRNA for Alnylam). Additionally, in 2015, we and Alnylam entered into an alliance in which we exclusively cross-licensed 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.

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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 yields and process efficiencies, 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.

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 October 2031. 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 ourselves and Sobi. 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 approved indications.

DAWNZERA

For DAWNZERA’s commercial drug supply, we are using CMOs to produce API and finished goods for ourselves and Otsuka. 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 maintaining adequate levels of safety stock.

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.

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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 Sobi and PTC. For WAYLIVRA’s commercial drug supply, we are using API that we have manufactured and CMOs to produce the finished goods.

Zilganersen

We and our CMOs have supplied the API and the finished drug product for zilganersen clinical supply. We intend to use the same supply chain for future commercial drug supply.

Ulefnersen

We and our CMOs have supplied the API and the finished drug product for ulefnersen that we believe will be sufficient through the completion of the Phase 3 programs. Our partner, Otsuka, will be responsible for future commercial drug supply.

Obudanersen

We supplied API and drug product for the obudanersen Phase 1 and Phase 2 programs and intend to continue to supply drug for the ongoing Phase 3 program and any 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 launches of TRYNGOLZA, DAWNZERA and WAINUA in the U.S. 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.

We entered a new chapter as a fully integrated commercial-stage biotechnology company with our first independent commercial launch of TRYNGOLZA in December 2024. We have continued 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, DAWNZERA and olezarsen (sHTG) field sales team and plan to build additional field teams as we approach each of our launches.

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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.

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. Patent applications to protect TRYNGOLZA in other jurisdictions have been granted or are being pursued. The table below lists some key issued patents protecting TRYNGOLZA 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 TRYNGOLZA

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

United States

12,509,684

COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION

2034

Methods of treating FCS or hypertriglyceridemia by administering TRYNGOLZA

Europe

2991656

COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN C-III EXPRESSION

2034

Composition of TRYNGOLZA

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 TRYNGOLZA at identified doses

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Trademark

The name “TRYNGOLZA” is protected by trademarks throughout the world.

DAWNZERA and PKK

We believe DAWNZERA is protected from generic competition in the U.S. and Europe until at least 2035. Patent applications to protect DAWNZERA in other jurisdictions have been granted or are being pursued. The table below lists some key issued patents protecting DAWNZERA 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 DAWNZERA

Europe

3137091

COMPOSITIONS AND METHODS FOR MODULATING PKK EXPRESSION

2035

Composition of DAWNZERA

Trademark

The name "DAWNZERA" 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. Patent applications to protect WAINUA/WAINZUA in other 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 WAINUA

Europe

3524680

COMPOSITIONS AND METHODS FOR MODULATING TTR EXPRESSION

2034

Composition of WAINUA

Trademarks

The names “WAINUA” and “WAINZUA” are protected by trademarks owned by our commercial partner Astra Zeneca.

21

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

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

Trademarks

The name “SPINRAZA” is protected throughout the world by trademarks owned by our commercial partner Biogen.

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QALSODY and SOD-1

Patents

We believe QALSODY is protected from generic competition in the U.S. and Europe until at least 2035. Patent applications to protect QALSODY in other jurisdictions have been granted or 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

8,697,860

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.

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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

Zilganersen and GFAP

We believe zilganersen is protected from generic competition in the U.S. and Europe until at least 2041. The table below lists key issued patents protecting zilganersen in the U.S. and Europe:

Jurisdiction

Patent No.

Title

Expiration

Description of Claims

United States

11,786,546

COMPOUNDS AND METHODS FOR MODULATING GFAP

2041

Composition of zilganersen

Europe

3956450

COMPOUNDS AND METHODS FOR MODULATING GFAP

2040

Composition of zilganersen

Obudanersen and UBE3A

We believe obudanersen is protected from generic competition in the U.S. and Europe until at least 2040. Patent applications to protect obudanersen in other jurisdictions have been granted or are being pursued. The table below lists key issued patents protecting obudanersen 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 obudanersen

Europe

3947684

COMPOUNDS AND METHODS FOR MODULATING UBE3A-ATS

2040

Composition of obudanersen

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

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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. Patent applications to protect bepirovirsen in other jurisdictions have been granted for are 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

Pelacarsen and Apo(a)

We believe pelacarsen is protected from generic competition in the U.S. and Europe until at least 2034. Patent applications to protect pelacarsen in other jurisdictions have been granted or are 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

United States

12,291,709

COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION

2034

Methods of administering pelacarsen

Europe

2992009

COMPOSITIONS AND METHODS FOR MODULATING APOLIPOPROTEIN (a) EXPRESSION

2034

Composition of pelacarsen

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Sefaxersen and Factor B

We believe sefaxersen is protected from generic competition in the U.S. and Europe until at least 2035. Patent applications to protect sefaxersen in other jurisdictions are 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

We believe ulefnersen will be protected from generic competition in the U.S. and Europe until at least 2040. The table below lists a key pending patent application designed to protect ulefnersen in the U.S. and a key issued patent protecting ulefnersen in 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

3976791

COMPOUNDS AND METHODS FOR REDUCING FUS EXPRESSION

2040

Composition of ulefnersen

Platform IP

In addition to the IP that provides exclusivity for specific products, we also pursue IP that provides exclusivity for our core technology 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.

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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

27

LIgand-Conjugated Antisense (LICA) Technology

We also have patent claims to chemistries created to enhance targeting of antisense medicines to specific tissues and cells to improve a drug’s properties. We designed our GalNAc LIgand-Conjugated Antisense, or 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.

The FDA must approve any new medicine or new indication before a manufacturer can market it in the U.S. To obtain approval, we and our partners must complete clinical studies and prepare and submit an NDA or supplemental NDA to the FDA. When 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.

28

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.

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. For example, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act of 2010, or collectively the Affordable Care Act, substantially changed the way healthcare is financed by both governmental and private insurers and continues to significantly impact the U.S. pharmaceutical industry. Since its enactment, there have been amendments and judicial, Congressional and executive branch challenges to certain aspects of the Affordable Care Act, as well as efforts to repeal or replace certain aspects of the Affordable Care Act. We expect that additional U.S. federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that the U.S. federal government will pay for healthcare products and services, which could result in reduced demand or revenue for our commercial medicines and our medicines in development.

29

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 the U.S. Department of Health and Human Services, or 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, or CMS. The IRA, among other things, (1) directed 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) imposed rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation. Each year, up to 20 products will be selected by HHS for the Medicare Drug Price Negotiation Program. Products subject to the Medicare Drug Price Negotiation Program are expected to experience a significant reduction in reimbursement from the Medicare program on a per unit basis.

The current U.S. Presidential administration is pursuing policies to reduce regulations and expenditures across government agencies, including at HHS, the FDA, CMS, and other related agencies, with a particular focus on most favored nation pricing equal to or lower than those paid in other developed nations. These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose additional policy changes that create uncertainty for our business. For example, in furtherance of the administration’s drug pricing initiatives, in December 2025, CMS issued proposed rules that, if finalized, would implement new mandatory and voluntary payment models to implement a most favored nation rebate model. These models are referred to as the GLOBE Model, GUARD Model and GENEROUS Model. At this time, it remains unclear whether the proposed models will be finalized and, if so, whether any changes will be made prior to their implementation.

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.

Other Healthcare Laws

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.

Numerous regulatory authorities in addition to the FDA, including, in the U.S., CMS, 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’ pre-approval communications and 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.

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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. Moreover, healthcare reform legislation has strengthened certain of these laws. For example, the 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 federal 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, civil and administrative 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.

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 imposes requirements relating to the privacy,
security and transmission of individually identifiable health information on
certain health care providers, health care clearinghouses, and health plans,
known as covered entities, and their covered subcontractors, known as business
associates;

● HIPAA also created additional federal criminal statutes that prohibit,
among other actions, knowingly and willfully executing, or attempting to
execute, a scheme to defraud any healthcare benefit program, including private
third-party payers and knowingly and willfully falsifying, concealing or
covering up a material fact or making any materially false, fictitious or
fraudulent statement in connection with the delivery of or payment for
healthcare benefits, items or services;

● 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;

● The Physician Payments Sunshine Act, which requires certain
manufacturers of medicines, devices, biologics, and medical supplies to report
annually to CMS 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; and

● Foreign laws requiring reporting on transfers of value to physicians,
which may differ from those in the U.S.

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.

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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, which may impact these laws. Further, such laws may be subject to future amendments, updated guidance or varying interpretations.

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 contract 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.

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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)

Redemplo

(Plozasiran)

Arrowhead Pharmaceuticals

Targets APOCIII by utilizing Targeted RNAi Molecule Platform

Approved in U.S. for FCS,

under review in the EU for FCS, Phase 3 sHTG

Subcutaneous Injection

Pegozafermin

Roche

FGF21 analog

Phase 3 sHTG

Subcutaneous Injection

NST-1024

NorthSea Therapeutics

CETP Inhibitor

Phase 2 sHTG

Oral

Solbinsiran

Eli Lilly

ANGPTL3 inhibitor; siRNA

Phase 2 sHTG

Subcutaneous Injection

(1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.

DAWNZERA

We believe that the following medicines could compete with DAWNZERA 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

Andembry (Garadacimab)

CSL Behring

An anti-factor XIIa monoclonal antibody

Approved for HAE patients 12 years and older

Subcutaneous Injection

Haegarda (C1 esterase inhibitor)

CSL Behring

C1 esterase inhibitor

Approved for HAE patients 6 years and older

Subcutaneous Injection

Deucrictibant

Pharvaris

An oral B2-receptor antagonist

Phase 3

Oral

Lonvoguranziclumeran (lonvo-z)

(NTLA-2002)

Intellia

CRISPR therapeutic candidate designed to inactivate the kallikrein B1 gene

Phase 3

Intravenous Infusion

STAR-0215 (Navenibart)

Astria/BioCryst

A monoclonal antibody inhibitor of plasma kallikrein

Phase3

Subcutaneous Injection

ADX-324

ADARx

An siRNA designed to reduce the product of PKK

Phase 3

Subcutaneous Injection

BW-20805

Argo

An siRNA designed to reduce the product of PKK

Phase 2

Subcutaneous Injection

(1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.

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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 U.S., 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 U.S.); ATTR-CM approved in the U.S., EU and other geographies

Oral

Amvuttra

(Vutrisiran)

Alnylam

An RNAi medicine conjugated with GalNAc to inhibit TTR mRNA

Approved for ATTRv-PN and ATTR-CM in the U.S., EU and Japan

Subcutaneous Injection

Attruby (Acoramidis)

BridgeBio

Small molecule that binds and stabilizes TTR in the blood

Approved in U.S., EU and Japan for ATTR-CM

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

Cliramitug (ALXN2220)

AstraZeneca

A monoclonal IgG1 which acts by depleting TTR protein

Phase 3 ATTR-CM

Intravenous Infusion

Coramitug (NNC6019-0001)

Novo Nordisk

A monoclonal antibody to deplete amyloid

Phase 3 ATTR-CM

Intravenous Infusion

Nucresiran

Alnylam

Third generation RNAi TTR therapy

Phase 3 ATTR-CM

Subcutaneous Injection

(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

Itvisma
(Onasemnogene abeparvovec)

Novartis

Gene therapy targeting the genetic root cause of SMA by replacing the missing or nonworking SMN1 gene

Approved for SMA in pediatric and adult patients

Intrathecal Injection

(1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.

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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)

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

Zilganersen

We are not aware of any medicines in clinical development for AxD other than zilganersen.

Obudanersen

We believe that the following medicines could compete with obudanersen in Angelman syndrome:

Medicine

Company

Medicine Description(1)

Phase(1)

Route of Administration(1)

Apazunersen (GTX-102)

Ultragenyx

An ASO designed to inhibit expression of UBE3A-ATS

Phase 3

Intrathecal

Rugonersen

Oak Hill Bio / Roche

A locked nucleic acid that targets UBE3A gene

Phase 3

Intrathecal

Alogabat

Roche

A small molecule that is GABA A alpha 5 receptor modulator

Phase 2

Oral

NNZ-2591

Neuren

A small molecule, cGP analog, that targets IGF-1

Phase 2

Oral

MVX-220

MavriX Bio

Hu68AAV gene therapy designed to deliver the human UBE3A gene to neurons

Phase 1/2

Intra Cisterna Magna Injection

(1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.

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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

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

Pevifoscorvir sodium (ALG-000184)

Aligos

Capsid assembly modulator (CAM-E)

Phase 2

Oral

AHB-137

AusperBio

Antisense oligonucleotide targeting HBV RNA

Phase 3 (China)

Subcutaneous 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

Eli Lilly

RNAi therapeutic designed to lower Lp(a)

Phase 3

Subcutaneous Injection

Muvalaplin

Eli Lilly

Small molecule therapy to lower Lp(a)

Phase 3

Oral

DII235

Argo Biopharmaceutical

RNAi therapeutic designed to lower Lp(a)

Phase 3 ready

Subcutaneous Injection

Zerlasiran

Silence

RNAi therapeutic designed to lower Lp(a)

Phase 2

Subcutaneous Injection

Obicetrapib

NewAmsterdam Pharma

CETP inhibitor

Phase 2

Oral

(1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.

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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 to slow kidney-function decline in adults with IgAN

Oral

Filspari (Sparsentan)

Travere

An endothelin & angiotensin II receptor antagonist to reduce proteinuria in adults with primary IgAN

Approved to slow kidney-function decline in adults with IgAN

Oral

Fabhalta

(Iptacopan)

Novartis (Chinook)

A factor B inhibitor of the alternative complement pathway

Approved to reduce proteinuria in adults with IgAN

Oral

Vanrafia (Atrasentan)

Novartis (Chinook)

An endothelin A receptor antagonist

Approved to reduce proteinuria in adults with IgAN

Oral

Voyxact (Sibeprenlimab)

Otsuka (Visterra)

A humanized IgG2 monoclonal antibody that inhibits APRIL

Approved to reduce proteinuria in adults with IgAN

Subcutaneous Injection

Zigakibart

Novartis (Chinook)

An anti-APRIL monoclonal antibody

Phase 3 (IgAN)

Subcutaneous Injection

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

Vertex (Alpine)

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

Felzartamab

Biogen (Hi-Bio)

A monoclonal antibody directed against CD38

Phase 3 (IgAN)

Intravenous Infusion

Mezagitamab

Takeda

anti-CD38 IgG1 monoclonal antibody

Phase 3

Subcutaneous Injection

WAL0921

Walden Biosciences

uPAR antagonist monoclonal antibody

Phase 2

Intravenous Infusion

(1) Taken from public documents including respective company press releases, company presentations, and scientific presentations.

Ulefnersen

We are not aware of any medicines in clinical development for FUS-ALS other than ulefnersen.

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 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 2025, we reported progress on our CR goals aligned to the three strategic CR pillars that we believe are most important to our business:

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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 continue to share progress on our CR goals and more details on our initiatives in our 2025 CR Report, which we expect to publish in April 2026 and will be 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 19, 2026, we employed 1,402 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 2025 was 7 percent, while the turnover for life sciences and medical device companies over this period was 20 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.

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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.

Our 2025 pay equity analysis confirmed that compensation for employees performing the same or similar work shows no statistically significant differences based on 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.

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