IONIS PHARMACEUTICALS INC

For three decades, we have invented medicines that bring better futures to people with serious diseases. As a pioneer in RNA-targeted medicines with a deep understanding of disease biology and an industry-leading drug discovery technology, we are driven to deliver innovative, life-changing advances for patients.

With multiple independent commercial launches now underway, we have transitioned into a fully integrated commercial-stage biotechnology company. We currently have nine marketed medicines to treat serious diseases, which include three Ionis-owned medicines: TRYNGOLZA (olezarsen), DAWNZERA (donidalorsen) and ZANVASTRO (zilganersen), and six partnered medicines: HIBSAGO (bepirovirsen), WAINUA (eplontersen), SPINRAZA (nusinersen), QALSODY (tofersen), TEGSEDI (inotersen) and WAYLIVRA (volanesorsen). Following approval by the U.S. Food and Drug Administration, or FDA, in June 2026, we independently launched TRYNGOLZA for the treatment of severe hypertriglyceridemia, or sHTG. In addition, we independently launched ZANVASTRO for the treatment of Alexander disease, or AxD, after receiving FDA approval in September 2026. Our partner, GSK, launched HIBSAGO for the treatment of chronic hepatitis B, or CHB, in Japan after receiving approval from the Ministry of Health, Labour and Welfare, or MHLW, in August 2026. HIBSAGO also received FDA approval in October 2026. We also have a rich innovative pipeline across our focus areas of neurology, cardiometabolic diseases and select areas of high patient needs. We currently have multiple medicines advancing in Phase 3 development, including obudanersen for Angelman syndrome, or AS, which is wholly owned and recently completed enrollment. In addition, our partnered medicines, ulefnersen and sefaxersen, recently delivered positive Phase 3 results. We also have additional medicines in early and mid-stage development.

Our multiple sources of revenue and solid financial foundation enable 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 by the end of 2027, position us well to help millions of patients with serious diseases and deliver increasing product and royalty revenue.

Our Marketed Medicines

TRYNGOLZA is a once monthly, self-administered RNA-targeted medicine approved in the United States, or U.S., asan adjunct to diet to reduce triglycerides and the risk of acute pancreatitis in adults with sHTG and asan adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome, or FCS. TRYNGOLZA is the first and only treatment approved by the FDA that significantly and substantially reduces triglyceride levels in adults with sHTG and provides a clinically meaningful reduction in acute pancreatitis, or AP, events. TRYNGOLZA is also approved in the European Union, or EU, Canada and the United Kingdom, or UK, as an adjunct to diet in adult patients for the treatment of genetically confirmed FCS. TRYNGOLZA is the first medicine we began commercializing independently in the U.S. Sobi has exclusive rights to commercialize TRYNGOLZA in countries outside of the U.S., Canada and China.

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DAWNZERA is an RNA-targeted medicine approved in the U.S. for prophylaxis to prevent attacks ofhereditary angioedema, or HAE, in adult and pediatric patients 12 years of age and older. DAWNZERA is the first and only FDA-approved RNA-targeted prophylactic therapy for HAE. DAWNZERA is also approved in the EU, UK and Canada for the routine prevention of recurrent attacks of HAE in the same age group. DAWNZERA is self-administered via subcutaneous autoinjector once every four or eight weeks. DAWNZERA has the potential to offer durable efficacy, a favorable safety and tolerability profile, and the longest available dosing interval. DAWNZERA is the second medicine we are commercializing independently in the U.S. We licensed commercialization rights for DAWNZERA in Europe and the Asia-Pacific region to Otsuka Pharmaceutical Co., Ltd., or Otsuka.

ZANVASTRO is an RNA-targeted medicine approved in the U.S. for the treatment of AxD in pediatric and adult patients. It is administered intrathecally every three months. ZANVASTRO is the first and only FDA-approved disease modifying treatment for AxD. ZANVASTRO is the third medicine we are commercializing independently in the U.S. We licensed commercialization rights for ZANVASTRO in countries outside of the U.S. to Recordati. ZANVASTRO was granted Orphan Drug designation from the European Medicines Agency, or EMA.

SPINRAZA is an antisense medicine for the treatment of patients with spinal muscular atrophy, or SMA, a progressive, debilitating and often fatal genetic disease. Higher dose SPINRAZA was approved and launched in the U.S., EU and Japan for the treatment of SMA. Higher dose SPINRAZA is also approved in the UK and Switzerland. Our partner, Biogen, is responsible for commercializing SPINRAZA worldwide.

HIBSAGO (bepirovirsen) is an RNA-targeted medicine approved in the U.S. and Japan for CHB virus infection in adult patients without cirrhosis receiving nucleos(t)ide analogue therapy and with hepatitis B virus, or HBV, surface antigen, or HBsAg, levels ≤3000 IU/ml as determined by an FDA-authorized test. It is a six-month finite treatment that can be administered at-home after the first dose. HIBSAGO offers unprecedented functional cure rates compared to current standard of care. Our partner, GSK, is responsible for commercializing HIBSAGO worldwide.

WAINUA (WAINZUA in Europe) is a once monthly, self-administered subcutaneous RNA-targeted medicine that is approved in numerous countries, including the U.S., EU, UK, Canada and China, for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis, or ATTRv-PN, a debilitating, progressive, and fatal disease. In January 2024, we and AstraZeneca launched WAINUA in the U.S. for the treatment of adults with ATTRv-PN. The launch of WAINUA is underway in numerous countries, including the countries in the EU, following the approval by the European Commission, or EC, in March 2025. AstraZeneca is our commercialization partner for WAINUA.

QALSODY is an antisense medicine that received accelerated approval from the FDA in April 2023 and marketing authorization under exceptional circumstances from the EMA in May 2024 for the treatment of adult patients with superoxide dismutase 1 amyotrophic lateral sclerosis, or SOD1-ALS, a rare, neurodegenerative disorder that causes progressive loss of motor neurons leading to death. QALSODY was the first treatment approved to target a genetic cause of ALS. Our partner, Biogen, is responsible for commercializing QALSODY worldwide. Biogen is also evaluating QALSODY as a potential treatment for presymptomatic SOD1-ALS patients in the ongoing ATLAS study. QALSODY was granted Orphan Drug designation by the FDA and EMA.

TEGSEDI is a once weekly, self-administered subcutaneous medicine approved in Europe and Brazil for the treatment of patients with ATTRv-PN. We currently sell TEGSEDI in Europe through our distribution agreement with Swedish Orphan Biovitrum AB, or Sobi. 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 a once weekly, self-administered, subcutaneous medicine approved in Europe and Brazil as an adjunct to diet in adult patients with genetically confirmed FCS and at high risk for pancreatitis. 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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Our Innovative Late-Stage Pipeline of Investigational Medicines

Obudanersen is our wholly owned medicine in development for AS. In July 2026, we completed enrollment of the Phase 3 study, REVEAL, which we designed to evaluate the efficacy and safety of obudanersen. In September 2026, we initiated the Phase 3 CHAMPION study in patients with AS due to paternal uniparental disomy or imprinting center defects. In addition, we are continuing to conduct the open label Phase 1/2 study, HALOS, of obudanersen in patients with AS designed to assess the safety, tolerability and activity of multiple ascending doses of obudanersen administered intrathecally. In 2025, we 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 designation to obudanersen. Additionally, the FDA granted Breakthrough Therapy, Fast Track and Rare Pediatric designations to obudanersen.

Eplontersen is our medicine in development to treat patients with transthyretin amyloidosis cardiomyopathy, or ATTR-CM. In July 2026, we and AstraZeneca announced that the CARDIO-TTRansform trial for eplontersen in patients with ATTR-CM missed the primary efficacy endpoint of the composite outcome of cardiovascular, or CV, mortality and recurrent CV clinical events up to Week 140 compared with placebo. In this contemporary patient population treated with standard of care, including a majority on a stabilizer, adding eplontersen did not provide a statistically significant benefit. AstraZeneca shared the results with the scientific community at the European Society of Cardiology, or ESC, Congress in August 2026 andis continuing to analyze the full data set.

Pelacarsen is our medicine in development to treat patients with elevated lipoprotein(a)-driven cardiovascular disease, or Lp(a)-driven CVD. In September 2026, Novartis announced that the pelacarsen Phase 3 Lp(a)HORIZON study did not meet its primary endpoint of reducing the risk of cardiovascular events compared to placebo. The full Lp(a)HORIZON data will be presented at the American Heart Association, or AHA, conference in November 2026.

Salanersen is our medicine in development for SMA. In the second quarter of 2026, Biogen advanced salanersen into Phase 3 development in patients with SMA and the FDA granted Breakthrough Therapy designation to salanersen based on positive interim Phase 1 results. Salanersen has also received Orphan Drug designation for the treatment of SMA.

Sapablursen is our medicine in development for polycythemia vera, or PV. In the second quarter of 2026, Ono advanced sapablursen into Phase 3 development in patients with PV. Sapablursen has received FDA Fast Track, Orphan Drug and Breakthrough Therapy designations for the treatment of PV.

Sefaxersen is our medicine in Phase 3 development for immunoglobulin A, or IgA, nephropathy, or IgAN. In September 2026, we and Roche announced positive interim data from the ongoing Phase 3 IMAgINATION study evaluating investigational sefaxersen in adults with primary IgAN, which were presented in October 2026 at the American Society of Nephrology, or ASN. Roche plans to share these data with health authorities.

Tofersen is our medicine in development for presymptomatic SOD1-ALS. Biogen is evaluating tofersen for treatment of presymptomatic individuals who have aSOD1 genetic mutation.

Ulefnersen is our medicine in development for amyotrophic lateral sclerosis, or ALS, with mutations in the fused in sarcoma gene, or FUS. In September 2026, we and Otsuka announced positive topline results from the Phase 3 FUSION study of ulefnersen in juvenile and adult patients with FUS-ALS. We licensed global commercialization rights for ulefnersen to Otsuka. The FDA and EMA granted Orphan Drug designation to ulefnersen. The FDA also granted Fast Track designation to ulefnersen.