Tofersen

iStock, BeritK Three years after Qalsody was approved by the FDA as the first drug to target a genetic cause of ALS, some patients are reporting not only disease stabilization but also improvement of symptoms. Saskatchewan is known for its harsh winters. For Paula Trefiak, a ballet dancer and mother of three, the winter of 2016 was harsher than most. Trefiak was diagnosed with ALS in February and given two to five years to live. Later that year, however, Trefiak got a glimmer of hope—a call from The Montreal Neurological Institute and Hospital, inviting her to participate in a clinical trial for a drug in development for her specific type of ALS that’s linked to a superoxide dismutase (SOD1) gene. “I jumped at the opportunity,” she recalled. “By late that afternoon, it was a Friday, I had my flights already ready to go to Montreal.” She flew out on Sunday and received the first dose of tofersen, an antisense oligonucleotide (ASO) developed by Biogen and Ionis Pharmaceuticals, in a Phase 1b trial. ezstandalone.cmd.push(function () { ezstandalone.showAds(129); }); At first the drug appeared to disappoint. Trefiak was given the lowest dose of 20 mg and continued to decline. Then the trial ended, Trefiak stopped receiving the drug and her disease kept progressing. “I was having more issues with my ankles, a lot more issues stuttering, my lip was drooping a lot more. . . . gripping things was becoming an issue.” Finally, in March 2018, Trefiak began taking a 100 mg dose of tofersen in an open label extension study, and things started to change. By the summer of that year, “I started to feel stronger,” she recalled. Her ankles were stronger; her shoulders—which would freeze when she tried to reach for something—weren’t freezing anymore; she could hold herself up longer in a ballet move called demi-pointe. Her overall quality of life improved. “I started to notice I was having a better sleep,” Trefiak said. “I wasn’t constantly waking up in agony for hours on end with cramping.” Today, more than 10 years after her diagnosis, Trefiak can still do all those things and more. “I can dance, I can swim again without drowning,” she said. Her forced vital capacity (FVC)—a key measure of disease progression in ALS—was down to 72% at its lowest, she said. In May, it was at 101%—well within normal range. It’s a striking outcome for the brutal neurodegenerative disease with only a handful of drugs on the market. And Trefiak is not alone. At least one patient in the Phase 2 trial of AL-S’s AP-101 has also experienced a reversal of decline, Angela Genge, chief medical officer at AL-S Pharma and the top recruiter for Qalsody’s Phase 1, 2 and 3 trials, told BioSpace . In a study of seven patients with SOD1-ALS treated with the therapy at Washington University in St. Louis from November 2021 to February 2024, all patients saw either disease stabilization or slight improvement in function as measured by the ALS Functional Rating Scale-Revised (ALSFRS-R), per the ALS Association. On the basis of biomarker data from the Phase 3 Valor trial, tofersen won FDA approval in April 2023 for patients with SOD1-ALS. Health Canada greenlit the therapy under its Special Access Program two years later. The drug is marketed in both countries as Qalsody. Policy FDA Approves Biogen and Ionis’ Qalsody as Fourth-Ever ALS Therapy Tuesday, the FDA approved Qalsody—formerly tofersen—on a conditional basis to treat SOD1-ALS. April 25, 2023 · 6 min read · Heather McKenzie Read more It’s been a tough slog for the ALS treatment space. Amylyx’s Relyvrio, approved in 2022, was voluntarily withdrawn from U.S. and Canadian markets in 2024 after failing to show significant benefit in a Phase 3 trial, and more late-stage trials have failed to show efficacy. But Qalsody’s success offers hope that researchers are on to something by targeting SOD1. Qalsody is currently indicated only for patients with ALS who have an SOD1 mutation. Notably, pathological levels of misfolding also occur in at least a third of sporadic ALS cases, according to Genge. AL-S Pharma is developing an antibody targeting this mutated protein. Researchers are hopeful that Qalsody can also help more patients than it’s currently indicated for. Most cases of ALS are sporadic, while 5 to 10% are familial, with approximately 2% linked to a SOD1 mutation. This subset of the disease affects less than 500 people in the U.S. Genge believes targeting SOD1 can be a real gamechanger in the treatment of ALS. “We’re looking at targeting a pathway [SOD1] that really seems to be fundamental,” she said. SOD1 and beyond The SOD1 gene encodes an enzyme that plays an important role in protecting cells from oxidative stress. Mutations in this gene can lead to a defective form of SOD1 protein, which has been implicated in ALS. Qalsody works by reducing the amount of toxic SOD1 in the body. While the antisense therapy missed the primary endpoint of a statistically significant change from baseline to week 28 on ALSFRS-R in the Phase 3 VALOR study , the FDA granted an accelerated nod based on its ability to reduce neurofilament light chain, a biomarker of neurodegeneration that the agency deemed “reasonably likely” to predict clinical benefit. WashU is running a Phase 2 study of the drug in patients with non-SOD1 ALS to test whether more patients could be helped. “In other neurodegenerative diseases . . . there’s often a link between the genetic causes of disease and what we find in terms of the pathophysiology of the disease,” Timothy Miller, co-director of WashU’s ALS Center and the study’s lead investigator, told BioSpace . In terms of a connection between SOD1 and sporadic ALS, he said the data are “mixed.” WashU’s study, per ClinicalTrials.gov, has a primary completion date of January 2027. Meanwhile, AL-S Pharma is targeting misfolded mutant and wildtype SOD1 with AP-101. Unlike Qalsody, the antibody treatment does not affect the level of healthy SOD1, according to Genge. This is important, she said, because “SOD1 is an obligatory protein in our biology, and so we don’t know how low we can knock it before we start building long-term side effects.” Notably, the company is testing AP-101 in both SOD1-ALS and sporadic forms of the disease. AL-S Pharma presented data at the ENCALS 2026 Congress in June from a Phase 2 trial of patients with both familial and sporadic ALS. The results showed that early treatment with AP-101 prolonged survival and delayed the need for patients to use a ventilator as compared to patients who were given placebo for six months followed by six months of treatment with the candidate. The results were consistent across patients with both SOD1- and sporadic ALS with moderately to significantly elevated levels of misfolded SOD1, Genge said. A Phase 3 trial is set to kick off in early 2027. It’s also becoming clear to drug developers that early treatment is key when it comes to neurodegenerative disease. While speaking with BioSpace last month about Biogen and Ionis’ tau-targeted Alzheimer’s therapy diranersen, Ionis Head of Development Holly Kordasiewicz compared the ASO to the companies’ other partnered therapies, Qalsody, and Spinraza—also an ASO—for spinal muscular atrophy. Alzheimer’s disease AAIC 2026: Biogen delivers hope, validation with anti-tau Alzheimer’s win Biogen touted an “unprecedented” drop in tau in a Phase 2 trial, backing the company’s decision to take diranersen to Phase 3 despite a missed primary endpoint and seemingly supporting the anti-tau approach. July 14, 2026 · 5 min read · Heather McKenzie Read more “Earlier intervention in any of these neurodegenerative diseases where you have a lifetime of pathology accumulation, like in SOD1-ALS or like in [Alzheimer’s disease], I think earlier is going to be better,” she said. When children were dosed with Spinraza at birth, Ionis started to see them meet normal motor milestones, Kordasiewicz recalled. “With [Qalsody], there’s a portion of the patients who, if you go in early enough, it’s looking like there’s reports that they’re now doing better as well.” Biogen is running the Phase 3 ATLAS trial studying Qalsody’s efficacy in presymptomatic individuals with a confirmed SOD1 mutation and elevated neurofilament. Primary completion is expected in August 2027. Not a cure Several members of Trefiak’s family have died from SOD1-ALS. Currently, Qalsody is keeping the disease at bay for her sister and two of her cousins—all of whom were showing early symptoms of ALS when they started on the drug. “They haven’t had the reversal like I have, but at least they’re not deteriorating,” she said. “They’re maintaining their health, which is significant.” Still, Qalsody is not a cure. Trefiak must undergo an intrathecal injection of Qalsody once every four weeks to maintain the stability of her disease. “I’ve now had officially 120 lumbar punctures or treatments with this drug that have gone into my spine. I don’t know what that’s doing to my spine long term,” she said. Intrathecal-related side effects can include benign intracranial hypertension and spinal cord inflammation. “To get this drug fewer times per year would be great as well,” Trefiak added. This is where a treatment like AP-101—if approved—could be especially valuable. As a human monoclonal antibody, AP-101 is delivered intravenously, so it is “very easy to give,” Genge said, adding that the drug is “very well tolerated.” For now, Trefiak and her family remain grateful for Qalsody. Her 18-year-old son learned, three days after Qalsody’s approval in Canada, that he also carries the G37R-SOD1 mutation. “His first reaction,” she said, “was, ‘at least I now have a treatable disease.’ It’s wonderful that we finally have something that works for our family.” ALS New Wave of ALS Therapies Signals Renaissance After Incremental Regression After a demoralizing period punctuated by the withdrawal of one of the few marketed therapies for ALS, investment in new biotechs, state-backed collaborative initiatives and buzz at BIO2025 suggest a new day in drug development for one of medicine’s most intractable diseases. September 2, 2025 · 6 min read · Heather McKenzie Read more

- TRYNGOLZA ® (olezarsen) demonstrating early sHTG launch momentum, underscoring multi-billion-dollar revenue potential in large patient population – - Completed enrollment in Phase 3 REVEAL trial in Angelman syndrome - - On track to achieve 2026 financial guidance - CARLSBAD, Calif.--(BUSINESS WIRE)--Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the “Company”) today reported financial results and provided key updates for the second quarter ended June 30, 2026. ezstandalone.cmd.push(function () { ezstandalone.showAds(131); }); “With the approval of TRYNGOLZA in late June, Ionis is bringing the first and only treatment to reduce triglycerides and acute pancreatitis to people living with severe hypertriglyceridemia. We are encouraged by the early launch momentum and look forward to accelerating growth from TRYNGOLZA and our other wholly owned medicines in the quarters and years to come,” said Brett P. Monia, Ph.D., chief executive officer of Ionis. “In the second half of this year, we expect multiple important milestones, including approval of zilganersen for Alexander disease, positioning us for our first independent launch from our leading neurology portfolio. We also expect results from the landmark pelacarsen Lp(a) HORIZON cardiovascular outcomes trial and the global launch of bepirovirsen for chronic hepatitis B. With our advancing pipeline and growing commercial momentum, Ionis is on track to deliver accelerating value to patients and all Ionis stakeholders.” Second Quarter 2026 Summary Financial Results (1) : Three months ended Six months ended June 30, June 30, 2026 2025 2026 2025 (amounts in millions) Total revenue $268 $452 $514 $584 Operating expenses $370 $312 $734 $591 Operating expenses on a non-GAAP basis $325 $282 $645 $532 Income (loss) from operations ($102) $140 ($220) ($7) Income (loss) from operations on a non-GAAP basis ($57) $170 ($131) $52 (1) Reconciliation of GAAP to non-GAAP basis contained later in this release. Second Quarter 2026 Financial Highlights Revenue in the second quarter and first half of 2026 increased by 56% and 69% respectively, compared to the same periods last year, excluding the one-time sapablursen upfront payment recognized in the second quarter of 2025, driven by continued commercial success and substantial R&D revenue from multiple partnerships Operating expenses for the second quarter and first half of 2026 were in line with expectations and increased year over year primarily from investments related to the commercialization efforts for TRYNGOLZA and DAWNZERA and launch preparations for zilganersen in Alexander disease Ended the second quarter of 2026 with cash and short-term investments of $2.1 billion as of June 30, 2026, enabling continued investments to drive value in Ionis’ wholly owned portfolio Second Quarter 2026 Financial Results “Our performance in the first half of this year reflects the strength and resilience of our business. We delivered significantly increased commercial revenue from our independent launches, substantial R&D revenue from multiple partnered medicines and invested in our advancing wholly owned pipeline,” said Elizabeth L. Hougen, chief financial officer of Ionis. “Even with the outcome of the CARDIO-TTRansform study of eplontersen in ATTR-CM, our first-half execution and positive outlook for the second half of the year keep us on track to achieve our 2026 financial guidance. We also remain on track to achieve our goal of cashflow breakeven in 2028 and deliver substantial growth and long-term value-creation.” Recent Highlights - Wholly Owned Medicines TRYNGOLZA ® (olezarsen), the first FDA-approved treatment to reduce triglycerides and acute pancreatitis risk in adults with severe hypertriglyceridemia (sHTG) as an adjunct to diet Generated U.S. net product sales of $5 million and $32 million in the second quarter and first half of 2026, respectively Demonstrated continued strong demand in FCS, offset by the reduced net price effective April 1, 2026 On track to achieve full year 2026 product sales of $100-110 million, in line with revenues generated in 2025 sHTG U.S. launch demonstrating early momentum following June 2026 approval FCS launch outside the U.S. underway; sHTG marketing application under review in the European Union (EU) with potential launch in 2027 Results from the CORE and CORE2 open-label extension study (CORE-OLE) will be presented at the European Society of Cardiology (ESC) Congress in August 2026 DAWNZERA ® (donidalorsen), the first and only RNA-targeted prophylactic therapy for hereditary angioedema (HAE) in patients 12 years of age and older Generated U.S. net product sales of $26 million and $42 million in the second quarter and first half of 2026, respectively; second quarter net product sales increased 63% compared to the first quarter of 2026 On track to achieve full year 2026 product sales of $110-120 million, representing a continuing driver of year-over-year revenue growth Launch outside the U.S. underway, with new market approvals in the EU Zilganersen on track to launch this year as the first and only medicine to demonstrate clinically meaningful and disease-modifying benefit in children and adults with Alexander disease (AxD), assuming approval New Drug Application (NDA) under FDA Priority Review with PDUFA target action date of September 22, 2026 Entered a license agreement with Recordati to develop and commercialize zilganersen outside the U.S. Obudanersen, a potential treatment for Angelman syndrome, completed enrollment in the Phase 3 REVEAL study, with data anticipated in the second half of 2027 ION775, a potential treatment for sHTG, entered a Phase 2 study in people with sHTG and moderately elevated triglycerides (HTG) based on Phase 1 results showing robust triglyceride lowering with potential for extended dosing intervals Results from the Phase 1 study of ION775 will be presented at ESC in August 2026 Recent Highlights – Partnered Medicines SPINRAZA ® (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $402 million in the second quarter of 2026, resulting in royalty revenue of $54 million WAINUA ® (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) generated global sales of $70 million in the second quarter of 2026, resulting in royalty revenue of $16 million Global WAINUA ATTRv-PN launches continuing with additional submissions in progress to further expand global WAINUA access Phase 3 CARDIO-TTRansform study of eplontersen for the treatment of transthyretin-mediated amyloid cardiomyopathy (ATTR-CM) missed the primary composite endpoint in the overall population, demonstrated nominal significance in the pre-specified monotherapy population, and a favorable safety and tolerability profile Results from the CARDIO-TTRansform study will be presented at ESC in August 2026 Bepirovirsen, a potential first-in-class treatment of chronic hepatitis B (CHB), on track for global launch this year Under regulatory review in multiple countries, including the U.S., EU, Japan, and China Granted Priority Review in the U.S. and PDUFA target action date of October 26, 2026 Positive data from the Phase 3 B-Well studies showing unprecedented functional cure rates presented at the European Association for the Study of the Liver (EASL) Congress 2026 Salanersen, a potential treatment for SMA, entered Phase 3 development and granted Breakthrough Therapy Designation by the FDA, based on positive interim Phase 1 results demonstrating potential to achieve high efficacy with annual dosing Sapablursen, a potential treatment for polycythemia vera, entered Phase 3 development based on positive Phase 2 data Diranersen (IONIS-MAPT Rx / BIIB080), a potential treatment for Alzheimer’s disease, demonstrated benefit in measures of cognition with favorable safety and tolerability in the Phase 2 CELIA study; Biogen plans to advance diranersen into Phase 3 development Revenue Ionis’ revenue was comprised of the following: Three months ended June 30, Six months ended June 30, 2026 2025 2026 2025 Revenue: (amounts in millions) Commercial revenue: Product sales, net: TRYNGOLZA sales, net $ 5 $ 19 $ 32 $ 26 DAWNZERA sales, net 26 - 42 - Total product sales, net 31 19 74 26 Royalty revenue: SPINRAZA royalties 53 54 97 102 WAINUA royalties 16 10 27 20 Other royalties 7 6 10 12 Total royalty revenue 76 70 134 134 Other commercial revenue 12 14 18 19 Total commercial revenue 119 103 226 179 Research and development revenue: Collaborative agreement revenue 133 337 254 382 WAINUA joint development revenue 16 12 34 23 Total research and development revenue 149 349 288 405 Total revenue $ 268 $ 452 $ 514 $ 584 Commercial revenue for the second quarter and first half of 2026 increased 15% and 27%, respectively, compared to the same periods in 2025. This increase was primarily driven by DAWNZERA product sales. Research and development revenue was also higher in the second quarter and first half of 2026, compared to the same periods in 2025, driven by multiple payments for programs advancing under its R&D collaborations, and excluding the $280 million upfront payment for the global license of sapablursen to Ono Pharmaceutical Co., Ltd. the Company received in the second quarter of 2025. Operating Expenses Operating expenses for the second quarter and first half of 2026 increased year over year, in line with expectations, primarily from investments related to the commercialization efforts for TRYNGOLZA and DAWNZERA and launch preparations for zilganersen in Alexander disease, with full-year expenses remaining on track for low-teens percentage growth year-over-year. Balance Sheet As of June 30, 2026, Ionis’ cash, cash equivalents and short-term investments decreased to $2.1 billion, compared to $2.7 billion on December 31, 2025, primarily due to repayment of the 0% convertible notes on April 1, 2026. Webcast and Other Updates Management will host a conference call and webcast to discuss Ionis’ second quarter 2026 results at 8:30 a.m. Eastern time on Wednesday, July 29, 2026. Interested parties may access the webcast here . A webcast replay will be available for a limited time at the same address. To access the Company’s second quarter 2026 earnings slides click here . Ionis’ Marketed Medicines TRYNGOLZA ® (olezarsen): TRYNGOLZA was approved by the U.S. Food and Drug Administration as an adjunct to diet to reduce triglycerides (TG) and the risk of acute pancreatitis in adults with severe hypertriglyceridemia (sHTG: TG ≥500 mg/dL) and as an adjunct to diet to reduce TG in adults with familial chylomicronemia syndrome (FCS). For more information about TRYNGOLZA, including the full U.S. Prescribing Information, visit tryngolza.com . DAWNZERA ® (donidalorsen): DAWNZERA was approved by the U.S. Food and Drug Administration for prophylaxis to prevent attacks of hereditary angioedema (HAE) in adult and pediatric patients 12 years of age and older. For more information about DAWNZERA, including the full U.S. Prescribing Information, visit dawnzera.com . WAINUA ® (eplontersen): WAINUA was approved by the U.S. Food and Drug Administration for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. For more information about WAINUA, including the full U.S. Prescribing Information, visit wainua.com . For more information about SPINRAZA and QALSODY, visit and , respectively. QALSODY is approved under accelerated approval based on reduction in plasma neurofilament light chain (NfL) observed in patients treated with QALSODY. Continued approval may be contingent upon verification of clinical benefit in confirmatory trial(s). About Ionis Pharmaceuticals, Inc. For more than three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has marketed medicines and a leading pipeline in neurology, cardiometabolic disease and select areas of high patient need. As the pioneer in RNA-targeted medicines, Ionis continues to drive innovation in RNA therapies in addition to advancing new approaches in gene editing. A deep understanding of disease biology and industry-leading technology propels our work, coupled with a passion and urgency to deliver life-changing advances for patients. To learn more about Ionis, visit Ionis.com and follow us on X (Twitter) , LinkedIn and Instagram . Ionis Forward-looking Statements This press release includes forward-looking statements regarding Ionis’ business, financial guidance and the therapeutic and commercial potential of our commercial medicines, additional medicines in development, technologies and our expectations regarding development and regulatory milestones. Any statement describing Ionis’ goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement. Such statements are subject to certain risks and uncertainties including those inherent in the process of discovering, developing and commercializing medicines that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such medicines. Ionis’ forward-looking statements also involve assumptions that, if they never materialize or prove correct, could cause its results to differ materially from those expressed or implied by such forward-looking statements. Although Ionis’ forward-looking statements reflect the good faith judgment of its management, these statements are based only on facts and factors currently known by Ionis. Except as required by law, we undertake no obligation to update any forward-looking statements for any reason. As a result, you are cautioned not to rely on these forward-looking statements. These and other risks concerning Ionis' programs are described in additional detail in Ionis' annual report on Form 10-K for the year ended December 31, 2025, and most recent Form 10-Q, which are on the Securities and Exchange Commission. Copies of these and other documents are available from the Company. In this press release, unless the context requires otherwise, “Ionis,” “Company,” “we,” “our” and “us” all refer to Ionis Pharmaceuticals and its subsidiaries. Ionis Pharmaceuticals ® is a registered trademark of Ionis Pharmaceuticals, Inc. TRYNGOLZA ® is a registered trademark of Ionis Pharmaceuticals, Inc. DAWNZERA ® is a trademark of Ionis Pharmaceuticals, Inc. AKCEA TM is a trademark of Akcea Therapeutics, Inc. TEGSEDI TM is a trademark of Akcea Therapeutics, Inc. WAYLIVRA TM is a trademark of Akcea Therapeutics, Inc. SPINRAZA ® and QALSODY ® are registered trademarks of Biogen. WAINUA ® is a registered trademark of the AstraZeneca group of companies. IONIS PHARMACEUTICALS, INC. SELECTED FINANCIAL INFORMATION Condensed Consolidated Statements of Operations (In Millions, Except Per Share Data) Three months ended June 30, Six months ended June 30, 2026 2025 2026 2025 (unaudited) Revenue: Commercial revenue: Product sales, net $ 31 $ 19 $ 74 $ 26 Royalty revenue 76 70 134 134 Other commercial revenue 12 14 18 19 Total commercial revenue 119 103 226 179 Research and development revenue: Collaborative agreement revenue 133 337 254 382 WAINUA joint development revenue 16 12 34 23 Total research and development revenue 149 349 288 405 Total revenue 268 452 514 584 Expenses: Cost of sales 3 4 6 6 Research, development and patent 217 217 427 418 Selling, general and administrative 150 91 301 167 Total operating expenses 370 312 734 591 Income (loss) from operations (102 ) 140 (220 ) (7 ) Other income (expense): Interest expense related to the sale of future royalties (18 ) (19 ) (35 ) (37 ) Other income, net 6 3 49 21 Income (loss) before income tax benefit (expense) (114 ) 124 (206 ) (23 ) Income tax benefit (expense) (1 ) - (1 ) - Net income (loss) ($ 115 ) $ 124 ($ 207 ) ($ 23 ) Basic net income (loss) per share ($ 0.69 ) $ 0.78 ($ 1.25 ) ($ 0.15 ) Diluted net income (loss) per share ($ 0.69 ) $ 0.70 ($ 1.25 ) ($ 0.15 ) Shares used in computing basic net income (loss) per share 165 159 165 159 Shares used in computing diluted net income (loss) per share 165 182 165 159 IONIS PHARMACEUTICALS, INC. Reconciliation of GAAP to Non-GAAP Basis: Condensed Consolidated Operating Expenses, Income (Loss) From Operations, and Net Income (Loss) (In Millions) Three months ended June 30, Six months ended June 30, 2026 2025 2026 2025 (unaudited) As reported cost of sales according to GAAP $ 3 $ 4 $ 6 $ 6 Excluding compensation expense related to equity awards (1) - - - - Non-GAAP cost of sales $ 3 $ 4 $ 6 $ 6 As reported research, development and patent expenses according to GAAP $ 217 $ 217 $ 427 $ 418 Excluding compensation expense related to equity awards (25 ) (20 ) (50 ) (40 ) Non-GAAP research, development and patent expenses $ 192 $ 197 $ 377 $ 378 As reported selling, general and administrative expenses according to GAAP $ 150 $ 91 $ 301 $ 167 Excluding compensation expense related to equity awards (20 ) (10 ) (39 ) (19 ) Non-GAAP selling, general and administrative expenses $ 130 $ 81 $ 262 $ 148 As reported operating expenses according to GAAP $ 370 $ 312 $ 734 $ 591 Excluding compensation expense related to equity awards (45 ) (30 ) (89 ) (59 ) Non-GAAP operating expenses $ 325 $ 282 $ 645 $ 532 As reported income (loss) from operations according to GAAP ($ 102 ) $ 140 ($ 220 ) ($ 7 ) Excluding compensation expense related to equity awards (45 ) (30 ) (89 ) (59 ) Non-GAAP income (loss) from operations ($ 57 ) $ 170 ($ 131 ) $ 52 As reported net income (loss) according to GAAP ($ 115 ) $ 124 ($ 207 ) ($ 23 ) Excluding compensation expense related to equity awards and related tax effects (45 ) (30 ) (89 ) (59 ) Non-GAAP net income (loss) ($ 70 ) $ 154 ($ 118 ) $ 36 (1) Amounts appear as zero due to rounding in millions. Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP income (loss) from operations, and non-GAAP net income (loss) were adjusted from GAAP to exclude compensation expense related to equity awards and the related tax effects. Compensation expense related to equity awards are non-cash. These measures are provided as supplementary information and are not a substitute for financial measures calculated in accordance with GAAP. Ionis reports these non-GAAP results to better enable financial statement users to assess and compare its historical performance and project its future operating results and cash flows. Further, the presentation of Ionis’ non-GAAP results is consistent with how Ionis’ management internally evaluates the performance of its operations. IONIS PHARMACEUTICALS, INC. Condensed Consolidated Balance Sheets (In Millions) June 30, December 31, 2026 2025 (unaudited) Assets: Cash, cash equivalents and short-term investments $ 2,055 $ 2,677 Contracts receivable 59 66 Other current assets 378 247 Property, plant and equipment, net 155 123 Right-of-use assets 232 239 Other assets 116 172 Total assets $ 2,995 $ 3,524 Liabilities and stockholders’ equity: Current portion of deferred contract revenue $ 74 $ 74 0% convertible senior notes due April 2026, net – current - 432 Other current liabilities 242 277 0% convertible senior notes due 2030, net 753 751 1.75% convertible senior notes due 2028, net 569 568 Liability related to sale of future royalties, net 563 551 Long-term lease liabilities 262 262 Long-term obligations, less current portion 29 28 Long-term deferred contract revenue 63 92 Total stockholders’ equity 440 489 Total liabilities and stockholders’ equity $ 2,995 $ 3,524 Key 2026 Value Driving Events (1) New Product Launches Program Indication Location Status DAWNZERA HAE EU Achieved Olezarsen sHTG U.S. Achieved Zilganersen Alexander disease U.S. • Bepirovirsen CHB U.S. & Japan • Regulatory Actions Program Indication Regulatory Action Status Donidalorsen HAE EU approval decision Achieved Olezarsen sHTG U.S. approval decision Achieved EU approval decision • Zilganersen Alexander disease U.S. submission Achieved U.S. approval decision • Nusinersen (high dose) SMA EU approval decision Achieved U.S. approval decision Achieved Eplontersen ATTR-CM Regulatory submission(s) • Bepirovirsen CHB Regulatory submission(s) Achieved Regulatory decision(s) • Pelacarsen Lp(a)- CVD U.S. submission • Key Phase 3 Clinical Events Program Indication Event Status Obudanersen Angelman syndrome REVEAL fully enrolled Achieved Bepirovirsen HBV B-Well data Achieved Pelacarsen Lp(a)-CVD Lp(a) HORIZON data • Eplontersen ATTR-CM CARDIO-TTRansform data Not Achieved Sefaxersen IgAN IMAGINATION data • Ulefnersen FUS-ALS FUSION data • Salanersen SMA Phase 3 initiation Achieved Sapablursen Polycythemia Vera Phase 3 initiation Achieved Key Phase 2 Clinical Events Program Indication Event Status Diranersen Alzheimer’s disease Phase 2 CELIA data Achieved Tominersen Huntington’s disease Phase 2 data Not Achieved Tonlamarsen Acute Severe Hypertension Phase 2 data Achieved (1) Timing expectations based on current assumptions and subject to change. Indicates that the milestone is anticipated in 2026. Contacts Ionis Investor Contact: D. Wade Walke, Ph.D. IR@ionis.com 760-603-2331 Ionis Media Contact: Hayley Soffer media@ionis.com 760-603-4679