Obudanersen

编者按：寡核苷酸药物已成为全球新药研发的核心领域之一，近年来发展迅猛，在罕见病等多个领域得到快速应用。当前，全球超300款寡核苷酸疗法管线已进入临床开发阶段，有望在未来造福更多病患。为助力全球合作伙伴更高效地推动寡核苷酸药物从实验室走向临床，药明康德旗下WuXi TIDES平台围绕寡核苷酸、多肽及其相关化学偶联药物建立了一体化解决方案，覆盖定制合成、共价偶联、工艺开发和CMC等关键环节，赋能创新项目加速进入临床阶段。 寡核苷酸疗法持续在罕见病领域突破 寡核苷酸疗法正逐步成为罕见病治疗领域的重要突破方向。2025年第三季度，寡核苷酸疗法也持续迎来多项进展。 8月，美国FDA批准反义寡核苷酸配体偶联药物Dawnzera（donidalorsen），用于预防12岁及以上成人和儿童患者的遗传性血管性水肿（HAE）发作。据相关新闻稿，Dawnzera是FDA批准的首个用于HAE的RNA靶向药物。 9月，欧盟批准反义寡核苷酸（ASO）疗法Tryngolza（olezarsen）作为饮食控制的辅助疗法，用于治疗经遗传学确认的家族性乳糜微粒血症（FCS）成人患者。同期，该疗法用于治疗重度高甘油三酯血症（sHTG）的3期试验也迎来积极结果：每月一次的olezarsen使患者空腹甘油三酯较安慰剂平均下降72%，急性胰腺炎事件减少85%。这些进展表明，寡核苷酸疗法在罕见病治疗中的成功，为其向更广泛疾病领域的拓展奠定了基础。 此外，补体C5靶向siRNA疗法cemdisiran，在用以治疗成人全身性重症肌无力（gMG）的NIMBLE临床3期试验中达到主要终点。数据显示，每三个月皮下注射一次cemdisiran单药可平均抑制74%的补体活性，而与C5抗体pozelimab联用后，补体抑制率提升至近99%。同期，ASO疗法zilganersen也在亚历山大病（AxD）的关键试验中显著改善患者步行能力，成为首款在该疾病中显示出潜在疾病修饰作用的在研疗法。上述两款疗法预计将于2026年第一季度提交监管申请。 另一方面，用于治疗Dravet综合征的在研ASO疗法zorevunersen在为期三年的扩展研究中表现出持续的抗癫痫发作效果，并伴随认知与行为指标的持续改善，该疗法已在今年8月完成3期试验的首位患者给药。 在2025年三季度，FDA还向多款寡核苷酸疗法授予突破性疗法认定，适应症涵盖多种罕见疾病。其中包括适用于外显子44和51跳跃的杜氏肌营养不良症（DMD）的抗体-寡核苷酸偶联疗法del-zota与DYNE-251，以及用于天使综合征的ASO疗法apazunersen与ION582。 向更广泛适应症推进 寡核苷酸疗法的应用领域正从罕见病向常见疾病拓展。7月，FDA批准诺华（Novartis）的siRNA疗法Leqvio（inclisiran）扩展适应症，作为单药与饮食控制和运动联合使用，以降低成人高胆固醇血症患者的低密度脂蛋白胆固醇（LDL-C）水平。该药物每年仅需给药两次。此次标签更新是FDA基于该PCSK9靶向疗法降低LDL-C的积极数据主动发起。 在代谢性疾病领域，用于治疗代谢功能障碍相关脂肪性肝炎（MASH）的ASO疗法ION224也在三季度获得积极的2期结果：最高剂量组中有近60%的患者实现MASH疾病活动度改善，安慰剂组仅为19%。 同期，两款分别针对肥胖与阿尔茨海默病的siRNA疗法RN3161与ARO-MAPT于9月在澳大利亚和新西兰提交临床试验申请，标志着寡核苷酸疗法正向更广泛疾病领域推进。 在癌症领域也有多项进展。PD-1靶向siRNA疗法PH-762在皮肤癌1b期试验中，13例皮肤鳞状细胞癌（cSCC）患者中有6人在接受治疗后达到病理学完全缓解或接近完全缓解。另外，DNA癌症疫苗SCIB1与其改良版iSCIB1+在晚期不可切除黑色素瘤患者中展现亮眼疗效。临床2期试验结果显示，当两者与当前标准免疫检查点抑制剂联用时，疾病控制率（DCR）高达88.0%。 9月，两款分别针对肥胖与阿尔茨海默病的siRNA疗法RN3161与ARO-MAPT，也分别在澳洲与新西兰递交临床试验申请，意味着着寡核苷酸疗法正向更广泛适应症领域推进。 高额合作加码，彰显产业信心 三季度以来，寡核苷酸领域的商业研发合作也有诸多进展，多家企业通过高额合作加码siRNA领域布局。 9月，诺华接连达成两项大额siRNA疗法授权合作：其一，与Arrowhead Pharmaceuticals就后者开发的α-突触核蛋白靶向siRNA疗法ARO-SNCA达成总额高达20亿美元的合作。该疗法处于临床前阶段，拟开发治疗包括帕金森病在内的突触核蛋白病。其二，与Argo Biopharma就多项心血管siRNA管线达成合作，合作总额最高可达52亿美元，进一步夯实其在心血管代谢管线。 同时，Arrowhead Pharmaceuticals控股子公司维亚臻（Visirna Therapeutics）与赛诺菲达成最高2.65亿美元的合作：赛诺菲将获得siRNA疗法plozasiran（VSA001）在大中华区的开发与商业化独家权利。该疗法通过抑制载脂蛋白C-III（APOC3）的产生，用于治疗家族性乳糜微粒血症综合征及重度高甘油三酯血症。 此外，专注于开发RNA疗法的Arnatar Therapeutics宣布已于2024年完成5200万美元A轮融资。该公司专有的DARGER平台将siRNA沉默技术与基于ASO的基因上调技术相结合，开发具双重作用机制的RNA疗法，针对心脏代谢、肝、肾及中枢神经系统等疾病。 总而言之，2025年第三季度，寡核苷酸疗法在多个疾病领域持续取得突破，展现出从罕见病向更广泛疾病领域拓展的明确趋势。同时，产业涌现出的高额融资、合作等趋势，显示产业对这一领域的信心。 作为医药创新的赋能者，药明康德化学业务旗下专注于寡核苷酸和多肽及相关化学偶联药物的新分子业务平台——WuXi TIDES平台，围绕siRNA、ASO等寡核苷酸疗法，建立了化合物合成、工艺开发及生产的一站式服务平台，覆盖从药物发现、CMC开发，到商业化生产的全生命周期，加速将合作伙伴的创新构想转化为现实，更好地造福全球病患。以下案例将展示WuXi TIDES的一体化平台如何加速合作伙伴ASO药物的开发进程。 2023年，一家生物技术公司与WuXi TIDES合作进行ASO药物的早期筛选研究，WuXi TIDES的药物化学团队为其提供了超过400种携带骨架化学修饰的ASO化合物，以协助确定最具前景的分子。然而，早期研究发现，创新骨架修饰导致候选化合物中出现新的杂质。在最初的合成过程中，这些杂质占比高达25%，不仅降低了产率和纯化效率，还可能带来潜在毒性，给后续临床开发带来挑战。 面对这一难题，WuXi TIDES药物化学团队和工艺研发团队密切配合，从两个方向入手解决问题。一方面，药物化学团队与合作伙伴共同探索杂质产生的潜在原因，设计出定制化的amidite和分子砌块，规避杂质产生的关键合成机制，并快速生产这些新分子砌块，协助工艺研发团队加速验证工艺设计策略，以有效地控制杂质。此外，工艺研发团队通过优化工艺参数，系统性地降低了杂质的产生。最终，经过持续工艺优化，杂质占比成功从25%降低至5%，同时最终收率也从最初的0.5 g/mol提高到3.4 g/mol。 在该项目中，WuXi TIDES各团队高效协作，不仅在12个月内完成了先导化合物的优化、工艺开发及GMP生产，更帮助合作伙伴基于数据进行快速决策，选出综合效力、稳定性和开发潜力俱佳的ASO候选化合物，为后续临床研究奠定了坚实基础。随着越来越多的ASO以及其他寡核苷酸药物进入临床开发，这种产业协同模式将成为加快研发步伐的重要推动力。 免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。 版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号回复“转载”，获取转载须知。

- TRYNGOLZA® generated $32 million in net product sales in the third quarter 2025 - - DAWNZERA™ (donidalorsen) launch off to encouraging start - - Olezarsen significantly reduced triglycerides and acute pancreatitis events in severe hypertriglyceridemia (sHTG) in landmark Phase 3 studies; sNDA submission on track by year-end – - Positive pivotal zilganersen results in Alexander disease position Ionis for first independent neurology launch in 2026 - - Increasing 2025 financial guidance driven by continued strength across the business – CARLSBAD, Calif. --(BUSINESS WIRE)--Oct. 29, 2025-- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the “Company”) today reported financial results and provided key updates for the third quarter ended September 30, 2025 . "The third quarter was a watershed moment for Ionis, as we made important progress advancing our Ionis-owned medicines. With two independent launches now underway, and two more anticipated in 2026, we are delivering on our goal to bring a steady cadence of new medicines to people in need,” said Brett P. Monia , Ph.D., chief executive officer of Ionis. “Last month, we announced groundbreaking, positive topline Phase 3 results for olezarsen in severe hypertriglyceridemia and for zilganersen in Alexander disease, with regulatory filings planned in the coming months. Our approved and late-stage portfolio continues to deliver — positioning Ionis for substantial growth while, most importantly, offering the opportunity to profoundly improve the lives of people with serious diseases." Third Quarter 2025 Summary Financial Results(1): Three months ended Nine months ended September 30 , September 30 , 2025 2024 2025 2024 (amounts in millions) Total revenue $ 157 $ 134 $ 740 $ 479 Operating expenses $ 317 $ 282 $ 907 $ 843 Operating expenses on a non-GAAP basis $ 286 $ 250 $ 816 $ 749 Loss from operations ($ 160 ) ($ 148 ) ($ 167 ) ($ 364 ) Loss from operations on a non-GAAP basis ($ 129 ) ($ 116 ) ($ 76 ) ($ 270 ) (1) Reconciliation of GAAP to non-GAAP basis contained later in this release. Recent Financial Highlights Revenue increased 17% in the third quarter of 2025 and increased 55% in the nine months ended September 30, 2025 , compared to the same periods last year, driven by the continued successful launch of TRYNGOLZA and increased royalty revenues. Contributing to the year-to-date increase, Ionis earned a $280 million upfront payment for the global license of sapablursen to Ono Pharmaceutical Co., Ltd. in the second quarter of 2025 Operating expenses on a non-GAAP basis increased 14% in the third quarter of 2025 and increased 9% in the nine months ended September 30, 2025 , compared to the same periods last year, primarily due to investments related to commercialization efforts for TRYNGOLZA, DAWNZERA and WAINUA Increasing 2025 financial guidance reflects strong overall revenue performance experienced year-to-date and fourth quarter outlook, including strong momentum seen with TRYNGOLZA revenues: Full Year 2025 Guidance Previous Guidance New Guidance Total Revenue $825-850 million $875-900 million TRYNGOLZA product sales, net $75-80 million $85-95 million Operating loss on a non-GAAP basis $300-325 million $275-300 million Cash, cash equivalents and short-term investments ~$2.0 billion > $2.1 billion Third Quarter 2025 Financial Results "In the third quarter of 2025, we delivered strong revenue performance, highlighted by TRYNGOLZA’s nearly 70% increase over the prior quarter. As a result of this strength and our fourth quarter outlook, we are increasing our financial guidance again for 2025," said Elizabeth L. Hougen , chief financial officer of Ionis. "Looking ahead, we expect the 2026 independent launches of olezarsen in severe hypertriglyceridemia and zilganersen in Alexander disease to further strengthen our commercial portfolio. We anticipate that growth in our product revenues coupled with additional partner revenues will position Ionis to achieve cash flow breakeven in 2028 and generate substantial and sustainable positive cash flow for years to come." Recent Highlights - Wholly Owned Medicines TRYNGOLZA® (olezarsen), the first and only FDA approved treatment for adults living with familial chylomicronemia syndrome (FCS) as an adjunct to diet Generated net product sales of $32 million in the third quarter of 2025, its third full quarter on the market, a nearly 70% increase over the prior quarter, and $57 million in the nine months ended September 30, 2025 Approved in the European Union (EU) as an adjunct to diet in adult patients for the treatment of genetically confirmed FCS ; Sobi anticipates launching in the fourth quarter 2025 Olezarsen demonstrated positive topline results in the pivotal Phase 3 CORE and CORE2 studies in sHTG Olezarsen demonstrated a highly statistically significant placebo-adjusted mean reduction in fasting triglycerides of up to 72% and a highly statistically significant reduction in acute pancreatitis events of 85% with favorable safety and tolerability sNDA submission on track for the end of 2025 with approval anticipated in the fourth quarter of 2026 Detailed data to be presented at the American Heart Association Conference on November 8, 2025 , in a late-breaking session DAWNZERA™ (donidalorsen) was approved on August 21, 2025 , by the FDA for prophylaxis to prevent attacks of hereditary angioedema ( HAE) in adult and pediatric patients 12 years of age and older First and only RNA-targeted prophylactic therapy that has the potential to offer durable efficacy, a favorable safety and tolerability profile, and the longest available dosing interval, with self-administration via autoinjector every four or eight weeks U.S. launch underway and off to an encouraging start Currently under regulatory review in the EU Zilganersen demonstrated positive results in the pivotal study in children and adults with Alexander disease (AxD), a rare, progressive, and often fatal neurological disorder with no approved disease-modifying treatments 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 (10MWT), compared to control at week 61 (mean difference 33.3%) with favorable safety and tolerability Additional data from the pivotal study in children and adults living with Alexander disease were presented at the Child Neurology Society Annual Meeting in October 2025 NDA submission planned for the first quarter of 2026 with approval anticipated next year ION582 granted Breakthrough Therapy designation from FDA for the treatment of Angelman syndrome Phase 3 REVEAL study expected to be fully enrolled in 2026 Phase 2 HALOS study showed continued improvement across multiple functional measures versus natural history through 18 months including expressive communication Generated net product sales of $32 million in the third quarter of 2025, its third full quarter on the market, a nearly 70% increase over the prior quarter, and $57 million in the nine months ended September 30, 2025 Approved in the European Union (EU) as an adjunct to diet in adult patients for the treatment of genetically confirmed FCS ; Sobi anticipates launching in the fourth quarter 2025 Olezarsen demonstrated a highly statistically significant placebo-adjusted mean reduction in fasting triglycerides of up to 72% and a highly statistically significant reduction in acute pancreatitis events of 85% with favorable safety and tolerability sNDA submission on track for the end of 2025 with approval anticipated in the fourth quarter of 2026 Detailed data to be presented at the American Heart Association Conference on November 8, 2025 , in a late-breaking session First and only RNA-targeted prophylactic therapy that has the potential to offer durable efficacy, a favorable safety and tolerability profile, and the longest available dosing interval, with self-administration via autoinjector every four or eight weeks U.S. launch underway and off to an encouraging start Currently under regulatory review in the EU 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 (10MWT), compared to control at week 61 (mean difference 33.3%) with favorable safety and tolerability Additional data from the pivotal study in children and adults living with Alexander disease were presented at the Child Neurology Society Annual Meeting in October 2025 NDA submission planned for the first quarter of 2026 with approval anticipated next year Phase 3 REVEAL study expected to be fully enrolled in 2026 Phase 2 HALOS study showed continued improvement across multiple functional measures versus natural history through 18 months including expressive communication Recent Highlights – Partnered Medicines WAINUA® (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) generated sales of $59 million and $143 million resulting in royalty revenue of $13 million and $33 million in the third quarter and the nine months ended September 30, 2025 , respectively Launches underway in numerous regions, including the EU; additional submissions in progress to expand WAINUA access globally SPINRAZA® (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $374 million and $1.2 billion resulting in royalty revenue of $56 million and $158 million in the third quarter and the nine months ended September 30, 2025 , respectively Launches underway in numerous regions, including the EU; additional submissions in progress to expand WAINUA access globally Revenue Ionis’ revenue was comprised of the following: Three months ended Nine months ended September 30 , September 30 , 2025 2024 2025 2024 Revenue: (amounts in millions) Commercial revenue: Product sales, net: TRYNGOLZA sales, net $ 32 $ - $ 57 $ - Total product sales, net 32 - 57 - Royalty revenue: SPINRAZA royalties 56 57 158 152 WAINUA royalties 13 5 33 10 Other royalties 7 5 19 18 Total royalty revenue 76 67 210 180 Other commercial revenue 8 9 27 27 Total commercial revenue 116 76 294 207 Research and development revenue: Collaborative agreement revenue 31 45 414 237 WAINUA joint development revenue 10 13 32 35 Total research and development revenue 41 58 446 272 Total revenue $ 157 $ 134 $ 740 $ 479 Commercial revenue for the third quarter and the nine months ended September 30, 2025 , increased 53% and 42%, respectively, compared to the same periods in 2024. This increase was primarily driven by TRYNGOLZA product sales. Higher royalty revenue also contributed to the year over year increase. The remainder of the Company’s revenue came from programs under its R&D collaborations, including a $280 million upfront payment for the global license of sapablursen to Ono Pharmaceutical Co., Ltd. in the second quarter of 2025, reflecting the value that Ionis’ pipeline and technology continues to generate. Operating Expenses SG&A expenses increased as anticipated for the third quarter and the nine months ended September 30, 2025 , compared to the same periods in 2024, primarily due to the launches of TRYNGOLZA, DAWNZERA and WAINUA. This increase was partially offset by a decrease in R&D expenses as several late-stage studies ended. Overall, this led to a modest year-over-year increase in total operating expenses, which was in line with expectations. Balance Sheet As of September 30, 2025 , Ionis’ cash, cash equivalents and short-term investments were $2.2 billion , compared to $2.3 billion on December 31, 2024 . Ionis’ working capital decreased over the same period primarily due to the reclassification of the Company’s 0% convertible notes as a current liability. Webcast and Other Updates Management will host a conference call and webcast to discuss Ionis’ third quarter 2025 results at 11:30 a.m. Eastern time on Wednesday, October 29, 2025 . 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 third quarter 2025 earnings slides click here. Ionis’ Marketed Medicines INDICATION for TRYNGOLZA® (olezarsen) TRYNGOLZA® (olezarsen) was approved by the U.S. Food and Drug Administration as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome (FCS). IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS TRYNGOLZA is contraindicated in patients with a history of serious hypersensitivity to TRYNGOLZA or any of the excipients in TRYNGOLZA. Hypersensitivity reactions requiring medical treatment have occurred. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions (including symptoms of bronchospasm, diffuse erythema, facial swelling, urticaria, chills and myalgias) have been reported in patients treated with TRYNGOLZA. Advise patients on the signs and symptoms of hypersensitivity reactions and instruct patients to promptly seek medical attention and discontinue use of TRYNGOLZA if hypersensitivity reactions occur. ADVERSE REACTIONS The most common adverse reactions (incidence >5% of TRYNGOLZA-treated patients and >3% higher frequency than placebo) were injection site reactions, decreased platelet count and arthralgia. Please see full Prescribing Information for TRYNGOLZA. INDICATION for DAWNZERATM (donidalorsen) DAWNZERA™ (donidalorsen) 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. IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS DAWNZERA is contraindicated in patients with a history of serious hypersensitivity reactions, including anaphylaxis, to donidalorsen or any of the excipients in DAWNZERA. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Hypersensitivity reactions, including anaphylaxis, have been reported in patients treated with DAWNZERA. If signs and symptoms of serious hypersensitivity reactions occur, discontinue DAWNZERA and institute appropriate therapy. ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 5%) are injection site reactions, upper respiratory tract infection, urinary tract infection, and abdominal discomfort. Please see full Prescribing Information for DAWNZERA. INDICATION for WAINUA® (eplontersen) WAINUA injection, for subcutaneous use, 45 mg is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. IMPORTANT SAFETY INFORMATION for WAINUA® (eplontersen) WARNINGS AND PRECAUTIONS Reduced Serum Vitamin A Levels and Recommended Supplementation WAINUA leads to a decrease in serum vitamin A levels. Supplement with recommended daily allowance of vitamin A. Refer patient to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. ADVERSE REACTIONS Most common adverse reactions (≥9% in WAINUA-treated patients) were vitamin A decreased (15%) and vomiting (9%). Please see link to U.S. Full Prescribing Information for WAINUA. For more information about SPINRAZA and QALSODY, visit https://www.spinraza.com/ and https://www.qalsody.com/, 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 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 Statement 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, 2024 , and most recent Form 10-Q, which are on file with 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® is a registered trademark of Ionis Pharmaceuticals, Inc. TRYNGOLZA® is a registered trademark of Ionis Pharmaceuticals, Inc. DAWNZERATM is a trademark of Ionis Pharmaceuticals, Inc. AKCEATM is a trademark of Akcea Therapeutics, Inc. TEGSEDITM is a trademark of Akcea Therapeutics, Inc. WAYLIVRATM 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 Nine months ended September 30 , September 30 , 2025 2024 2025 2024 (unaudited) Revenue: Commercial revenue: Product sales, net $ 32 $ - $ 57 $ - Royalty revenue 76 67 210 180 Other commercial revenue 8 9 27 27 Total commercial revenue 116 76 294 207 Research and development revenue: Collaborative agreement revenue 31 45 414 237 WAINUA joint development revenue 10 13 32 35 Total research and development revenue 41 58 446 272 Total revenue 157 134 740 479 Expenses: Cost of sales 2 1 8 7 Research, development and patent 218 220 636 656 Selling, general and administrative 97 61 263 180 Total operating expenses 317 282 907 843 Loss from operations (160 ) (148 ) (167 ) (364 ) Other income (expense): Interest expense related to the sale of future royalties (18 ) (19 ) (55 ) (55 ) Other income, net 49 23 70 66 Loss before income tax benefit (129 ) (144 ) (152 ) (353 ) Income tax benefit - 4 - 3 Net loss ($ 129 ) ($ 140 ) ($ 152 ) ($ 350 ) Basic and diluted net loss per share ($ 0.80 ) ($ 0.95 ) ($ 0.95 ) ($ 2.38 ) Shares used in computing basic and diluted net loss per share 160 149 159 147 IONIS PHARMACEUTICALS, INC. Reconciliation of GAAP to Non-GAAP Basis: Condensed Consolidated Operating Expenses, Loss From Operations, and Net Loss (In Millions) Three months ended September 30 , Nine months ended September 30 , 2025 2024 2025 2024 (unaudited) As reported research, development and patent expenses according to GAAP $ 218 $ 220 $ 636 $ 656 Excluding compensation expense related to equity awards (21 ) (22 ) (61 ) (67 ) Non-GAAP research, development and patent expenses $ 197 $ 198 $ 575 $ 589 As reported selling, general and administrative expenses according to GAAP $ 97 $ 61 $ 263 $ 180 Excluding compensation expense related to equity awards (10 ) (10 ) (29 ) (26 ) Non-GAAP selling, general and administrative expenses $ 87 $ 51 $ 234 $ 154 As reported operating expenses according to GAAP $ 317 $ 282 $ 907 $ 843 Excluding compensation expense related to equity awards (31 ) (32 ) (91 ) (94 ) Non-GAAP operating expenses $ 286 $ 250 $ 816 $ 749 As reported loss from operations according to GAAP ($ 160 ) ($ 148 ) ($ 167 ) ($ 364 ) Excluding compensation expense related to equity awards (31 ) (32 ) (91 ) (94 ) Non-GAAP loss from operations ($ 129 ) ($ 116 ) ($ 76 ) ($ 270 ) As reported net loss according to GAAP ($ 129 ) ($ 140 ) ($ 152 ) ($ 350 ) Excluding compensation expense related to equity awards and related tax effects (31 ) (32 ) (91 ) (94 ) Non-GAAP net loss ($ 98 ) ($ 108 ) ($ 61 ) ($ 256 ) Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP loss from operations, and non-GAAP net 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) September 30 , December 31 , 2025 2024 (unaudited) Assets: Cash, cash equivalents and short-term investments $ 2,240 $ 2,298 Contracts receivable 25 92 Other current assets 254 230 Property, plant and equipment, net 106 94 Right-of-use assets 242 162 Other assets 166 127 Total assets $ 3,033 $ 3,003 Liabilities and stockholders’ equity: Current portion of deferred contract revenue $ 77 $ 79 0% convertible senior notes, net – current 631 - Other current liabilities 195 229 1.75% convertible senior notes, net 567 565 0% convertible senior notes, net - 629 Liability related to sale of future royalties, net 545 542 Long-term lease liabilities 263 162 Long-term obligations, less current portion 29 52 Long-term deferred contract revenue 108 157 Total stockholders’ equity 618 588 Total liabilities and stockholders’ equity $ 3,033 $ 3,003 Key 2025 and 2026 Value Driving Events(1) New Product Launches Program Indication 2025 2026 DAWNZERA ( U.S. ) HAE Achieved TRYNGOLZA ( U.S. ) FCS Achieved WAINZUA (EU) ATTRv-PN Achieved Olezarsen ( U.S. ) sHTG • Zilganersen ( U.S. ) Alexander disease • Regulatory Actions Program Indication Regulatory Action 2025 2026 Donidalorsen HAE U.S. approval decision Achieved EU approval decision • TRYNGOLZA FCS EU approval decision Achieved Olezarsen sHTG U.S. submission • U.S. approval decision • Zilganersen Alexander disease U.S. submission • U.S. approval decision • Nusinersen (higher dose) SMA U.S. and EU submissions Achieved U.S. approval decision Refiling process on track WAINZUA ATTRv-PN EU approval decision Achieved Pelacarsen Lp(a)- CVD U.S. submission • Bepirovirsen HBV Regulatory submission(s) • Regulatory decision(s) • Key Phase 3 Clinical Events Program Indication Event 2025 2026 Olezarsen sHTG CORE, CORE2 data Achieved Essence data Achieved Zilganersen Alexander disease Phase 3 data Achieved ION582 Angelman syndrome Phase 3 study start Achieved Phase 3 enrollment completion • Pelacarsen Lp(a)-CVD Lp(a) HORIZON data • Bepirovirsen HBV B-Well data • Eplontersen ATTR-CM CARDIO-TTRansform data • Sefaxersen IgAN IMAGINATION data • Ulefnersen FUS-ALS FUSION data • Timing expectations based on current assumptions and subject to change. Indicates that the milestone is anticipated in the respective year. View source version on businesswire.com: https://www.businesswire.com/news/home/20251029676166/en/ 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 Source: Ionis Pharmaceuticals, Inc.