Sapablursen

编者按：今日（2026年2月28日）是第19个国际罕见病日。根据世界卫生组织（WHO）2025年发表的数据，目前已知的罕见病超过7000种，影响到全球3亿多人。在罕见病新药研发领域，寡核苷酸疗法凭借独特的作用机制，正成为重要的突破方向。当前，全球范围内已有十多款寡核苷酸疗法获监管机构批准治疗罕见病，此外还有上百项寡核苷酸管线在针对罕见病适应症进行临床研究，未来有望造福更多患者。作为全球医药创新的赋能者，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WuXi TIDES平台，围绕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。 寡核苷酸药物是全球新药开发的重要热点，凭借其直接调控基因表达的独特机制，在多种疾病治疗领域展现出潜力。尤其在罕见病领域，更是成为新药研发的重要突破方向。 通过公开渠道梳理，当前全球范围内已有十多款寡核苷酸疗法获监管机构批准治疗罕见病，为遗传性血管性水肿、血友病、转甲状腺素蛋白淀粉样变性多发性神经病、转甲状腺素蛋白淀粉样变心肌病、肌萎缩侧索硬化症、脊髓性肌萎缩症、杜氏肌营养不良、纯合子型家族性高胆固醇血症、肝卟啉症等患者带来了新的治疗选择。尤其是在刚刚结束的2025年，美国FDA批准了至少2款治疗罕见病的寡核苷酸疗法，包括反义寡核苷酸配体偶联（LICA）药物donidalorsen获批用于预防遗传性血管性水肿（HAE）发作、靶向抗凝血酶的皮下注射siRNA药物fitusiran获批用于血友病A或B患者常规预防，引起行业关注。 除了已经获批的疗法，还有近百项寡核苷酸疗法管线在针对罕见病适应症进行临床研究，未来有望造福更多患者。通过梳理，其中有10多款新药目前已经进入3期临床研究阶段，意味着其有望即将为患者带来新的治疗选择。 近一年来，多款处于3期临床阶段的寡核苷酸新药迎来新进展，这些新药包括反义寡核苷酸（ASO）、siRNA、抗体偶联siRNA疗法，涉及的适应症涵盖：天使综合征、1型肌强直性营养不良、Dravet综合征、重症肌无力、脊髓性肌萎缩症、面肩肱型肌营养不良症、真性红细胞增多症等。 多款3期临床阶段罕见病寡核苷酸疗法迎新进展 在过去一年，多款治疗罕见病的寡核苷酸疗法获得FDA授予突破性疗法认定，彰显其临床潜力。比如，2025年9月，Ionis Pharmaceuticals公司在研的ASO疗法ION582获FDA授予突破性疗法认定，用于治疗天使综合征。这是一种罕见遗传性神经发育疾病。ION582旨在抑制UBE3A反义转录本（UBE3A-ATS）的表达，并激活来自父体的UBE3A等位基因以增加患者大脑中UBE3A蛋白的产生，为天使综合征的潜在疗法。Ionis此前已启动ION582的全球3期关键性REVEAL研究，计划纳入携带母源UBE3A基因缺失或突变的儿童和成人天使综合征患者，公司预计该研究将在2026年完成入组，这将为ION582未来的上市申请奠定重要基础。 再如，2025年7月，Ultragenyx公司在研ASO疗法GTX-102（apazunersen）获得FDA授予突破性疗法认定，用于治疗天使综合征。GTX-102通过鞘内给药方式递送，该疗法可以促进神经元细胞中父系UBE3A的等位基因表达，产生患者体内所缺失的关键蛋白产物。该疗法的相关全球3期试验正在进行中。 除此之外，还有多款新药公布最新临床研究数据，比如： 今年2月，Avidity Biosciences宣布其在研抗体偶联RNAi疗法delpacibart etedesiran（del-desiran，AOC 1001）在1型肌强直性营养不良（DM1）患者中开展的1/2期MARINA试验最终结果发表于《新英格兰医学杂志》。研究结果显示，del-desiran成功递送至肌肉组织，在所有接受治疗的受试者中，DMPK mRNA平均降低约40%。DM1是一种逐步加重且往往致命的罕见神经肌肉疾病。Del-desiran是Avidity利用其抗体偶联寡核苷酸（AOC）平台开发的候选疗法，它将与转铁蛋白受体1（TfR1）结合的专有单克隆抗体与靶向DMPK基因的siRNA偶联，旨在通过降低与疾病相关的DMPK基因的mRNA水平，解决DM1的根本原因。 Avidity公司另一款在研AOC候选药物delpacibart braxlosiran（del-brax）也于2025年6月公布了治疗面肩肱型肌营养不良症（FSHD）的临床1/2期试验FORTITUDE积极新数据：与安慰剂相比，在接受del-brax治疗的FSHD患者中观察到肌肉功能活动能力、肌肉力量和患者报告的结局（PROs）衡量的生活质量方面的改善，并且生物标志物出现了快速而显著的下降。FSHD是一种罕见的遗传性疾病，其特征是终身、持续的肌肉功能丧失、显著的疼痛、疲劳和渐进性残疾。Del-brax旨在治疗FSHD根本原因，由一种专有的TfR1靶向单克隆抗体与靶向DUX4 mRNA的siRNA偶联所组成。 再如，2025年10月，渤健（Biogen）与Stoke Therapeutics公司共同宣布了针对Dravet综合征的在研ASO药物zorevunersen的最新研究进展。Dravet综合征是一种严重且进展性的罕见遗传性癫痫。该药物旨在通过增强SCN1A基因非突变（野生型）拷贝的功能，提升脑细胞中NaV1.1蛋白的表达，从而治疗Dravet综合征的根本病因。最新公布的两年分析数据显示，接受zorevunersen治疗的Dravet综合征患者在认知和行为方面持续改善，这与一项同样为期两年的自然病史研究中患者几乎无改善的结果形成鲜明对比。在为期三年的OLE研究中，临床医生和护理人员分别报告了95%（n=19）的患者整体临床状况得到改善。 渤健另一款在研ASO疗法salanersen治疗脊髓性肌萎缩症（SMA）的一项1期临床试验的积极结果也于2025年6月公布。该药物与渤健已获批的ASO疗法Spinraza（nusinersen）具有相同的作用机制，但在设计上追求更高效力，并有望实现每年仅需一次给药。SMA是一种遗传性神经肌肉病。研究结果显示，salanersen表现出良好的耐受性，在基线NfL浓度较高的患者中，治疗6个月后平均神经退行性标志物神经丝轻链（NfL）下降幅度达70%，这一效果可持续维持至一年。 2025年8月，再生元（Regeneron）也宣布其与Alnylam公司联合开发的补体C5靶向siRNA疗法cemdisiran，在治疗成人全身性重症肌无力（gMG）的临床3期试验中达到了主要和关键次要终点。再生元计划在与FDA沟通后，于2026年第一季度提交cemdisiran单药的监管申请。分析显示，每三个月皮下注射一次的cemdisiran单药显示出平均74%的补体活性抑制率。而cemdisiran与C5抗体pozelimab的联合疗法则达成接近99%的补体活性抑制。 交易合作方面也迎来新进展，比如，2025年3月，Ono Pharmaceutical宣布与Ionis Pharmaceuticals签订许可协议，获得ASO疗法sapablursen的开发及商业化权益。ONO将支付2.8亿美元前期付款，并根据达到研发、监管及销售里程碑，支付高达6.6亿美元的额外里程碑付款。Sapablursen是一种用于治疗真性红细胞增多症（PV）的在研ASO药物，其设计旨在降低TMPRSS6基因编码的跨膜蛋白酶丝氨酸6的产生，从而增加铁稳态关键调控因子铁调素（hepcidin）的表达。通过提高铁调素的产生，sapablursen有望对真性红细胞增多症等血液疾病产生积极影响。 除了上述进展，还有多款治疗罕见病的寡核苷酸新药处于积极的临床开发阶段，并取得新进展。限于篇幅，此处不再一一介绍。很高兴看到这些创新疗法取得积极进展，为患者带来新的治疗希望。 一体化CRDMO平台赋能寡核苷酸疗法创新 凭借其高度靶向性、灵活可编程和相对较短的开发周期等特点，寡核苷酸疗法近年来发展迅速，受到产业界的广泛关注，在包括罕见病在内的多个疾病治疗领域发挥着重要作用。 在此背景下，作为全球医药创新的赋能者，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。 具体而言，WuXi TIDES的寡核苷酸平台可为全球合作伙伴针对性地提供从药物发现到商业化生产的一体化CRDMO服务。药物发现阶段的合成服务支持高通量库合成和定制合成，涵盖多种类型的寡核苷酸及其单体、连接子、配体和偶联物，助力合作伙伴快速推进临床前研究。同时，可无缝衔接到工艺开发阶段，放大到从mmol到mol的任何规模，充分满足从临床前、临床到商业化阶段的需求。 在寡核苷酸的偶联方面，WuXi TIDES全面的平台能力可支持寡核苷酸与多肽、脂质、小分子、毒素/药物等组件的偶联，为复杂的寡核苷酸偶联药物提供一体化解决方案。 破解罕见病新药研发困境，需要全球生物医药生态圈的持续协同合作和共同努力。药明康德也将继续以一体化、端到端的CRDMO赋能平台，助力全球合作伙伴加速新药研发进程，降低研发成本，让包括罕见病在内的各类疾病药物研发更高效、更易行。 参考资料： [1]World Health Organization.Rare diseases: A global health priority for equity and inclusion. Retrieved Feb 10 , 2025. From https://apps.who.int/gb/ebwha/pdf_files/EB156/B156_(15)-en.pdf 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。

CARLSBAD, Calif.--(BUSINESS WIRE)--Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the “Company”) today reported financial results and provided key updates for the fourth quarter and year ended December 31, 2025. "2025 was a defining year for Ionis, marked by the successful execution of our first two independent launches and multiple positive data readouts across our pipeline, positioning Ionis for continued success in 2026,” said Brett P. Monia, Ph.D., chief executive officer of Ionis. “This year, we are poised for two additional independent launches of groundbreaking therapies — olezarsen for severe hypertriglyceridemia, our first launch in a broad patient population, and zilganersen for Alexander disease, our first launch from our leading neurology pipeline. Our partnered pipeline is also on track for multiple groundbreaking Phase 3 readouts, beginning with the recent positive data for bepirovirsen in chronic hepatitis B to be followed by two cardiovascular outcome trials — the pelacarsen Lp(a) HORIZON trial mid-year 2026 and the eplontersen CARDIO-TTRansform trial in the second half of 2026. Together, this progress positions Ionis to continue delivering a steady cadence of transformative medicines to people living with serious diseases, fueling substantial growth and long-term value creation." Fourth Quarter and Full Year 2025 Summary Financial Results(1): Three months ended Year ended December 31, December 31, 2025 2024 2025 2024 (amounts in millions) Total revenue $203 $227 $944 $705 Operating expenses $418 $337 $1,326 $1,180 Operating expenses on a non-GAAP basis $375 $301 $1,192 $1,050 Loss from operations ($215) ($110) ($382) ($475) Loss from operations on a non-GAAP basis ($172) ($74) ($248) ($345) (1) Reconciliation of GAAP to non-GAAP basis contained later in this release. Recent Financial Highlights Revenue for the year ended December 31, 2025 substantially exceeded expectations due to continued commercial success. In addition, Ionis earned substantial R&D revenue, including a $280 million upfront payment for the global license of sapablursen to Ono Pharmaceutical Co., Ltd. in the second quarter of 2025 Operating expenses for the year ended December 31, 2025 were in line with expectations and increased year over year from investments related to commercialization efforts for TRYNGOLZA, DAWNZERA and WAINUA Cash and short-term investments of $2.7 billion as of December 31, 2025, included refinancing proceeds Ionis plans to use to repay its 2026 Convertible Notes Fourth Quarter and Full Year 2025 Financial Results "In 2025 we exceeded our revenue guidance, driven by growing commercial revenue from our independent launches and substantial R&D revenue from continued pipeline success," said Elizabeth L. Hougen, chief financial officer of Ionis. "In 2026, we will continue to invest in go-to-market activities to support our ongoing and upcoming independent launches, including the recent expansion of our top-tier sales force ahead of our expected olezarsen sHTG launch. We anticipate growth in product revenues, together with additional royalties, to 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 FDA-approved treatment for adults living with familial chylomicronemia syndrome (FCS) as an adjunct to diet Generated net product sales of $50 million in the fourth quarter of 2025, a 56% increase over the prior quarter, and $108 million for the year ended December 31, 2025 Approved and launched in the European Union (EU) as an adjunct to diet in adult patients for the treatment of genetically confirmed FCS Generated net product sales of $50 million in the fourth quarter of 2025, a 56% increase over the prior quarter, and $108 million for the year ended December 31, 2025 Approved and launched in the European Union (EU) as an adjunct to diet in adult patients for the treatment of genetically confirmed FCS Olezarsen on track to launch this year as a transformational medicine for severely elevated triglycerides (sHTG), assuming approval Positive groundbreaking results in the pivotal Phase 3 CORE and CORE2 studies in sHTG presented at the American Heart Association Conference, in a late-breaking session, and published in the New England Journal of Medicine sNDA submitted for marketing approval in U.S. Positive groundbreaking results in the pivotal Phase 3 CORE and CORE2 studies in sHTG presented at the American Heart Association Conference, in a late-breaking session, and published in the New England Journal of Medicine sNDA submitted for marketing approval in U.S. DAWNZERA™ (donidalorsen), the first and only RNA-targeted prophylactic therapy for hereditary angioedema (HAE) in patients 12 years of age and older Generated net product sales of $7 million in the fourth quarter of 2025, in the first full quarter on the market Encouraging early launch momentum with prescriptions written for all patient segments and growing number of repeat prescribers Approved in the European Union (EU) in January and recently launched for the routine prevention of recurrent attacks of HAE in patients 12 years of age and older Positive one-year results from OASISplus open-label extension cohort published in the Journal of Asthma and Allergy Generated net product sales of $7 million in the fourth quarter of 2025, in the first full quarter on the market Encouraging early launch momentum with prescriptions written for all patient segments and growing number of repeat prescribers Approved in the European Union (EU) in January and recently launched for the routine prevention of recurrent attacks of HAE in patients 12 years of age and older Positive one-year results from OASISplus open-label extension cohort published in the Journal of Asthma and Allergy Zilganersen on track for launch this year as the first and only medicine to demonstrate clinically meaningful and disease-modifying impact in children and adults with Alexander disease (AxD), assuming approval NDA submitted with approval decision anticipated in H2:2026 Expanded access program (EAP) in U.S. underway NDA submitted with approval decision anticipated in H2:2026 Expanded access program (EAP) in U.S. underway Recent Highlights – Partnered Medicines SPINRAZA ® (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $356 million and $1.5 billion resulting in royalty revenue of $54 million and $212 million in the fourth quarter and the year ended December 31, 2025, respectively High dose approved and launched in the EU; under review for marketing approval in U.S. (PDUFA date of April 3, 2026) Positive high dose results from pivotal DEVOTE study published in Nature Medicine High dose approved and launched in the EU; under review for marketing approval in U.S. (PDUFA date of April 3, 2026) Positive high dose results from pivotal DEVOTE study published in Nature Medicine WAINUA ® (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) generated sales of $69 million and $212 million resulting in royalty revenue of $16 million and $49 million in the fourth quarter and the year ended December 31, 2025, respectively Launches underway in numerous regions, including the EU; recently approved in China; additional submissions in progress to expand WAINUA access globally Launches underway in numerous regions, including the EU; recently approved in China; additional submissions in progress to expand WAINUA access globally Bepirovirsen, a potential first-in-class medicine for chronic hepatitis B (CHB), achieved primary endpoint and demonstrated a statistically significant and clinically meaningful functional cure rate in B-Well 1 and B-Well 2 Phase 3 studies Presentation planned for European Association for the Study of the Liver (EASL) Congress 2026, assuming acceptance Global regulatory filings planned beginning in Q1:2026 with 2026 anticipated launch, assuming approval Presentation planned for European Association for the Study of the Liver (EASL) Congress 2026, assuming acceptance Global regulatory filings planned beginning in Q1:2026 with 2026 anticipated launch, assuming approval Ulefnersen for the treatment of FUS-ALS granted U.S. Fast Track designation Sapablursen for the treatment of polycythemia vera (PV) demonstrated positive Phase 2 results, which were presented at American Society of Hematology (ASH) conference; Ono advancing sapablursen into Phase 3 development Opemalirsen for the treatment of APOL1-mediated chronic kidney disease (AMKD) granted U.S. Fast Track designation Revenue Ionis’ revenue was comprised of the following: Three months ended Year ended December 31, December 31, 2025 2024 2025 2024 Revenue: (amounts in millions) Commercial revenue: Product sales, net: TRYNGOLZA sales, net $50 $- $108 $- DAWNZERA sales, net 7 - 8 - Total product sales, net 57 - 116 - Royalty revenue: SPINRAZA royalties 54 64 212 216 WAINUA royalties 16 10 49 20 Other royalties 6 3 24 21 Total royalty revenue 76 77 285 257 Other commercial revenue 8 9 35 36 Total commercial revenue 141 86 436 293 Research and development revenue: Collaborative agreement revenue 52 97 466 333 WAINUA joint development revenue 10 44 42 79 Total research and development revenue 62 141 508 412 Total revenue $203 $227 $944 $705 Commercial revenue for the fourth quarter and the year ended December 31, 2025, increased 64% and 49%, 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 continue to generate. Operating Expenses Operating expenses increased modestly for the fourth quarter and the year ended December 31, 2025, which was in line with expectations. The increase was driven by investments to support the launches of TRYNGOLZA, DAWNZERA and WAINUA. Balance Sheet As of December 31, 2025, Ionis’ cash, cash equivalents and short-term investments increased to $2.7 billion, compared to $2.3 billion on December 31, 2024, primarily due to the refinancing proceeds Ionis received from its convertible debt issuance in the fourth quarter, which Ionis plans to use to repay its 2026 Convertible Notes. 2026 Financial Guidance The Company’s 2026 financial guidance reflects its evolution to a fully integrated commercial-stage biotechnology company independently launching multiple medicines and advancing commercialization efforts for additional upcoming planned launches. As a result, the Company expects to earn substantial revenue from numerous diverse sources, including increasing commercial revenue. The Company is currently awaiting acceptance of its olezarsen sNDA submission, as such the Company’s 2026 financial guidance assumes a standard review timeline. With acceptance anticipated shortly, the Company expects to provide TRYNGOLZA and DAWNZERA product level guidance at its first quarter 2026 earnings. The Company expects a modest increase in its non-GAAP operating expenses in line with its plan to invest in independent launches and advance its wholly owned pipeline of innovative medicines. The Company expects that these investments will enable Ionis to deliver accelerating value. Overall, the Company anticipates total revenue to grow approximately 20 percent year over year and its non-GAAP operating loss to be similar to 2025, excluding the one-time sapablursen upfront payment recognized in 2025. Full Year 2026 Guidance Revenue $800- $825 million Operating loss on a non-GAAP basis $500-550 million Cash, cash equivalents and short-term investments ~$1.6 billion Webcast and Other Updates Management will host a conference call and webcast to discuss Ionis’ fourth quarter and full year 2025 results at 8:30 a.m. Eastern time on Wednesday, February 25, 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 fourth quarter and full year 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 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, 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 Year ended December 31, December 31, 2025 2024 2025 2024 (unaudited) Revenue: Commercial revenue: Product sales, net $57 $- $116 $- Royalty revenue 76 77 285 257 Other commercial revenue 8 9 35 36 Total commercial revenue 141 86 436 293 Research and development revenue: Collaborative agreement revenue 52 97 466 333 WAINUA joint development revenue 10 44 42 79 Total research and development revenue 62 141 508 412 Total revenue 203 227 944 705 Expenses: Cost of sales 8 4 16 11 Research, development and patent 280 245 916 902 Selling, general and administrative 130 88 394 267 Total operating expenses 418 337 1,326 1,180 Loss from operations (215) (110) (382) (475) Other income (expense): Interest expense related to the sale of future royalties (18) (19) (73) (73) Other income, net 5 22 75 88 Loss before income tax benefit (expense) (228) (107) (380) (460) Income tax benefit (expense) (1) 3 (1) 6 Net loss ($229) ($104) ($381) ($454) Basic and diluted net loss per share ($1.41) ($0.66) ($2.38) ($3.04) Shares used in computing basic and diluted net loss per share 162 158 160 150 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 December 31, Year ended December 31, 2025 2024 2025 2024 (unaudited) As reported research, development and patent expenses according to GAAP $280 $245 $916 $902 Excluding compensation expense related to equity awards (29) (25) (90) (92) Non-GAAP research, development and patent expenses $251 $220 $826 $810 As reported selling, general and administrative expenses according to GAAP $130 $88 $394 $267 Excluding compensation expense related to equity awards (13) (11) (42) (37) Non-GAAP selling, general and administrative expenses $117 $77 $352 $230 As reported operating expenses according to GAAP $418 $337 $1,326 $1,180 Excluding compensation expense related to equity awards (43) (36) (134) (130) Non-GAAP operating expenses $375 $301 $1,192 $1,050 As reported loss from operations according to GAAP ($215) ($110) ($382) ($475) Excluding compensation expense related to equity awards (43) (36) (134) (130) Non-GAAP loss from operations ($172) ($74) ($248) ($345) As reported net loss according to GAAP ($229) ($104) ($381) ($454) Excluding compensation expense related to equity awards and related tax effects (43) (36) (134) (130) Non-GAAP net loss ($186) ($68) ($247) ($324) 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) December 31, December 31, 2025 2024 (unaudited) Assets: Cash, cash equivalents and short-term investments $2,677 $2,298 Contracts receivable 66 92 Other current assets 247 230 Property, plant and equipment, net 123 94 Right-of-use assets 239 162 Other assets 172 127 Total assets $3,524 $3,003 Liabilities and stockholders’ equity: Current portion of deferred contract revenue $74 $79 0% convertible senior notes due 2026, net – current 432 - Other current liabilities 277 229 0% convertible senior notes due 2030, net 751 - 1.75% convertible senior notes due 2028, net 568 565 0% convertible senior notes due 2026, net - 629 Liability related to sale of future royalties, net 551 542 Long-term lease liabilities 262 162 Long-term obligations, less current portion 28 52 Long-term deferred contract revenue 92 157 Total stockholders’ equity 489 588 Total liabilities and stockholders’ equity $3,524 $3,003 Key 2026 Value Driving Events(1) New Product Launches Program Indication Location DAWNZERA HAE EU Achieved Olezarsen sHTG U.S. ● Zilganersen Alexander disease U.S. ● Bepirovirsen CHB U.S. & Japan ● Regulatory Actions Program Indication Regulatory Action Donidalorsen HAE EU approval decision Achieved Olezarsen sHTG U.S. approval decision ● EU submission ● Zilganersen Alexander disease U.S. submission ● U.S. approval decision ● Nusinersen (high dose) SMA EU approval decision Achieved U.S. approval decision ● Eplontersen ATTR-CM Regulatory submission(s) ● Bepirovirsen HBV Regulatory submission(s) ● Regulatory decision(s) ● Pelacarsen Lp(a)- CVD U.S. submission ● Key Phase 3 Clinical Events Program Indication Event Obudanersen Angelman syndrome Phase 3 enrollment completion ● Bepirovirsen HBV B-Well data Achieved Pelacarsen Lp(a)-CVD Lp(a) HORIZON data ● Eplontersen ATTR-CM CARDIO-TTRansform data ● Sefaxersen IgAN IMAGINATION data ● Ulefnersen FUS-ALS FUSION data ● Salanersen SMA Phase 3 initiation ● Sapablursen Polycythemia Vera Phase 3 initiation ● Key Phase 2 Clinical Events Program Indication Event IONIS-MAPTRx/ BIIB080 Alzheimer’s disease Phase 2 CELIA data ● Tominersen Huntington’s disease Phase 2 GENERATION HD2 data ● Tonlamarsen Uncontrolled hypertension Phase 2 data ● (1) Timing expectations based on current assumptions and subject to change.