Pelacarsen

1.恒瑞药业核心管线：HRS-5635：靶向HBV（乙肝病毒），II期临床，2025年9月获CDE公示拟纳入突破性疗法目录，是全球进展较快的国产乙肝siRNA药物之一。HRS-7249：高脂血症（与拓界生物合作），2024年6月获临床试验，目前高脂血症处于临床II期。HRS-9563：siRNA高血压，正在推进I期临床试验。HRS-5817：超重/肥胖（INHBE靶点），2025年3月获批临床，正在开展I期临床研究。HRS-2141：2型糖尿，IND获批，2025年10月获批临床，拟开展2型糖尿病适应症试验。25年3月恒瑞将旗下Lp(a)小分子抑制剂HRS5346的海外权益(临床II期)，以总交易额19.7亿美元授权给默沙东，其中首付款达2亿美元。2.瑞博生物(HK06938)，瑞博生物今年1月刚在港股上市，成为"小核酸第一股"，已有7款产品进入临床，覆盖心血管、代谢、肾病等多领域，其中针对心血管和肝病的管线进展较快，构建了拥有自主知识产权的三大核心技术平台——RiboGalSTAR™（肝靶向）、RiboPepSTAR™（肝外靶向）和RiboOncoSTAR™（肿瘤）。2024年勃林格殷格翰与瑞博生物达成20亿美元合作，共同开发MASH领域小核酸疗法。核心管线：核心产品SR059，靶向FXI的siRNA药物，以长效、低出血风险的优势突破传统抗凝疗法痛点，处于临床II期。26年2月6号，拜耳公布了FXI小分子抑制剂asundexian在全球三期临床的积极结果，能使复发缺血瘁中相对风险降低26%且不增加重大出血风险。SR043，23年12月将在大中华区授权给齐鲁制药，PCSK9靶点siRNA，交易金额达7亿美元，处于II期临床。RBD5044，紧随Arrowhead同类药物的获批路径，治疗高甘油三酯血症的小核酸药物,欧盟处于临床II期，国内26年已进入II期。RBD1016，基于HBV靶点，其适应症包括慢性乙型肝炎（CHB）和丁型肝炎（HDV），处于临床II期；SR044，Apoc3靶点，混合型高脂血症，临床II期。26年2月与全球制药企业MadrigalPharmaceuticals达成全球独家许可协议，双方将基于肝靶向RiboGalSTAR平台，联合开发六款针对代谢功能障碍相关脂肪性肝炎(MASH)的创新siRNA疗法，获6000万美元首付款，潜在交易总金额高达44亿美元。3.舶望制药核心管线：BW-00112(ANGPTL3靶点）美国处于II期临床，适应症为混合型高脂血症高胆固醇血症；BW-20507（HBV靶点），适应症为慢性乙肝，国内处于II期临床；BW-20805（PKK靶点），适应症为遗传性血管性水肿，国内处于II期；BW-40202（CFB靶点），适应症为IGA肾病，国内处于II期。BW-00163(AGT靶点），美国处于II期临床，国内I期，适应症为高血压；领先的RADS平台技术，管线聚焦于心血管疾病、神经系统疾病、病毒性肝炎、代谢疾病、罕见病等领域，已有5个新药处于临床阶段。与诺华深化战略合作，加速心血管疾病新药研发。舶望制药与诺华于2024年1月、2025年9月两度达成战略合作，聚焦心血管领域siRNA疗法，两次合作交易总额总潜在价值超95亿美元，是国内siRNA领域最大的海外授权交易之一。4.圣因生物核心管线：SGB-9768，基于C3靶点，IgA肾病，C3小球病、免疫复合物介导的膜增生性肾小球肾炎3个适应症，处于临床II期。SGB-3383，基于CFB靶点，非典型溶血尿毒综合症、阵发性睡眠性血红蛋白尿疹，处于临床I期。SGB-3908，基于AGT靶点，高血压，处于临床I期。SGB-7342，基于INHBE靶点，肥胖症，处于临床I期分别在25年11月与礼来达成12亿美元基于平台的总包合作，26年2月与罗氏达成首付2亿美元，总包17亿美元的合作。圣因生物25年12月完成超1.1亿美元B轮融资。目前布局了17条管线，涵盖自免疾病、心血管疾病、代谢疾病/肥胖、凝血功能障碍等未满足的领域。具有自主知识产权的GalNAc肝脏递送平台和专有的LEAD™（新型配体与增效基团协同递送）肝外递送平台。5、成都先导（688222）：核心管线：LDR2402注射液，25年进入II期临床试验，AGTsiRNA（高血压）临床前数据优于Alnylam与罗氏（Roche）合作开发的Zilebesiran（待完成11000名患者III期临床，每6个月给药）；A24110He，靶点ANGPTL4siRNA（降血脂），处于临床II期；LDR005INHBEsiRNA（减肥），2个月超长效设计差异化显著，I期临床。基于寡核苷酸的药物研发平台，自主开发肝外靶向递送系统（优于Alnylam的C16平台），突破小核酸非肝靶向递送瓶颈，支持心血管、中枢神经系统（CNS）等多器官治疗。公告预计2025年归母公司净为10,400.00万元到12,700.00万元，与同比增加102.50%到147.29%。归母扣非净利为10,600.00万元到12,900.00万元，与上年同期相比，将增加4,856.28万元到7,156.28万元，同比增加84.55%到124.59%。6.圣诺医药（HK2257），小核酸第一股（港股）核心管线：涉肿瘤、局域减脂、医美、心血管诸症，多项产品循序推进临床。STP705：TGF-β1/COX-2双靶siRNA，用于皮肤鳞癌（isSCC）、基底细胞癌（BCC）、肝癌等，皮肤鳞癌与基底细胞癌美国II期临床（IIb数据显示实现了100%完全清除）脂肪重塑美国I期；STP707：TGF-β1/COX-2双靶siRNA，实体瘤胰腺癌，25年12月完成临床I期期。STP122G，靶向XI因子，抗凝剂血栓性疾病，美国I期。PNP多肽纳米导入台，破肝外递送之限，可精准靶向皮肤、脂肪、肌肉诸组织和GalaHead递送台，专适肝脏递送，具长效给药之能，无偶联物小核酸双靶点。7、信立泰（002294）核心管线：SAL0132（AGTsiRNA）双靶小核酸，适应症为高血压，处于临床II期。SAL0145注射液，治疗代谢功能障碍相关脂肪性肝炎（MASH），26年1月IND，开展I期临床。8、石药集团核心管线：SYH2053（PCSK9siRNA），长效降脂药，对照药英格司兰纳，已进入II期临床试验；SYH2061（靶向C5的siRNA），2025年11月进入临床I期；SYH2062（AGTsiRNA），适应症为高血压，处于I期临床；SYH2068（Lp(a)siRNA），适应症方向为高血脂，25年4月获批处于I期临床阶段。2024年10月，石药集团与阿斯利康达成Lp(a)小分子药物YS2302018授权交易，总交易金额达20.2亿美元，首付款1亿美元。26年1月石药集团再次与阿斯利康授权合作，在全球范围内（不含中国内地及港澳台地区）独家开发、生产与商业化八个创新长效多肽药物项目，包括SYH2082（长效GLP1R/GIPR激动剂，I期临床），以及3个处于临床前阶段、具备不同作用机制的研发项目。阿斯利康支付合计12亿美元的总首付款和最高185亿美元里程碑款项。公司拥有siRNA、mRNA、ADC、纳米药物等八大创新技术平台，依托siRNA创新技术平台，小核酸药物在心血管领域布局领先，目前已有3款siRNA药物进入临床阶段。9、再生元（美股REGN）核心管线：Cemdisiran，靶向C5siRNA药物，全身性重症肌无力（gMG），III期临床，预计26年向FDA报产BLA；针对肾脏疾病（IgA肾病）II期临床试验中。ALN-APP（靶向淀粉样前体蛋白APP），与Alnylam合作开发的一款siRNA药物，针对早发性阿尔茨海默病（EOAD），I期临床。10、福元医药（601089.SH）核心管线：FY101：ANGPTL3靶点siRNA，用于高甘油三酯血症/混合型高脂血症进展：Ⅰ期完成，2026年启动Ⅱ期首例给药，快速跟随Alnylam验证靶点。FY103：2025年12月申报IND，启动I期临床。11、悦康药业（688658.SH）核心管线：YKYY015：PCSK9靶点siRNA，用于高胆固醇血症/降血脂，6个月给药一次，对标诺华（英克司兰纳Inclisiran），Ⅰ期临床。进展：24年7月、10月美中双报IND，Ia期SAD临床研究已完成，结果显示该药物拥有良好的安全性和耐受性，北京协和医院顺利启动Ib期临床试验；YKYY013：乙肝siRNA，25年9月、11月提交美中IND，处于临床I期；YKYY029：降压siRNA，25年7月中美双报，处于Ⅰ期临床。2025年年度实现归属于母公司所有者的净利润为-28,000.00万元到-23,500.00万元；实现归母扣非净为-30,500.00万元到-26,000.00万元。12、君实生物（688180.SH/01877.HK）核心管线：JS401：ANGPTL3siRNA，针对代谢性疾病用于高脂血症，处于I期临床。RP903：肿瘤适应症siRNA药物，处于I期临床。IAMA-001：免疫调节小核酸鼻用喷雾剂，主要用于治疗季节性过敏性鼻炎。从吉盛澳玛引进，支付4000万元首付款，相应里程碑款及销售提成，总交易金额最高超过15亿元。董事长熊俊自2025年4月12日起12个月内，增持公司A股股份及H股股份，合计增持金额不低于1亿元，其中A股不低于人民币5,000万元。截至26年1月底，累计增持公司A股100,000股，累计成交总额为人民币383.84万元。公告预计2025年归母扣非净-98,500.00万元左右，与上年同期相比亏损减少30,488.79万元左右。13、前沿生物U(688221.SH)、核心管线：FB7011：（MASP-2、CFB）双靶siRNA，用于IgA肾病，预计26年上半年IND；FB7013：MASP-2的单靶点药物，用于IgA肾病，有望实现每6个月给药一针，25年12月向NMPA递交IND；26年2月与葛兰素史克GSK达成合作，独家授权许可协议，7011和7013，获得首付款4000万美元和最高9.63亿美元里程碑款项。此前2025年11月美国肾脏病学会（ASN）发布该小核酸药物，在食蟹猴IgAN模型中最新的临床前药效数据。技术亮点：自研ACORDE递送系统，实现肾靶向，动物数据优于国际竞品。2025年1-12月预计增亏,归属于上市公司股东的净利润为-2.90亿至-2.55亿,净利润同比下降44.00%至26.62%,预计营业收入为1.40亿至1.45亿，同比增加8.13%到11.99%。14、海昶生物HC0301（AKT-1ASO，原发性肝癌）：同步推进中美国际多中心II期临床，是全球小核酸肿瘤治疗领域进展最快的管线之一。HC016（TLR9免疫激动剂，脂质复合物注射液）：已获得中美IND批件，进入临床I期，用于实体瘤。聚焦药物递送系统技术开发与产业化应用，构建了具有自主知识产权的QTsome®等技术平台，主要适应症聚焦于肿瘤。还有如信达生物、靖因药业、迈威生物(2025年9月迈威生物与AditumBio宣布成立KalexoBio，就心血管领域双靶点siRNA创新药2MW7141达成全球独家授权协议，获得最高可达10亿美元的预付款与里程碑付款和1200万美元的首付款)等。综上所述，1、小核酸药物在已上市产品，最近获批的是Arrowhead旗下Plozasiran普乐司兰纳（ARO-APOC3）25年11月、26年1月先后获得美国与中国（授权赛诺菲）批准，用于治疗家族性乳糜微粒血症综合征和严重高甘油三酯血症。截止25年底，全球共获批上市23款，13款ASO药物、8款siRNA药物、2款核酸适配体药物。其中遗传罕见病类目是获批最多的适应症类别，16款小核酸药物是针对遗传罕见病，3款针对眼科疾病，2款针对心血管疾病，1款针对血液肿瘤并发症。2024年全球小核酸药物52.47亿美元，其中已获批的siRNA+ASO药物销售总额达到41.25亿美元，据MaximizeMarketResearch统计，到2029年小核酸治疗市场预计将大幅增长至392亿美元。2、接下去面临申报上市的有GSK旗下成为全球首款乙肝功能性治愈药物Bepirovirsen；2026年上半年Ionis/罗氏的CFBASO管线Sefaxersen有望读出IgA肾病的三期数据，冲击肾病的第一个小核酸重磅炸弹，会给国内类似靶点企业舶望、再生元、圣因生物、$前沿生物-U(SH688221)$带来验证与利好。处于III期临床数据罗氏全球首个高血压小核酸药物Zilebesiran若读出良好数据，高血压疾病有望实现长效治疗（6个月一针），则给处于II期临床$成都先导(SH688222)$成都先导、$信立泰(SZ002294)$、舶望（美国）和处于I期临床的舶望（中国）、恒瑞医药等类似适应症带来利好。3、目前进展较快处于临床III期一个热门靶点是脂蛋白[Lp(a)]，诺华的pelacarsen（有望26年上公布数据），安进的olpasiran和礼来的lepodisiran，国内恒瑞授权默沙东（脂蛋白a水平升高）处于临床II期，石药集团授权阿斯利康（脂蛋白a水平升高）处于临床I期。4、国内企业进展最快的是再生元1款产品（全身性重症肌无力）进入III期末,Cemdisiran是一款靶向补体C5的siRNA疗法，以及针对IgA肾病适应症处于II期。瑞博生物（5个）、舶望生物（5个）多个产品进入临床II期。恒瑞医药（乙肝和脂蛋白a水平升高）和成都先导（降血脂和高血压）以及圣诺医药（皮肤鳞癌和胰腺癌）各有2个处于临床II期。石药（长效降脂）、信立泰（高血压）、福元（高血脂）、海昶（原发性肝癌）圣因生物（IgA肾病，C3小球病、免疫复合物介导的膜增生性肾小球肾炎）均有1款产品进入II期。悦康、君实、前沿生物处于临床I期。小核酸药物九问及相关上市公司简介（一）#分散染料板块拉升，海翔药业涨停#

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.