Sefaxersen

- First independent launch underway following TRYNGOLZATM approval - - Second independent launch on track with donidalorsen PDUFA - - WAINUATM launch delivering accelerating sequential growth - - Ionis exceeds 2024 financial guidance and provides full year 2025 guidance - CARLSBAD, Calif. --(BUSINESS WIRE)--Feb. 19, 2025-- Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the “Company”) today reported financial results for the fourth quarter and full year ended December 31, 2024 . “With the recent launch of our first independent medicine, TRYNGOLZA for familial chylomicronemia syndrome, Ionis has begun a new chapter as a fully integrated commercial-stage biotechnology company,” said Brett P. Monia , Ph.D., chief executive officer, Ionis. “Over the next three years, we expect three more independent launches, including donidalorsen later this year for hereditary angioedema and olezarsen for severe hypertriglyceridemia in 2026, pending Phase 3 results in the second half of this year. Additionally, our partners are on track to launch four Ionis-discovered medicines over the same time period, including several that address broad patient populations. Ionis continues to advance our next wave of potentially transformational wholly owned medicines, including ION582 for Angelman syndrome, which is on track to start Phase 3 development in the first half of this year. Our recent achievements, combined with our strong commercial execution and advancing pipeline, position Ionis to deliver increasing value for all our stakeholders.” Fourth Quarter and Full Year 2024 Summary Financial Results(1): Three months ended December 31 , Year ended December 31 , 2024 2023 2024 2023 (amounts in millions) Total revenue $ 227 $ 325 $ 705 $ 788 Operating expenses $ 337 $ 331 $ 1,180 $ 1,141 Operating expenses on a non-GAAP basis $ 301 $ 305 $ 1,050 $ 1,035 Loss from operations $ (110 ) $ (6 ) $ (475 ) $ (353 ) Income (Loss) from operations on a non-GAAP basis $ (74 ) $ 20 $ (345 ) $ (247 ) (1) Reconciliation of GAAP to non-GAAP basis contained later in this release. Financial Highlights Revenue for the year ended December 31, 2024 substantially exceeded guidance as Ionis continued to generate revenue from diverse sources. Ionis added new sources of revenue in 2024 with the launch of WAINUA and TRYNGOLZA in the U.S. in late January and late December, respectively Operating expenses for the year ended December 31, 2024 were in line with expectations with increased expenses from commercialization efforts for WAINUA, TRYNGOLZA and donidalorsen Cash, cash equivalents and short-term investments of $2.3 billion as of December 31, 2024 exceeded revised guidance and enable continued investments to support ongoing and upcoming planned launches and advancing wholly owned medicines in development Recent Highlights- Marketed Medicines TRYNGOLZATM (olezarsen) launch underway following approval on December 19, 2024 in the U.S as first-ever treatment for adults living with familial chylomicronemia syndrome (FCS) as an adjunct to diet WAINUATM (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) achieved multiple commercial and regulatory milestones: Generated sales of $85 million resulting in royalty revenue of $20 million in the year ended December 31, 2024 . Substantial sequential growth throughout 2024 as launch progressed, including an 84% increase in product sales in the fourth quarter, compared to the third quarter Launch underway in numerous countries, including the UK , following approval by the Medicines and Healthcare products Regulatory Agency (MHRA) with an accelerated National Institute for Health and Care Excellence (NICE) recommendation Received positive Committee for Medicinal Products for Human Use (CHMP) opinion from European Medicines Agency (EMA) for the treatment of hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy SPINRAZA® (nusinersen) for the treatment of spinal muscular atrophy (SMA) generated global sales of $1.6 billion resulting in royalty revenue of $216 million in year ended December 31, 2024 . Product sales increased 2% in the fourth quarter of 2024, compared to the same period in 2023 Higher dose nusinersen under regulatory review in U.S. (PDUFA date of September 22, 2025 ) and EU QALSODY® (tofersen) for the treatment of SOD1-ALS generated global sales of $32 million resulting in royalty revenue of $4 million in the year ended December 31, 2024 . Product sales grew sequentially throughout 2024 Granted marketing approval in China and Japan Generated sales of $85 million resulting in royalty revenue of $20 million in the year ended December 31, 2024 . Substantial sequential growth throughout 2024 as launch progressed, including an 84% increase in product sales in the fourth quarter, compared to the third quarter Launch underway in numerous countries, including the UK , following approval by the Medicines and Healthcare products Regulatory Agency (MHRA) with an accelerated National Institute for Health and Care Excellence (NICE) recommendation Received positive Committee for Medicinal Products for Human Use (CHMP) opinion from European Medicines Agency (EMA) for the treatment of hereditary transthyretin-mediated amyloidosis in adult patients with stage 1 or stage 2 polyneuropathy Higher dose nusinersen under regulatory review in U.S. (PDUFA date of September 22, 2025 ) and EU Granted marketing approval in China and Japan Recent Highlights- Late-Stage Pipeline Olezarsen on track for Phase 3 data in patients with severe hypertriglyceridemia (sHTG) in H2:2025, positioning it to potentially treat this second more prevalent patient population with urgent unmet need Olezarsen and donidalorsen Canadian commercialization rights licensed to Theratechnologies Donidalorsen on track for potential launch this year as the first RNA-targeted prophylactic treatment for people with hereditary angioedema (HAE): Under review in U.S. (PDUFA date of August 21, 2025 ) and EU Presented positive Phase 2 open label extension (OLE) study data demonstrating an overall sustained mean reduction in HAE attack rates of 96% in patients treated up to three years with every four weeks or every eight weeks dosing ION582 on track to initiate Phase 3 development in Angelman syndrome (AS) in H1:2025 Ulefnersen global commercialization rights licensed to Otsuka; Phase 3 development ongoing for the treatment of patients with FUS-ALS Under review in U.S. (PDUFA date of August 21, 2025 ) and EU Presented positive Phase 2 open label extension (OLE) study data demonstrating an overall sustained mean reduction in HAE attack rates of 96% in patients treated up to three years with every four weeks or every eight weeks dosing Fourth Quarter, Full Year 2024 Financial Results and 2025 Financial Guidance “In 2024, we exceeded our revenue guidance due to our continued pipeline and technology successes, which drove a smaller than anticipated operating loss. Importantly, we added two new sources of commercial revenue with TRYNGOLZA product revenue from Ionis’ first independent launch and WAINUA royalties,” said Elizabeth L. Hougen , chief financial officer, Ionis. “In 2025, we will continue to invest in go-to-market activities for TRYNGOLZA for FCS and scale our resources to support our next planned launches, including donidalorsen for hereditary angioedema later this year. At the same time, we are investing in our next wave of medicines, including Phase 3 development and pre-commercialization activities for ION582 for Angelman syndrome. These important investments position Ionis to deliver substantial and growing product revenue; and when combined with increasing royalty revenue from anticipated partner launches, provides us with a clear path to achieve sustained positive cash flow.” Revenue Ionis’ revenue was comprised of the following: Three months ended Year ended December 31 , December 31 , 2024 2023 2024 2023 Revenue: (amounts in millions) Commercial revenue: SPINRAZA royalties $ 64 $ 62 $ 216 $ 240 WAINUA royalties 10 - 20 - Other commercial revenue: TEGSEDI and WAYLIVRA revenue, net 8 9 34 35 Other revenue 4 8 23 34 Total commercial revenue 86 79 293 309 Research and development revenue: Amortization from upfront payments 27 76 132 125 Milestone payments 30 11 106 101 License fees 34 92 71 117 Other services 6 - 24 10 Collaborative agreement revenue 97 179 333 353 WAINUA joint development revenue 44 67 79 126 Total research and development revenue 141 246 412 479 Total revenue $ 227 $ 325 $ 705 $ 788 Commercial revenue for the year ended December 31, 2024 included new sources of commercial revenue with the launch of WAINUA in the U.S. in late January 2024 and the launch of TRYNGOLZA in the U.S. in late December 2024 . SPINRAZA product sales in the U.S. increased slightly in 2024 compared to 2023. SPINRAZA product sales outside of the U.S. were impacted from an annual order from a single country that did not recur in 2024. R&D revenue decreased for the year ended December 31, 2024 compared to 2023 primarily due to the decrease in WAINUA joint development revenue as development activities relating to ATTRv-PN wound down with the launch of WAINUA. Operating Expenses Ionis’ operating expenses increased slightly for the year ended December 31, 2024 compared to 2023. SG&A expenses increased year over year primarily due to the launches of WAINUA and TRYNGOLZA, and advancing launch preparation activities for donidalorsen. R&D expenses were flat year over year. Balance Sheet As of December 31, 2024 , Ionis’ cash, cash equivalents and short-term investments were $2.3 billion , consistent with December 31, 2023 . In September 2024 , Ionis generated gross proceeds of $500 million from a public offering of its common stock. Ionis’ working capital increased as of December 31, 2024 , compared to December 31, 2023 primarily from the Company’s lower current liabilities as a result of lower deferred contract revenue. 2025 Financial Guidance The Company’s 2025 financial guidance reflects its evolution to a fully integrated commercial-stage biotechnology company independently launching its first medicine, TRYNGOLZA, and advancing commercialization efforts for multiple additional upcoming planned launches. As a result, the Company expects to earn substantial revenue from numerous diverse sources, with a shift toward increasing commercial revenue. Additionally, the Company expects a modest increase in its non-GAAP operating expenses in line with its plan to invest in the Company’s independent launches and advance its wholly owned pipeline of innovative medicines. The Company expects that these investments will enable Ionis to deliver accelerating value. Full Year 2025 Guidance Revenue > $600 million Operating loss on a non-GAAP basis < $495 million Cash, cash equivalents and short-term investments ~$1.7 billion Webcast Management will host a conference call and webcast to discuss Ionis’ fourth quarter and full year 2024 results at 11:30 a.m. Eastern time on Wednesday, February 19, 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 fourth quarter and full year 2024 earnings slides click here. 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). 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 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 Full Prescribing Information for WAINUA. About Ionis Pharmaceuticals, Inc. For three decades, Ionis has invented medicines that bring better futures to people with serious diseases. Ionis currently has six marketed medicines and a leading pipeline in neurology, cardiology 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 and technologies. 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, 2023 , 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 Pharmaceuticals ® is a registered trademark of Ionis Pharmaceuticals, Inc. TRYNGOLZATM is a trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics ® is a registered trademark of Akcea Therapeutics, Inc. TEGSEDI® is a registered trademark of Akcea Therapeutics, Inc. WAYLIVRA® is a registered trademark of Akcea Therapeutics, Inc. SPINRAZA® and QALSODY® are registered trademarks of Biogen. WAINUATM 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 , 2024 2023 2024 2023 (unaudited) Revenue: Commercial revenue: SPINRAZA royalties $ 64 $ 62 $ 216 $ 240 WAINUA royalties 10 - 20 - Other commercial revenue 12 17 57 69 Total commercial revenue 86 79 293 309 Research and development revenue: Collaborative agreement revenue 97 179 333 353 WAINUA joint development revenue 44 67 79 126 Total research and development revenue 141 246 412 479 Total revenue 227 325 705 788 Expenses: Cost of sales 4 3 11 9 Research, development and patent 245 257 902 900 Selling, general and administrative 88 71 267 232 Total operating expenses 337 331 1,180 1,141 Loss from operations (110 ) (6 ) (475 ) (353 ) Other income (expense): Interest expense related to the sale of future royalties (19 ) (18 ) (73 ) (69 ) Other income, net 22 21 88 88 Loss before income tax benefit (expense) (107 ) (3 ) (460 ) (334 ) Income tax benefit (expense) 3 (6 ) 6 (32 ) Net loss $ (104 ) $ (9 ) $ (454 ) $ (366 ) Basic and diluted net loss per share $ (0.66 ) $ (0.06 ) $ (3.04 ) $ (2.56 ) Shares used in computing basic and diluted net loss per share 158 144 150 143 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 , 2024 2023 2024 2023 (unaudited) As reported research, development and patent expenses according to GAAP $ 245 $ 257 $ 902 $ 900 Excluding compensation expense related to equity awards (25 ) (20 ) (92 ) (78 ) Non-GAAP research, development and patent expenses $ 220 $ 237 $ 810 $ 822 As reported selling, general and administrative expenses according to GAAP $ 88 $ 71 $ 267 $ 232 Excluding compensation expense related to equity awards (11 ) (6 ) (37 ) (27 ) Non-GAAP selling, general and administrative expenses $ 77 $ 65 $ 230 $ 205 As reported operating expenses according to GAAP $ 337 $ 331 $ 1,180 $ 1,141 Excluding compensation expense related to equity awards (36 ) (26 ) (130 ) (106 ) Non-GAAP operating expenses $ 301 $ 305 $ 1,050 $ 1,035 As reported loss from operations according to GAAP $ (110 ) $ (6 ) $ (475 ) $ (353 ) Excluding compensation expense related to equity awards (36 ) (26 ) (130 ) (106 ) Non-GAAP loss from operations $ (74 ) $ 20 $ (345 ) $ (247 ) As reported net loss according to GAAP $ (104 ) $ (9 ) $ (454 ) $ (366 ) Excluding compensation expense related to equity awards and related tax effects (36 ) (26 ) (130 ) (106 ) Non-GAAP net loss $ (68 ) $ 17 $ (324 ) $ (260 ) 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 , 2024 2023 (unaudited) Assets: Cash, cash equivalents and short-term investments $ 2,298 $ 2,331 Contracts receivable 92 98 Other current assets 230 213 Property, plant and equipment, net 94 71 Right-of-use assets 162 172 Other assets 127 105 Total assets $ 3,003 $ 2,990 Liabilities and stockholders’ equity: Current portion of deferred contract revenue $ 79 $ 151 0.125% convertible senior notes, net – short-term - 44 Other current liabilities 229 253 1.75% convertible senior notes, net 565 562 0% convertible senior notes, net 629 625 Liability related to sale of future royalties, net 542 514 Long-term lease liabilities 162 171 Long-term obligations, less current portion 52 42 Long-term deferred contract revenue 157 241 Total stockholders’ equity 588 387 Total liabilities and stockholders’ equity $ 3,003 $ 2,990 Key 2025 and 2026 Value Driving Events(1) New Product Launches Program Indication 2025 2026 Donidalorsen ( U.S. ) HAE • TRYNGOLZA ( U.S. ) FCS Achieved WAINZUA (EU) ATTRv-PN • Olezarsen ( U.S. ) sHTG • Zilganersen ( U.S. ) Alexander disease • Regulatory Actions Program Indication Regulatory Action 2025 2026 Donidalorsen HAE U.S. approval decision • EU approval decision • TRYNGOLZA FCS EU approval decision • 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 • WAINZUA ATTRv-PN EU approval decision • 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 and Essence data • Zilganersen Alexander disease Phase 3 data • ION582 Angelman syndrome Phase 3 study start • Phase 3 enrollment completion • Pelacarsen Lp(a)-CVD HORIZON data • Bepirovirsen HBV B-Well data • Eplontersen ATTR-CM CARDIO-TTRansform data • Sefaxersen IgAN IMAGINATION data • Ulefnersen FUS-ALS Phase 3 data • (1) Timing expectations based on current assumptions and subject to change. • View source version on businesswire.com: https://www.businesswire.com/news/home/20250219347982/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.

近期，恒瑞医药公布了CFB抑制剂HRS-5965治疗阵发性睡眠性血红蛋白尿（PNH）患者的II期研究结果，早期数据表明略优于诺华的Iptacopan（伊普可泮）。 而据Evaluate预测，伊普可泮2028年销售额将达到11亿美元（约合人民币80亿元）。 瞄准80亿大药 一年一度的美国血液学会（ASH）年会，即将于12月盛大开启。恒瑞医药将在本次会议上公布HRS-5965治疗阵发性睡眠性血红蛋白尿（PNH）的II期研究结果。 HRS-5965是新型口服CFB抑制剂，在研适应症包括PNH（III期）、IgA肾病（II期）、补体参与介导的原发性/继发性肾小球疾病（Ⅰ期）、补体参与介导的溶血性贫血（Ⅰ期）。其中，PNH是一种罕见的危及生命的补体诱导的溶血性疾病。 根据已公布的摘要显示，在未接受补体抑制剂治疗的PNH患者中，HRS-5965单药治疗（50 mg或75 mg）可降低LDH水平并且快速、持久、无需输血的改善血红蛋白水平，而且两种剂量均耐受良好，表明其有望为PNH患者群体提供一种新的治疗选择。 同类竞品中，全球仅有诺华的Iptacopan（伊普可泮）于去年12月获批上市，目前已相继拿下PNH和IgA肾病两个适应症，Evaluate预测该药2028年销售额将达到11亿美元（约合人民币80亿元）。 伊普可泮的市场前景，体现在头对头击败了阿斯利康两大补体C5抑制剂——Soliris（依库珠单抗）和Ultomiris（瑞利珠单抗），而这两款产品2023年销售额分别高达31.45亿美元、29.65亿美元。2020年，阿斯利康豪掷390亿美元收购亚力兄（Alexion），将这两款产品纳入囊中。 图片来源：平安证券研报 事实上，C5抑制剂并非完美无缺。作为针对补体蛋白C5进行抑制的药物，由于它不能完全阻断补体系统，尤其是C3介导的血管外溶血途径，导致一些PNH患者在治疗后出现残留贫血。 相比之下，CFB抑制剂通过作用于补体因子B（即C3激活剂前体），能够更有效地减少血管内和血管外溶血，从而帮助患者改善血红蛋白水平，甚至可能无需输血。 此外，CFB抑制剂是口服给药，相比抗C5疗法的静脉注射方式更具依从性，能满足患者对于便捷、灵活治疗方式的需求。 目前，恒瑞医药HRS-5965已经启动了头对头依库珠单抗用于PNH的III期研究。值得一提的是，HRS-5965在治疗PNH的II期研究中，显示出了略优于伊普可泮的早期数据。 据II期研究结果显示（主要终点是血红蛋白从基线到第12周的变化），在第12周，HRS-5965的50 mg BID组和75 mg BID组的血红蛋白水平均较基线明显升高（LSM分别为37.6 g/L和37.7 g/L），且LDH水平平均下降87%和85%。 而伊普可泮首次人体研究的中期结果数据显示，两种给药组（25 mg/100 mg、50 mg/200 mg组）血红蛋白水平平均改善+26.7 g/L、+32.1 g/L，LDH水平在第12周均下降了86%。 当然，目前还无法确定HRS-5965的最终疗效是否能超过伊普可泮，需要更多的临床数据和长期观察来验证。但HRS-5965不是恒瑞医药唯一布局的补体系统靶向疗法。 肾病赛道迎大变革？ 无论CFB抑制剂还是补体C5抑制剂，都属于补体系统靶向疗法的范畴。 补体系统是参与机体免疫反应和炎症反应的重要系统之一，当补体系统发生异常激活时，会攻击自身细胞，导致免疫性疾病。 目前，针对补体系统异常激活的补体活化途径，包括经典途径、凝集素途径和替代途径（又称旁路途径），由此也诞生了多种药物类别，包括补体C5aR抑制剂、C3补体抑制剂、MASP2抑制剂等。 有研究表明，IgA肾病的病情进展与凝集素途径和旁路途径有关。恒瑞医药另一款针对IgA肾病的补体系统靶向疗法SHR-2010，就是基于凝集素途径研发的MASP2抑制剂，目前已处于Ⅱ期临床。 在肾病治疗领域，恒瑞还布局了针对IgA肾病的SHR-2173、布地奈德缓释胶囊，针对慢性肾脏病的HRS-1780（盐皮质激素），以及处于Ⅲ期临床的SHR6508（拟钙剂），一种作用于钙敏感受体（CaSR）的变构调节剂，适应症为慢性肾脏病维持性血液透析患者的继发性甲状旁腺功能亢进。 恒瑞医药肾病治疗领域的管线 图片来源：恒瑞医药2024年半年报 特别是IgA肾病，由于患者数量庞大且缺少治疗手段，现已成为制药巨头的必争之地。 例如，诺华不仅拥有CFB抑制剂Iptacopan（伊普可泮），还在2023年以35亿美元收购Chinook，拿下了ETA拮抗剂Atrasentan（阿曲生坦）和APRIL单抗Zigakibart；今年4月，Vertex（福泰制药）也宣布斥资49亿美元收购Alpine，拿下后者核心管线Povetacicept（APRIL/BAFF双重拮抗剂）。 当然，IgA肾病只是补体系统靶向疗法的其中一个应用。 例如，罗氏与ASO领头羊Ionis公司合作开发的CFB反义疗法IONIS-FB-LRx，除了正在开展治疗lgA肾病的Ⅲ期临床，也曾探索用于地理萎缩（GA）。 安斯泰来也在2023年5月豪掷59亿美元收购Iveric Bio，押注后者的补体C5抑制剂Izervay（Avacincaptad pegol），该药于去年8月获FDA批准用于治疗年龄相关性黄斑变性（AMD）继发地图样萎缩（GA）。据统计，2020年全球约有2亿AMD患者。 阿斯利康的长效补体C5抑制剂瑞利珠单抗，除已获批治疗PNH，还斩获了非典型溶血性尿毒症综合征（aHUS）、重症肌无力、视神经脊髓炎等多种自免疾病。今年前9个月，瑞利珠单抗收入同比大增35%至28.35亿美元，超过了上一代产品依库珠单抗（同比增长11%至20.45亿美元）。 此外，阿斯利康还布局了第三代C5抑制剂Gefurulimab，目前正在国内开展治疗重症肌无力的III期临床，有望成为一款可居家用药的每周1次的皮下注射疗法。 新风口来临 补体系统靶向疗法展现出的市场前景，也吸引了其他中国药企下场布局，包括再鼎医药、康诺亚、科越医药、天辰生物等。 今年5月，再鼎医药与合作伙伴再生元在中国启动了C5抗体Pozelimab与C5靶向siRNA疗法Cemdisiran联合治疗阵发性夜间血红蛋白尿（PNH）的Ⅲ期试验。此外，该联合疗法还在开发用于重症肌无力症。 目前，Pozelimab已于2023年获FDA批准上市，成为FDA批准的首款治疗成人和1岁以上儿童CD55缺乏型蛋白丢失性肠病（CHAPLE）药物。 康诺亚研发了MASP-2单抗CM338，现已进入临床研究阶段；科越医药开发了全球首创的双功能抗C5抗体和因子H融合蛋白KP104，并在2024 EHA会议上公布了II期研究结果，显示出可作为PNH新型单药疗法但同时靶向补体旁路途径和末端途径的同类最佳治疗（BIC）的潜力。 另外，天辰生物开发的全球首创补体双功能抗体LP-005，是一款靶向C5/C3的双特异性抗体，预计2024年内启动II期临床试验，在研适应症包括PNH、IgA肾病等，特点在于可同时抑制三条补体信号通路，并具备一个月给药一次的便利性优势。 值得一提的是，朗来科技全资子公司美悦生物的CFB抑制剂MY008211A片，是中国企业自主研发的首个进入PNH临床试验的小分子药物，目前已进入III期阶段。 综上可见，补体系统靶向疗法的风口正在来临。令人欣慰的是，中国药企的管线中不乏创新药物，无疑值得期待。 来源：药智网 作者：粽哥2025 商务合作 130 6172 3098 zakk.cui@siqibest.com 点击 阅读原文 了解更多