Sefaxersen

CARLSBAD, Calif.--(BUSINESS WIRE)--Ionis Pharmaceuticals, Inc. (Nasdaq: IONS) (the “Company”) today reported financial results and provided key updates for the second quarter ended June 30, 2025. “During the second quarter, we continued to build momentum across our business,” said Brett P. Monia, Ph.D., chief executive officer of Ionis. “Our strong performance included excellent commercial execution, resulting in a substantial increase in TRYNGOLZA revenues, our first independently launched medicine. We expect additional advancements in the second half, including Ionis’ second independent launch with donidalorsen for hereditary angioedema, anticipated next month, and important Phase 3 results for olezarsen in severe hypertriglyceridemia and zilganersen in Alexander disease. We believe these four programs collectively represent multi-billion-dollar revenue potential and a transformational opportunity for Ionis and for patients.” Second Quarter 2025 Summary Financial Results(1): Three months ended Six months ended June 30, June 30, 2025 2024 2025 2024 (amounts in millions) Total revenue $452 $225 $584 $345 Operating expenses $312 $291 $591 $560 Operating expenses on a non-GAAP basis $282 $260 $532 $498 Income (loss) from operations $140 ($66) ($7) ($215) Income (loss) from operations on a non-GAAP basis $170 ($35) $52 ($153) (1) Reconciliation of GAAP to non-GAAP basis contained later in this release. Recent Financial Highlights Revenue doubled in the second quarter of 2025 and increased nearly 70% in the first half compared to the same period last year, driven by the continued successful launch of TRYNGOLZA and increased royalty and R&D revenues Operating expenses increased by single digits in the second quarter and first half of 2025, compared to the same periods last year, primarily due to investments related to commercialization efforts for TRYNGOLZA, donidalorsen and WAINUA Increased 2025 financial guidance reflects an improved outlook for the full year, strong overall revenue performance experienced year-to-date, including the early strength in TRYNGOLZA revenues: Full Year 2025 Guidance Previous Guidance New Guidance Total Revenue $725-750 million $825-850 million TRYNGOLZA product sales, net Not provided $75-80 million Operating loss on a non-GAAP basis <$375 million $300-325 million Cash, cash equivalents and short-term investments ~$1.9 billion ~$2.0 billion Second Quarter 2025 Financial Results “For the second time this year, we are significantly raising our 2025 financial guidance — this time driven by an improved outlook for the year and strong revenue performance to date, which includes the early launch excellence with TRYNGOLZA. In addition to strong commercial performance, our second quarter results included the substantial revenue we earned from licensing sapablursen, a medicine outside our core areas of focus. We are in a strong financial position, with a commitment to drive operating leverage as we continue executing on our strategic priorities,” said Elizabeth L. Hougen, chief financial officer, Ionis. “Moving forward, the three additional independent launches anticipated over the next eighteen months, including donidalorsen for hereditary angioedema, olezarsen in severe hypertriglyceridemia and zilganersen in Alexander disease, position Ionis to deliver substantial and growing product revenue. This product revenue, coupled with anticipated increasing royalty revenue from multiple partner launches, along with disciplined investment, position Ionis to achieve sustained growth and positive cash flow in the next few years.” Recent Highlights - Wholly Owned Medicines TRYNGOLZA TM (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 $19 million in the second quarter of 2025, its second full quarter on the market, and $26 million in the first half of 2025 Received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), paving the way to bring TRYNGOLZA to patients across Europe Generated net product sales of $19 million in the second quarter of 2025, its second full quarter on the market, and $26 million in the first half of 2025 Received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP), paving the way to bring TRYNGOLZA to patients across Europe Olezarsen on track for topline Phase 3 data from pivotal CORE and CORE2 studies in patients with sHTG in September 2025, positioning olezarsen to potentially treat this second, more prevalent patient population with high unmet need Announced positive topline results from the Essence study in people with moderately elevated triglycerides; achieved primary and all key secondary endpoints for 80 mg and 50 mg monthly doses with favorable safety and tolerability Announced positive topline results from the Essence study in people with moderately elevated triglycerides; achieved primary and all key secondary endpoints for 80 mg and 50 mg monthly doses with favorable safety and tolerability Donidalorsen on track to launch this year, assuming approval, with a U.S. PDUFA date of August 21, 2025 Poised to transform the treatment paradigm for individuals with hereditary angioedema (HAE) as the 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 monthly or every other month Donidalorsen is currently under regulatory review in the EU Poised to transform the treatment paradigm for individuals with hereditary angioedema (HAE) as the 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 monthly or every other month Donidalorsen is currently under regulatory review in the EU First patient dosed in the Phase 3 REVEAL study of ION582, an investigational medicine for the treatment of people living with Angelman syndrome (AS), a serious and rare neurodevelopmental disorder Recent Highlights – Partnered Medicines WAINUA TM (eplontersen) (WAINZUA in EU) for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (ATTRv-PN) continues to perform well, achieving several important commercial milestones: Generated sales of $44 million and $84 million resulting in royalty revenue of $10 million and $20 million in the second quarter and first half of 2025, respectively New launches underway in numerous regions, including the EU; additional submissions in progress to expand WAINUA access globally Generated sales of $44 million and $84 million resulting in royalty revenue of $10 million and $20 million in the second quarter and first half of 2025, respectively New 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 $393 million and $817 million resulting in royalty revenue of $54 million and $102 million in the second quarter and first half of 2025, respectively Higher dose nusinersen under review for marketing approval in the U.S. (PDUFA date of September 22, 2025) and in the EU Higher dose nusinersen under review for marketing approval in the U.S. (PDUFA date of September 22, 2025) and in the EU Biogen to advance salanersen (formerly ION306/BIIB115), an investigational medicine for SMA into registrational studies based on positive interim Phase 1 results; developed using novel Ionis antisense chemistry with the potential to achieve high efficacy and annual dosing Phase 1 data with salanersen in SMA patients showed substantial slowing of neurodegeneration and clinically meaningful improvements in patients previously treated with gene therapy Phase 1 data with salanersen in SMA patients showed substantial slowing of neurodegeneration and clinically meaningful improvements in patients previously treated with gene therapy AstraZeneca initiated the Phase 2b study of opemalirsen (formerly ION532/AZD2373), an investigational medicine designed to reduce the production of apolipoprotein L1 (APOL1) for the treatment of APOL1-mediated kidney disease (AMKD) triggering a $30 million milestone payment to Ionis Corporate Updates In June 2025, Ionis announced that Richard Geary, Ph.D., executive vice president and chief development officer, will retire effective January 2026 and that Holly Kordasiewicz, Ph.D., currently senior vice president, neurology, will succeed him in the role Revenue Ionis’ revenue was comprised of the following: Three months ended Six months ended June 30, June 30, 2025 2024 2025 2024 Revenue: (amounts in millions) Commercial revenue: Product sales, net: TRYNGOLZA sales, net $19 $- $26 $- Total product sales, net 19 - 26 - Royalty revenue: SPINRAZA royalties 54 57 102 95 WAINUA royalties 10 4 20 5 Other royalties 6 3 12 13 Total royalty revenue 70 64 134 113 Other commercial revenue: TEGSEDI and WAYLIVRA revenue, net 14 8 19 17 Other revenue - - - 2 Total commercial revenue 103 72 179 132 Research and development revenue: Collaborative agreement revenue 337 141 382 191 WAINUA joint development revenue 12 12 23 22 Total research and development revenue 349 153 405 213 Total revenue $452 $225 $584 $345 Commercial revenue for the second quarter and first half of 2025 increased 43% and 36% respectively, compared to the same periods in 2024. This increase was 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., reflecting the value that Ionis’ pipeline and technology continues to generate. Operating Expenses SG&A expenses increased as anticipated for the second quarter and first half of 2025, compared to the same periods in 2024, primarily due to the launches of TRYNGOLZA and WAINUA, and advancing launch preparation activities for donidalorsen. 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. Balance Sheet As of June 30, 2025, Ionis’ cash, cash equivalents and short-term investments were $2.3 billion, consistent with December 31, 2024. Ionis received $280 million from the global license of sapablursen in the second quarter of 2025. 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’ second quarter 2025 results at 11:30 a.m. Eastern time on Wednesday, July 30, 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 second quarter 2025 earnings slides click here. Ionis will be initiating a quiet period starting July 31, 2025, as the Company plans to announce the topline results from both the CORE and CORE2 studies simultaneously. The quiet period will be lifted upon the data announcement, expected in September. 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 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, cardiology, and other 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, 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. 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 Six months ended June 30, June 30, 2025 2024 2025 2024 (unaudited) Revenue: Commercial revenue: Product sales, net $19 $- $26 $- Royalty revenue 70 64 134 113 Other commercial revenue 14 8 19 19 Total commercial revenue 103 72 179 132 Research and development revenue: Collaborative agreement revenue 337 141 382 191 WAINUA joint development revenue 12 12 23 22 Total research and development revenue 349 153 405 213 Total revenue 452 225 584 345 Expenses: Cost of sales 4 4 6 6 Research, development and patent 217 222 418 436 Selling, general and administrative 91 65 167 118 Total operating expenses 312 291 591 560 Income (loss) from operations 140 (66) (7) (215) Other income (expense): Interest expense related to the sale of future royalties (19) (18) (37) (36) Other income, net 3 18 21 42 Income (loss) before income tax benefit (expense) 124 (66) (23) (209) Income tax benefit (expense) - - - - Net income (loss) $124 ($66) ($23) ($209) Basic net income (loss) per share $0.78 ($0.45) ($0.15) ($1.43) Diluted net income (loss) per share $0.70 ($0.45) ($0.15) ($1.43) Shares used in computing basic net income (loss) per share 159 146 159 146 Shares used in computing diluted net income (loss) per share 182 146 159 146 IONIS PHARMACEUTICALS, INC. Reconciliation of GAAP to Non-GAAP Basis: Condensed Consolidated Operating Expenses, Income (Loss) From Operations, and Net Income (Loss) (In Millions) Three months ended June 30, Six months ended June 30, 2025 2024 2025 2024 (unaudited) As reported research, development and patent expenses according to GAAP $217 $222 $418 $436 Excluding compensation expense related to equity awards (20) (23) (40) (45) Non-GAAP research, development and patent expenses $197 $199 $378 $391 As reported selling, general and administrative expenses according to GAAP $91 $65 $167 $118 Excluding compensation expense related to equity awards (10) (8) (19) (17) Non-GAAP selling, general and administrative expenses $81 $57 $148 $101 As reported operating expenses according to GAAP $312 $291 $591 $560 Excluding compensation expense related to equity awards (30) (31) (59) (62) Non-GAAP operating expenses $282 $260 $532 $498 As reported income (loss) from operations according to GAAP $140 ($66) ($7) ($215) Excluding compensation expense related to equity awards (30) (31) (59) (62) Non-GAAP income (loss) from operations $170 ($35) $52 ($153) As reported net income (loss) according to GAAP $124 ($66) ($23) ($209) Excluding compensation expense related to equity awards and related tax effects (30) (31) (59) (62) Non-GAAP net income (loss) $154 ($35) $36 ($147) Reconciliation of GAAP to Non-GAAP Basis As illustrated in the Selected Financial Information in this press release, non-GAAP operating expenses, non-GAAP income (loss) from operations, and non-GAAP net income (loss) were adjusted from GAAP to exclude compensation expense related to equity awards and the related tax effects. Compensation expense related to equity awards are non-cash. These measures are provided as supplementary information and are not a substitute for financial measures calculated in accordance with GAAP. Ionis reports these non-GAAP results to better enable financial statement users to assess and compare its historical performance and project its future operating results and cash flows. Further, the presentation of Ionis’ non-GAAP results is consistent with how Ionis’ management internally evaluates the performance of its operations. IONIS PHARMACEUTICALS, INC. Condensed Consolidated Balance Sheets (In Millions) June 30, December 31, 2025 2024 (unaudited) Assets: Cash, cash equivalents and short-term investments $2,290 $2,298 Contracts receivable 53 92 Other current assets 235 230 Property, plant and equipment, net 112 94 Right-of-use assets 164 162 Other assets 131 127 Total assets $2,985 $3,003 Liabilities and stockholders’ equity: Current portion of deferred contract revenue $76 $79 0% convertible senior notes, net – current 630 - Other current liabilities 191 229 1.75% convertible senior notes, net 566 565 0% convertible senior notes, net - 629 Liability related to sale of future royalties, net 541 542 Long-term lease liabilities 164 162 Long-term obligations, less current portion 60 52 Long-term deferred contract revenue 125 157 Total stockholders’ equity 632 588 Total liabilities and stockholders’ equity $2,985 $3,003 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 Achieved 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 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 • Essence data Achieved Zilganersen Alexander disease Phase 3 data • 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 • (1) Timing expectations based on current assumptions and subject to change. Indicates that the milestone is anticipated in the respective year.

关注并星标CPHI制药在线RNA疗法正迅速成为现代医学中最具变革性的治疗策略之一。从反义寡核苷酸（ASO）和小干扰RNA（siRNA）等精准调控基因表达的工具，到mRNA疫苗和肿瘤免疫疗法等前沿应用，RNA技术已在多个疾病领域展现出巨大潜力。近年来，随着递送系统、生物偶联技术和修饰化学的不断进步，RNA疗法的临床管线迅速扩展，涵盖了罕见病、神经系统疾病、代谢性疾病以及肿瘤等多个领域。目前，RNA疗法的临床开发全景涵盖了ASO、siRNA、mRNA、核酸适体（aptamer）等主要技术路径，在不同适应症中布局广泛，关键企业的研发动态频繁，已获批上市的代表性药物不断涌现。本文总结了现有管线和上市的 RNA疗法，将这一新兴领域的开发全景呈现出来。1. ASO类 RNA资产梳理      1.1 I期ASO资产      • Praxis       ASO资产 ：Elsunersen（PRAX-222）       靶点：SCN2A基因       适应症：由SCN2A基因的功能获得性突变引起的早发性SCN2A发育性和癫痫性脑病。      • PYC Therapeutics       ASO资产：VP-001       靶点：PRPF31基因       适应症：由PRPF31基因突变引起的视网膜色素变性11型       ASO资产：PYC-001       靶点：OPA1基因       适应症：由OPA1基因突变引起的常染色体显性视神经萎缩（ADOA）       ASO资产：PYC-003       靶点：PKD1基因       适应症：常染色体显性多囊肾病（ADPKD）      • Bio-Path Holdings       ASO资产：BP1002（Liposomal Grb2 ASO）       适应症：急性髓性白血病（AML）、B细胞淋巴瘤（B-cell lymphoma）       技术特点：使用独特的中性脂质体递送系统（DNAbilize® Platform）递送ASO。1.2 II期ASO资产      • Stoke Therapeutics       ASO资产：Zorevunersen（STK-001）       靶点 ：SCN1A基因       适应症：Dravet综合征（一种严重癫痫）       ASO资产 ：STK-002       靶点：OPA1基因       适应症：常染色体显性视神经萎缩（ADOA）      • Entrada Therapeutics       ASO资产：ENTR-601-44       适应症：Duchenne肌营养不良（DMD）       靶点 ：DMD中的Exon 44跳跃     技术特点：使用Entrada独有的分子穿透技术（Endosomal Escape Vehicle, EEV）提高细胞内递送效率。       ASO资产：ENTR-601-45       靶点：DMD基因的外显子45（Exon 45）       适应症：适用于外显子45跳跃的杜氏肌营养不良症（DMD）患者      • Dyne Therapeutics       ASO资产：DYNE-251      适应症：Duchenne肌营养不良（DMD），针对DMD中的Exon 51跳跃。       技术特点：使用抗体-寡核苷酸结合平台（FORCE platform）进行肌肉组织特异性递送。       ASO资产 ：DYNE-101       适应症：肌强直性营养不良症1型（DM1）       靶点：DMPK基因的异常CTG重复序列      • Ribomic      ASO资产：Umedaptanib Pegol（原RBM-007，严格来说是核酸适体aptamer，而不是典型ASO)       靶点 ：FGF2（成纤维细胞生长因子2）。       适应症：湿性年龄相关性黄斑变性（wAMD），软骨发育不全症       • Wave Life Sciences       ASO资产：       WVE-N531：DMD（杜氏肌营养不良症）治疗，靶向Exon 53跳跃       WVE-003：亨廷顿舞蹈症（Huntington's Disease, HD），靶向HTT基因突变      • PepGen       ASO资产：PGN-EDO51       适应症：Duchenne肌营养不良（DMD）   技术特点：结合增强型细胞穿透肽（Enhanced Delivery Oligonucleotide, EDO）技术，提高ASO进入肌肉细胞的效率。       ASO资产 ：PGN-EDODM1       靶点：DMPK基因的异常CUG重复序列       适应症：肌强直性营养不良症1型（DM1）      • 罗氏       ASO资产 ：Tominersen（RG6042）       靶点：Huntingtin（HTT）基因       适应症：亨廷顿病（Huntington's Disease, HD）       ASO资产 ：IONIS-FB-LRx（RO7434656 / RG6299）       靶点：补体因子B（Factor B）       适应症：IgA肾病（IgAN）      • Ultragenyx       ASO资产 ：GTX-102       靶点：UBE3A-AS（UBE3A反义转录本）       适应症：天使综合征（Angelman Syndrome）1.3 ASO类3期资产      • Oncotelic Therapeutics       ASO资产：OT-101（也叫Trabedersen）       靶点：转化生长因子β2（TGF-β2）       适应症：胶质母细胞瘤（GBM）、胰腺癌、恶性黑色素瘤       机制：抑制TGF-β2，有望减轻肿瘤免疫抑制，增强抗肿瘤免疫反应      • 阿斯利康       ASO资产：ION449（亦称AZD8233），与Ionis合作开发的ASO疗法       靶点：PCSK9（一种影响低密度脂蛋白胆固醇LDL-C水平的蛋白质）       适应症：高胆固醇血症（hypercholesterolemia）      备注：主要竞争对手包括小分子抑制剂和PCSK9单抗（如Repatha、Praluent）      • GSK       ASO资产：bepirovirsen       靶点：乙型肝炎病毒（HBV）的前基因组RNA和mRNA       适应症：慢性乙型肝炎（chronic hepatitis B, CHB），通过抑制HBV基因表达，帮助病毒清除或实现功能性治愈（functional cure）。      • 诺华       ASO资产：Pelacarsen       靶点：LPA基因（编码脂蛋白(a)）       作用机制：Pelacarsen通过抑制LPA基因的mRNA，降低血液中脂蛋白(a)(Lp(a))水平，从而降低心血管疾病风险。Lp(a)是目前被认为的重要但尚无针对性治疗手段的心血管风险因子。       适应症：主要用于治疗动脉粥样硬化性心血管疾病高危患者中，血脂异常（特别是Lp(a)升高）的情况。       临床阶段：正在进行III期临床试验（Lp(a)HORIZON）。Pelacarsen可能成为首个专门针对Lp(a)升高治疗获批的药物。1.4 ASO类上市药物      • 渤健       Spinraza（nusinersen）       靶点：SMN2前体mRNA（促进功能性SMN蛋白表达）       适应症：脊髓性肌萎缩症（SMA）       获批时间：2016年12月（美国FDA批准）      备注：全球首个获批的SMA治疗药物。由Ionis开发，Biogen负责商业化。      • Sarepta Therapeutics       Exondys 51（eteplirsen）       靶点：DMD基因的Exon 51       适应症：Duchenne肌营养不良（DMD）       获批时间：2016年9月（FDA加速批准）       Vyondys 53（golodirsen）       靶点：DMD基因的Exon 53       适应症：DMD       获批时间：2019年12月       Amondys 45（casimersen）       靶点：DMD基因的Exon 45       适应症：DMD       获批时间：2021年2月（FDA加速批准）      • Ionis Pharmaceuticals       Tegsedi（inotersen）       靶点：TTR（转甲状腺素蛋白）       适应症：遗传性转甲状腺素蛋白淀粉样变性多发性神经病（hATTR-PN）       获批时间 ：2018年10月（FDA，EMA批准）      Waylivra（volanesorsen）       靶点：APOC3（载脂蛋白C-III）       适应症：家族性乳糜微粒血症综合征（FCS）       获批时间：2019年5月（欧洲EMA批准；未获美国FDA批准）      • NS Pharma       Viltepso（viltolarsen）       靶点：DMD基因的Exon 53       适应症：Duchenne肌营养不良（DMD）       获批时间：2020年8月（FDA加速批准）2.RNAi类 RNA资产2.1 I期RNAi资产      • Aligos Therapeutics       RNAi资产：ALG-125755       靶点：乙型肝炎病毒（HBV）RNA       适应症：慢性乙型肝炎（CHB）      • Regulus Therapeutics       RNAi资产：RGLS8429       靶点：microRNA-17（miR-17家族）       适应症：常染色体显性多囊肾病（ADPKD）      • Phio Pharmaceuticals       RNAi资产：PH-762       靶点：程序性死亡受体1（PD-1）       适应症：癌症免疫疗法（通过下调T细胞表面PD-1，增强免疫杀伤）       技术特点：采用其自有的INTASYL✓平台，优化了siRNA的稳定性和局部递送。      • TransCode Therapeutics       RNAi资产：VIR-2218 TTX-MC138       靶点：microRNA-10b（miR-10b）       适应症：针对转移性实体肿瘤（如乳腺癌、胰腺癌、脑肿瘤等）       技术特点：使用纳米颗粒系统高效递送siRNA药物，特别适合针对深部转移灶。2.2 II期RNAi资产      • Arbutus Biopharma       RNAi资产：AB-729       靶点：乙型肝炎病毒（HBV）表面抗原（HBsAg）       适应症：慢性乙型肝炎（CHB）       备注：AB-729是Arbutus当前最重要的核心资产之一。      • OliX Pharmaceuticals       RNAi资产：OLX703A       靶点：HBV病毒相关RNA       适应症：慢性乙型肝炎（CHB）       机制：抑制HBV病毒蛋白表达      • Silence Therapeutics       RNAi资产：SLN360       靶点：LPA基因（编码脂蛋白Lp(a)）       适应症：高脂蛋白(a)血症（Lp(a)过高相关的心血管疾病）       机制：通过降低血液中Lp(a)水平，减少动脉粥样硬化风险。       备注：SLN360是Silence在心血管RNA疗法领域的主力项目。      • Sirnaomics       RNAi资产：STP705       靶点：双靶点siRNA药物，靶向TGF-β1和COX-2。       适应症：瘢痕治疗（皮肤纤维化）、非黑色素瘤皮肤癌（如基底细胞癌、鳞状细胞癌）       机制：抑制纤维化、降低肿瘤微环境免疫抑制。       备注：Sirnaomics的特点是双靶点siRNA联合递送。      • GSK       RNAi资产：GSK4532990       靶点：靶向HSD17B13基因       适应症：代谢功能障碍相关脂肪性肝炎（MASH）      • 礼来       RNAi项目：LY3561774       靶点：SERPINA1基因       适应症：α1-抗胰蛋白酶缺乏症（AATD）       机制 ：降低异常α1-抗胰蛋白酶（AAT）积聚      • VIR Biotechnology       RNAi项目：VIR-2218       靶点 ： HBV RNA       适应症：慢性乙型肝炎（CHB）。       机制：抑制HBV表面抗原表达      • 罗氏       RNAi资产：Zilebesiran       靶点 ：肝脏表达的血管紧张素原（AGT）基因。       适应症：高血压，特别是高心血管风险患者。2.3 III期RNAi资产      • Arrowhead Pharmaceuticals       RNAi资产：ARO-APOC3       靶点 ：APOC3（载脂蛋白C-III），       适应症：高甘油三酯血症和罕见脂代谢异常      • 武田       RNAi资产：Fazirsiran       靶点：SERPINA1（编码α1-抗胰蛋白酶）       适应症：α1-抗胰蛋白酶缺乏症（AATD）引起的肝病      • 安进       RNAi资产：Olpasiran       靶点：LPA基因（脂蛋白(a)）       适应症：高脂蛋白(a)血症及其引发的心血管疾病风险       备注：这是一款非常重磅的RNAi项目，对心血管领域意义重大。      • Avidity Biosciences       RNAi资产：AOC 1001       靶点：DMPK基因（导致肌强直性营养不良症1型DM1）       适应症：肌强直性营养不良症1型（DM1）       技术特点：AOC（Antibody Oligonucleotide Conjugate，抗体-寡核苷酸偶联体），用于肌肉靶向递送siRNA。      • 赛诺菲       RNAi资产：Fitusiran       靶点：AT（抗凝血酶）       适应症：血友病A或B患者的出血预防      • VIR Biotechnology       RNAi资产：VIR-2218       靶点：HBV RNA       适应症：慢性乙型肝炎（CHB）2.4 上市RNAi资产      • Alnylam Pharmaceuticals       Alnylam是全球RNAi疗法先锋，拥有最多已上市RNAi药物。       Onpattro（Patisiran）       靶点：TTR      适应症：遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病（hATTR-PN）       批准情况：2018年FDA/EMA批准       Givlaari（Givosiran）       靶点：ALAS1       适应症：急性肝卟啉症（AHP）       批准情况：2019年FDA/EMA批准       Oxlumo（Lumasiran）       靶点：HAO1       适应症：原发性高草酸尿症1型（PH1）       批准情况：2020年FDA/EMA批准       Amvuttra（Vutrisiran）       靶点：TTR      适应症：遗传性转甲状腺素蛋白淀粉样变性引起的多发性神经病（hATTR-PN）（长效皮下注射版）       批准情况：2022年FDA批准      • 诺华       RNAi资产：Leqvio（Inclisiran）       靶点：PCSK9       适应症：高胆固醇血症，动脉粥样硬化性心血管疾病风险降低       批准情况：2020年欧洲EMA批准；2021年底美国FDA批准      • 诺和诺德       RNAi资产：Rivfloza (nedosiran)       靶点：肝脏中乳酸脱氢酶（LDH）mRNA     适应症：治疗9岁及以上、肾功能相对良好的原发性高草酸尿症1型（PH1）患者。       作用机制：抑制LDH蛋白表达，减少草酸过度生成，缓解PH1疾病过程，减少肾脏损害风险。       批准情况：2023年9月29日FDA正式批准Rivfloza上市。成为继Alnylam的Oxlumo（Lumasiran）之后，全球第二款获批用于PH1治疗的RNAi药物。3.mRNA类 RNA药物资产3.1 1期mRNA资产      • 赛诺菲       SP0237: 季节性流感 mRNA 疫苗       适应症：针对 A/H3N2 毒株的季节性流感。       SP0256 – RSV mRNA 疫苗（老年人群）       适应症：用于预防老年人群中的呼吸道合胞病毒（RSV）感染。       SP0268 – mRNA 痤疮疫苗       适应症：针对痤疮（Acne）的 mRNA 疫苗。       SP0291 – 多价呼吸道病毒 mRNA 疫苗      适应症：针对 RSV、人类偏肺病毒（hMPV）和副流感病毒 3 型（PIV3）的组合疫苗，主要用于老年人群。       沙眼衣原体（Chlamydia）mRNA 疫苗候选       适应症：预防沙眼衣原体感染，主要针对 18 至 29 岁的成人。      • Vertex       mRNA资产：VX-522：用于囊性纤维化（CF）的mRNA疗法       靶点：CFTR基因（囊性纤维化跨膜电导调节因子）。       适应症：无法通过CFTR调节剂治疗的CF（囊性纤维化）患者，尤其是那些由于CFTR基因突变导致CFTR蛋白缺失的患者。       作用机制：VX-522是一种mRNA疗法，通过脂质纳米颗粒（LNP）递送CFTR mRNA至肺部细胞，促使其合成功能性CFTR蛋白，从而恢复氯离子通道的功能。3.2 II期mRNA资产      • Gritstone Bio       GRANITE（GRT-C901/GRT-R902）      个体化肿瘤新抗原疫苗，采用腺病毒（ChAd68）和自扩增mRNA（samRNA）组成的异源prime-boost策略。       适应症：用于治疗转移性微卫星稳定型结直肠癌（MSS-CRC）。       CORAL       基于自扩增mRNA（samRNA）的COVID-19疫苗，诱导广泛且持久的中和抗体和T细胞免疫反应。      • CureVac/GSK       季节性流感mRNA疫苗候选       该疫苗候选基于CureVac的第二代mRNA平台，针对流感病毒株，包括A型和B型毒株。       COVID-19 mRNA疫苗候选CV0601和CV0701       CV0601为单价疫苗，编码Omicron BA.4/5变异株的刺突蛋白；CV0701为二价疫苗，编码Omicron BA.4/5变异株和原始SARS-CoV-2毒株的刺突蛋白。3.3 III期mRNA资产      • 第一三共       DS-5670a（原始毒株单价疫苗）       适应症：Covid-19疫苗，作为加强针用于已完成初始疫苗接种的成人和老年人。       DS-5670a/b（原始毒株与Omicron BA.4/5二价疫苗）       适应症：Covid-19疫苗，作为加强针用于12岁及以上已完成初始疫苗接种的人群。       DS-5670d（Omicron XBB.1.5单价疫苗）       适应症：Covid-19疫苗，作为季节性加强针用于12岁及以上人群，包括未接种疫苗者。      • 默沙东       mRNA资产：V940（mRNA-4157）       类型：肿瘤疫苗（个体化mRNA疫苗）       适应症：手术切除后的高风险黑色素瘤患者辅助治疗       靶点：个体化新抗原（根据患者肿瘤突变特异设计）3.4上市mRNA资产      • Arcturus Therapeutics       mRNA资产：KOSTAIVE（ARCT-154 / Zapomeran）       类型：自扩增mRNA（sa-mRNA）疫苗       适应症：用于预防COVID-19，适用于18岁及以上人群       靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）      • BioNTech/辉瑞       Comirnaty       类型：mRNA疫苗       适应症：用于预防COVID-19，适用于6个月及以上人群       靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）       获批时间：✓2020年12月获得FDA紧急使用授权，2021年8月获得美国FDA完全批准      • 莫德纳       Spikevax       类型：mRNA疫苗       适应症：用于预防COVID-19，适用于6个月及以上人群       靶点：SARS-CoV-2病毒刺突蛋白（Spike protein）       获批时间：2020年12月18日，美国FDA授予紧急使用授权；2022年1月31日，获得FDA完全批准Ref.       TD Cowen.      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