Sefaxersen

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.

IONIS RNA靶向技术平台：底层架构与肝外递送的技术突破 反义寡核苷酸（ASO）作为RNA靶向治疗的核心技术形式之一，其发展始终围绕两大核心命题：一是如何通过化学优化实现分子的成药性，二是如何通过递送体系的突破，实现对全身多组织靶点的精准覆盖。IONIS Pharmaceuticals作为全球最早深耕ASO技术的企业之一，历经三十年技术迭代，构建了一套覆盖化学修饰、作用机制、组织递送全链条的RNA靶向技术平台，尤其在肝外递送这一行业核心技术瓶颈上，实现了系统性突破。IONIS RNA靶向技术平台的底层核心架构 IONIS的技术平台并非单一的分子设计能力，而是一套经过数十项临床试验验证、可复用、可迭代的完整技术体系，其核心由三大相互支撑的技术模块构成，为该企业所有管线研发提供通用底层支撑。1. 迭代成熟的寡核苷酸化学修饰体系 化学修饰是寡核苷酸分子实现成药性的核心基础，直接决定分子的体内稳定性、靶标结合亲和力、安全性及组织分布特性，亦是IONIS技术平台迭代升级的核心方向。IONIS自深耕ASO领域以来，历经数十年持续优化与临床验证，形成了一套体系化的专有化学修饰体系，核心包括硫代磷酸酯骨架修饰、2'-甲氧基乙基（2'-MOE）、2'-氟（2'-F）等核糖位点的精准修饰，同时迭代出更先进的cEt双环核苷酸修饰技术（Generation 2.5），构建了从基础修饰到高阶优化的完整技术梯度。其中，硫代磷酸酯骨架修饰主要解决分子体内核酸酶降解问题，2'-MOE与2'-F修饰聚焦提升靶标结合能力，而cEt修饰作为新一代技术，相较于2'-MOE修饰的Gapmer ASO，效力提升约10倍，为肝外组织靶向提供了更优异的分子基础。 从技术原理层面分析，该修饰体系实现了多个关键技术目标的平衡： 通过骨架修饰显著提升寡核苷酸分子在血浆及组织中的核酸酶抗性，延长体内半衰期，为临床低频给药提供分子层面支撑； 通过核糖位点修饰增强分子与靶标RNA的结合亲和力，提升药物效价，降低临床给药剂量； 通过修饰位点与修饰类型的精准优化，显著降低分子的先天免疫激活风险及脱靶效应，优化临床应用中的安全性与耐受性。 该化学修饰体系并非局限于实验室阶段的理论探索，而是经过多款获批药物及上百项临床试验的体内验证，形成了明确的修饰规则与标准化流程。例如，IONIS已获批上市的Inotersen等产品，均采用2'-MOE修饰的Gapmer ASO设计，其中2'-MOE修饰负责提升药代动力学特性，Gapmer结构则增强药物效力，充分验证了该修饰体系的临床可行性。目前，该体系已实现从“靶点序列设计”至“成药性优化”的全流程标准化，可根据不同靶点的序列特征、组织分布需求，精准匹配修饰类型与位点，快速适配多领域管线的分子开发需求，大幅缩短研发周期。2. 多元化的RNA调控机制，拓展可成药靶点边界 与行业内多数研发主体聚焦于单一基因沉默机制不同，IONIS的技术平台实现了对RNA功能的多元化调控，从根本上拓展了寡核苷酸药物的可成药靶点范围。 其核心应用的调控机制主要分为两大类： 第一类是RNase H介导的靶标mRNA降解机制，该机制是IONIS应用最广泛、临床验证最充分的核心机制。其技术原理为：通过精准设计与靶标mRNA互补的ASO分子，使其特异性结合mRNA的编码区或非编码区，形成DNA-RNA杂合双链，进而招募细胞内的RNase H酶，该酶可特异性识别并切割杂合双链中的mRNA链，实现靶标mRNA的精准降解，最终达成下调致病蛋白表达的目标。该机制具备高度的靶点普适性，无需依赖靶蛋白的结构特征，仅需匹配mRNA序列即可完成分子设计，已在ApoC-III、Apo(a)等心血管靶点，以及SOD1等神经靶点的临床试验中得到充分验证。其中，针对SOD1基因突变所致肌萎缩侧索硬化症（ALS）的Tofersen，便是基于该机制开发，可实现SOD1蛋白剂量依赖性、持续性的体内下调，成为首个获批的遗传性ALS基因靶向疗法。 第二类是pre-mRNA的剪接调控机制，该机制打破了“仅能沉默靶点”的局限，为功能缺失型基因突变疾病提供了全新治疗路径。其核心技术逻辑为：通过靶向pre-mRNA的剪接位点（包括外显子-内含子交界区、剪接增强子或抑制子区域），设计特异性ASO分子，干扰剪接因子的结合，从而精准调控基因的剪接过程， either修正异常剪接事件、避免致病蛋白产生，or跳过异常外显子、生成功能性蛋白产物，最终解决功能缺失型基因突变的治疗难题。该机制最核心的技术验证，是针对脊髓性肌萎缩症（SMA）的SMN2基因剪接调控分子，通过修正SMN2基因的剪接模式，促进功能性SMN蛋白的表达，成为SMA治疗领域的里程碑式成果，亦充分验证了剪接调控机制的临床转化价值。 此外，该平台还可实现翻译激活、miRNA抑制、非编码RNA调控等多种生物学功能，既能够覆盖“功能获得性”致病靶点，也可解决“功能缺失性”基因缺陷，使寡核苷酸药物的治疗场景从单基因罕见病向慢性病、感染性疾病等多领域延伸。3. 肝脏靶向递送的成熟化与标准化 肝脏作为全身代谢的核心器官，是寡核苷酸药物经全身给药后最易富集的组织，因此肝脏靶向是寡核苷酸药物最先实现临床突破的领域，亦是IONIS技术平台的成熟模块之一。IONIS通过对ASO分子化学修饰的持续精准优化，结合对肝脏组织生理特性的深入研究，实现了肝脏靶向递送的完全成熟与标准化，其核心优势在于无需依赖额外递送载体（如LNP、GalNAc），仅通过分子自身的修饰优化即可实现高效靶向，大幅降低递送载体带来的安全性风险。目前，基于该肝脏靶向平台开发的多款药物已获批上市，针对肝源性血管紧张素原（AGT）的IONIS-AGT-LRx在临床试验中，可使患者血浆AGT水平显著下降54%-67%，充分验证了该平台的有效性。 其技术逻辑为：经过专有体系优化的ASO分子，可通过肝脏肝细胞表面高表达的受体介导内吞作用，高效富集于肝脏肝细胞内，实现对肝脏表达靶点的精准调控，同时减少在其他组织的非特异性分布，降低脱靶风险。该肝脏递送体系已实现高度可复用性，针对肝脏靶点的管线，从分子设计（理化性质参数设定）、临床前评价（体内富集效率、安全性检测）至临床试验设计，均形成了标准化流程，大幅降低了研发的技术不确定性，亦成为其心血管代谢、肝脏疾病领域管线开发的核心基础。此外，IONIS对肝脏靶向相关的化学修饰、递送技术均进行了全面专利覆盖，构建了坚实的技术壁垒，为其在肝脏靶向ASO领域的持续领先提供支撑。肝外靶向递送：IONIS技术平台的核心突破 长期以来，寡核苷酸药物经全身给药后主要富集于肝脏，难以在肝外组织实现有效暴露量与细胞摄取，这是制约寡核苷酸药物拓展治疗边界的核心行业瓶颈。IONIS经过十余年技术研发，在肝外靶向递送领域实现了多组织、多维度的技术突破，构建了差异化技术壁垒。1. 中枢神经系统（CNS）递送的技术实现与临床验证 中枢神经系统（CNS）是肝外靶向最核心的治疗领域，大量神经遗传病、神经退行性疾病的致病靶点均在中枢神经系统表达，而血脑屏障的存在，导致绝大多数药物无法实现有效中枢暴露。IONIS通过“化学修饰优化+鞘内给药体系”的协同创新，实现了CNS递送的技术成熟与充分临床验证。 从技术实现路径分析，其核心优化分为两个层面，二者协同作用实现CNS高效递送：其一，通过专有化学修饰（包括2'-MOE、cEt等）优化ASO分子的理化性质，重点调整分子的亲疏水性与电荷特性，一方面提升其在脑脊液中的稳定性，避免被脑脊液中的核酸酶快速降解，延长体内滞留时间；另一方面增强分子穿透血脑屏障的能力，使其可顺利进入神经元、星形胶质细胞、少突胶质细胞等中枢靶细胞，实现对靶标的精准调控。其二，通过鞘内注射给药方式，将药物直接注入蛛网膜下腔，使其快速进入脑脊液循环，均匀分布于整个中枢神经系统，规避了口服与静脉给药无法突破血脑屏障、中枢暴露量极低的核心难题，同时降低全身给药带来的外周组织脱靶风险。 该CNS递送体系已得到充分临床验证：已有3款基于该平台的药物获批上市，其中包括针对SOD1突变ALS的Tofersen，该药物通过鞘内注射给药，可显著降低患者脑脊液及血浆中的神经丝轻链（NfL）水平（神经元损伤的特异性生物标志物），凭借明确的生物学效应获得FDA加速批准；另有12款管线处于临床阶段，覆盖Alexander病、Angelman综合征、多系统萎缩、亨廷顿病等多种神经疾病。其中，针对Alexander病的zilganersen在关键性临床试验中取得积极结果，接受治疗的患者在第61周，经10米步行测试评估的步行速度指标保持稳定（平均差异33.3%，p=0.0412），呈现出统计学显著性及临床意义，实现了对中枢GFAP靶点的有效调控，且安全性与耐受性良好，验证了该递送体系可实现中枢靶点的疾病修饰效应，该企业计划于2026年第一季度向美国FDA提交NDA。 值得关注的是，该CNS递送技术具备高度可复用性，针对不同中枢靶点的管线，均采用同源化学修饰与给药体系，实现了从靶点验证至临床推进的快速转化。2. 心肌靶向递送的技术突破 心血管疾病相关的心肌细胞靶点，始终是寡核苷酸药物的开发难点——静脉给药后，常规ASO分子难以在心肌细胞中实现有效富集与摄取，无法发挥治疗效应。 针对该技术难点，IONIS依托其成熟的配体偶联技术（LICA，Ligand Conjugated Antisense），开发了基于转铁蛋白受体1（TfR1）的主动靶向递送技术，该技术为其心肌靶向的核心技术路径。TfR1在心肌细胞表面高表达，而在其他外周组织中表达量较低，具备天然的心肌组织特异性；IONIS通过化学偶联技术，将优化后的ASO分子与TfR1特异性配体进行精准偶联，偶联位点经过严格筛选，确保不影响ASO分子的靶标结合能力及TfR1配体的识别能力。该偶联分子可通过TfR1介导的内吞作用，被心肌细胞高效摄取，显著提升药物在心肌组织的富集效率，同时减少外周组织的非特异性摄取，解决了全身给药后心肌靶向不足的行业瓶颈。目前，基于该TfR1靶向技术的管线已进入心肌病相关临床开发阶段，临床前研究数据显示，其心肌组织富集效率较未偶联ASO分子提升数倍，靶蛋白下调效果显著。3. 肾脏靶向递送的技术实现 肾脏固有细胞的靶点递送，是慢性肾病治疗领域的关键技术瓶颈。常规寡核苷酸药物难以在肾小球系膜细胞、肾小管上皮细胞中实现有效摄取，无法针对肾病的病理根源进行干预。 IONIS通过对ASO分子化学修饰的精准优化，重点调整分子的分子量（控制在特定范围以利于肾小球滤过与细胞摄取）、等电点及电荷特性，降低分子与肾脏组织的非特异性结合，同时增强其与肾小球系膜细胞、肾小管上皮细胞表面受体的亲和力，使其可在上述肾脏固有细胞中实现高效摄取与滞留，完成肾脏靶向的技术突破，无需依赖额外递送载体即可实现肾脏组织的精准靶向。基于该技术，针对IgA肾病的sefaxersen已进入III期临床阶段，该药物通过靶向调控肾脏固有细胞中补体因子B的表达，从疾病的病理生理根源实施治疗干预，临床中期数据显示，其可显著降低补体因子B的表达水平，改善患者肾功能相关指标，且在肾脏组织的富集效率显著高于外周组织，安全性良好。4. 多组织靶向的持续技术拓展 除上述已进入临床验证的组织靶向体系外，IONIS基于底层化学修饰与配体偶联平台，正逐步向骨骼肌、肺、免疫细胞等更多肝外组织拓展靶向递送技术，形成多维度、全场景的肝外靶向布局。其核心技术逻辑为，针对不同组织的细胞表面特异性标志物（如骨骼肌细胞表面的特异性受体、肺上皮细胞的特异性抗原），开发对应的靶向配体，同时结合cEt等先进化学修饰技术，优化ASO分子的理化性质，构建适配不同组织的“修饰-配体”组合体系，实现对全身多组织靶点的精准覆盖。目前，骨骼肌靶向已进入临床前后期阶段，通过靶向骨骼肌细胞表面的特异性受体，结合cEt修饰技术，实现了ASO分子在骨骼肌组织的高效富集；肺靶向则聚焦于呼吸道相关疾病，通过优化分子的气道黏膜穿透能力，结合肺组织特异性配体，推动相关管线进入临床前验证阶段，持续拓展RNA靶向治疗的应用边界。IONIS技术平台的技术壁垒与行业启示 从行业技术发展视角分析，IONIS的RNA靶向平台最核心的价值，在于实现了寡核苷酸药物研发从“偶然发现”向“体系化产出”的跨越，构建了可重复、可延展的技术壁垒。 首先，该平台具备高度的技术可复用性。经过三十年积累，IONIS形成了从靶点验证、分子设计、化学优化、体内外评价，至临床试验设计与执行的全链条标准化流程。该流程已通过数百个项目、数十项临床试验的验证，大幅降低了靶点转化的技术不确定性，实现了研发管线的持续稳定产出。 其次，该平台具备极强的技术延展性。IONIS未局限于ASO单一技术类型，而是在底层化学与递送平台的基础上，持续向siRNA、DNA编辑、基因调控等前沿技术领域拓展。其平台的核心化学修饰、递送体系、序列设计能力，可无缝迁移至新型技术类型中，实现技术能力的持续迭代。 最后，肝外靶向技术的系统性突破，使该平台的应用边界实现指数级拓展。当寡核苷酸药物的靶向范围从肝脏延伸至中枢、心肌、肾脏、骨骼肌等全身组织，其可成药靶点数量实现质的飞跃，亦为大量此前“不可成药”的疾病靶点，提供了全新的治疗解决方案。 从客观行业视角来看，寡核苷酸药物的肝外递送仍存在尚未完全解决的技术挑战，包括部分组织的靶向效率仍有提升空间、长期大剂量给药的安全性数据仍需进一步积累、规模化生产的工艺仍需优化等，上述问题亦是整个RNA靶向治疗领域需持续突破的方向。 免责声明 本文仅为医药技术领域的科普与行业信息分享，不构成任何投资建议、医疗诊断或治疗推荐。文中提及的在研药物尚未获得监管机构批准用于临床治疗，相关临床数据仅供医药专业人士参考，具体用药请严格遵循医嘱。本文所引用内容均来自企业公开渠道发布的资料，如涉及版权或侵权问题，请及时与我方联系处理。 本文为行业技术概览，如需原始报告全文，请关注本公众号后通过后台留言获取。 检索词 #IONIS#RNA靶向治疗#反义寡核苷酸#ASO#寡核苷酸药物#肝外靶向#基因调控#RNA药物递送 一句话总结 IONIS通过三十年迭代构建的RNA靶向技术平台，实现了寡核苷酸化学修饰、多元化RNA调控与肝脏递送的成熟化，且在中枢神经系统、心肌、肾脏等肝外靶向领域取得关键技术突破，构建了可复用、可延展的寡核苷酸药物研发体系，拓展了RNA靶向治疗的临床应用边界。