Lumasiran sodium

氨基观察-创新药组原创出品 作者 | 沙晓威 在全球医药产业的版图中，小核酸正以前所未有的热度吸引着各方目光。 短短两天，诺华连续豪掷重金，加码RNAi赛道。 9月2日，Arrowhead宣布与诺华就临床前资产siRNA-ARO-SNCA达成全球授权合作。诺华将向Arrowhead支付2亿美元预付款，以及最高20亿美元的里程碑付款及销售分成。也是这笔交易，也为陷入困境的Arrowhead，再加翻盘筹码。 次日，诺华与舶望制药达成超52亿美元的交易，涉及4款siRNA药物，其中两款为处于早期研发阶段治疗心血管疾病的药物。这也是自去年诺华与舶望制药，达成41.65亿美元合作后的又一次携手。 先后两笔交易，释放了诺华在RNAi领域持续布局的强烈信号。几乎同时，诺和诺德以5.5亿美元押注Replicate Bioscience的srRNA小众技术。另外，由于阿柏西普营收承压的再生元，也正在大力布局小核酸技术。去年以来，再生元有 10 款新药首次进入了临床阶段，其中 6 款都是siRNA疗法。 显然，经历漫长且曲折的发展过后，小核酸正重新获得资本与产业的高度关注。 / 01 / 诺华已经“上头” 短短两天，诺华先后斥巨资与Arrowhead、舶望制药达成合作，覆盖帕金森、心血管等慢病领域。表面上是补管线，实际上是其长期战略的延续。 9月2日，诺华率先与Arrowhead就siRNA疗法ARO-SNCA达成全球许可与合作协议，根据协议，诺华直接支付2亿美元首付款，后续还将承担高达20亿美元的潜在里程碑付款。 ARO-SNCA利用Arrowhead专有靶向RNAi分子（TRiM）平台进行皮下给药和向中枢神经系统递送，旨在靶向编码α-突触核蛋白的基因，被视为该领域的潜在颠覆性疗法。同时，根据交易协议，诺华还可以选择Arrowhead现有产品线之外的其他疾病靶点，利用后者的技术平台进行研发。 诺华看中的，本质是Arrowhead的CNS递送平台。ARO-SNCA采用的TRiM平台能够实现皮下给药，通过转铁蛋白受体靶向配体实现非侵入性血脑屏障穿透，可每月或每季度给药，且安全窗口充足。此前，Arrowhead CEO表示，该平台已经“产生了令人印象深刻的临床前结果，证明了皮下注射后可以输送至中枢神经系统，包括分布至大脑深部区域”。 次日，诺华支付1.6亿美元预付款，潜在里程碑金额更是高达52亿美元，再次牵手舶望制药，双方此次合作涉及4款siRNA药物，其中两款为处于早期研发阶段治疗心血管疾病的siRNA药物。 这已是短短一年多时间内，双方的第二次重磅合作，这也暴露出诺华补强心血管业务的迫切需求。 回溯诺华在小核酸领域的布局，大手笔早已成为常态。2019年，诺华豪掷97亿美元收购The Medicines Company，将全球首个靶向PCSK9的小核酸药物Leqvio收入囊中。 这款药物打破了传统降脂药的治疗局限，一年仅两次的注射频次即可有效控制胆固醇，上市后迅速成为诺华心血管板块的增长核心之一，也让诺华真切尝到了小核酸的甜头。 自此，诺华在小核酸领域的布局，越来越深入。 2023年，其以10亿美元收购DTxPharma，获得了专有的Falcon脂质纳米颗粒递送平台。 2025年以来，诺华更是加速买买买。6月，诺华以17亿美元收购Regulus Therapeutics，拿下了治疗常染色体显性多囊肾病的microRNA疗法farabursen。 8月份有消息称，诺华正计划收购AOC（抗体偶联小核酸）领域的先驱Avidity Biosciences，后者当前市值已近60亿美元。 9月份，更是先后达成前述两笔重磅交易，从心血管疾病到肾脏疾病再到神经系统疾病，诺华不断拓展小核酸管线布局。更重要的是，其布局并没有局限在确定性更高的晚期管线，还大力押注早期管线、核心递送技术平台以及多元技术路线。 整体来看，经过几年时间的投入，诺华的小核酸管线已然全面铺开，覆盖RNAi、ASO、配体疗法等多种技术类型，靶点涵盖PCSK9、ASGPR、apo(a)、Tau、miR-17等20多种，适应症覆盖心血管、神经、感染、罕见病等多个领域。 这种上头式投入，本质上其是对行业趋势的精准把握。小核酸药物凭借精准靶向、长效持久等优势，被视为下一代药物研发的核心方向。除了诺华，包括诺和诺德、再生元、罗氏、辉瑞等大药企，也纷纷将目光投向这一赛道。 / 02 / 越来越多biotech上岸 大药企持续加码投入之际，小核酸赛道上岸的biotech也在变多。 过去，Alnylam几乎是整个赛道唯一的成功标杆：从Onpattro到Givlaari、Oxlumo，再到vutrisiran，Alnylam将RNAi药物从研发、临床再推向商业化。 尤其是随着vutrisiran的商业化爆发，Alnylam终于要见到盈利曙光，这也带动其市值一路高走，目前已经超过600亿美元。 而最近，RNAi老二Arrowhead，也让外界看到了其即将上岸的迹象。 如果说Alnylam是“顺境成长”的范本，Arrowhead则是“逆境突围”的典型。 作为一家以RNAi治疗技术为核心的平台型公司，Arrowhead拥有广泛的管线布局，涉及罕见病和高发病率疾病。但由于其融资策略失误，导致公司被资金链紧张的阴影笼罩。 2024年财报显示，其账面现金仅6.8亿美元，按当时的研发投入节奏，仅能支撑两年开销；叠加ARO-ENaC因安全性问题被叫停，合作项目临床数据未达预期，资金压力与研发挫折让公司前景蒙上迷雾。 好在，转折点在一年内密集出现，BD合作成为破解资金困局的关键。 2024年11月，其与Sarepta Therapeutics的合作成功输血。Arrowhead获得5亿美元的现金预付款，以及Sarepta以3.25亿美元购买其股票的定价，里程碑付款更是高达100亿美元。今年7月底，已经触发一笔1亿美元的里程碑付款，预计年底还将触发一笔2亿美元的里程碑付款。 8月初，赛诺菲与其子公司Visirna达成协议，获得Plozasiran在大中华区的独家研发及商业化权利，Visirna获1.3亿美元首付款及2.65亿美元潜在里程碑。 基于这些合作进展，Arrowhead管理层在三季度财报电话会上明确表示，现金储备已可支撑至2028年，且能支持多个自主及合作产品的商业化上市。 而近期与诺华的合作则进一步巩固其现金流：2亿美元首付款入账，叠加20亿美元的潜在里程碑付款。与诺华合作公告发布当天，Arrowhead股价暴涨17%。 拉长时间来看，自今年4月其股价创下历史新低至今，涨幅已超过200%。显然，随着现金流的好转，外界正在期待Arrowhead成为下一个Alnylam。 这不难理解。Arrowhead在小核酸领域的技术毋庸置疑，过去的困境更多是由于，在迎来真正的商业化成功之前，岌岌可危的财务储备，难以获得市场认可。 而眼下现金流日渐好转，Arrowhead也正处在从研发到商业化的关键转型期，核心产品Plozasiran离2025年11月18日的美国PDUFA截止日期已不到2个月，有望在年内获批上市。目前公司相关的商业化建设也按计划推进，支持家族性乳糜微粒血症综合征（FCS）上市的完整团队即将组建完毕。 除此之外，Plozasiran另一项治疗严重高甘油三酯血症的适应症，也已经完成3期临床入组，预计2026年中完成；减重管线逐步推进，阿尔兹海默症亦有积极进展，更有双靶（PCSK9+APOC3）年内迈入临床；与武田、安进合作的后期管线，也有望在未来两年带来回报。 核心产品上市在即、管线丰富且深度多元（多个后期及早期项目）、财务状况稳健（近期有大量现金流入）、并且拥有技术平台驱动未来增长……总之，在小核酸赛道继续爆发之际，Arrowhead也通过一笔笔交易及临床进展，扭转着市场对它的预期。 / 03 / 小核酸的新周期 当然，小核酸的热闹，不只是在海外。 国内该领域的融资和临床进展也是不断。不仅有黑马舶望制药，9月8日，华熙生物以1.38亿港元认购圣诺医药1156.83万股，后者也曾因资金问题陷入困境；ESC大会上，瑞博携手Ribocure联合发布四项siRNA在心血管领域的重要结果；恒瑞医药研发的siRNA药物HR-SIR01被纳入突破性疗法；9月17日，迈威生物与Aditum Bio达成NEWCO合作，共同成立Kalexo Bio，来推进心血管siRNA疗法2MW7141的开发。 种种趋势表明，从海外到国内、产业到资本，小核酸药物已正式迈入发展新周期。此轮爆发，其势已成，更在情理之中。 首先，小核酸药物在技术层面本身就有优势。 与小分子、抗体药物相比，小核酸药物直接靶向mRNA或非编码RNA，从基因表达源头阻断蛋白生成。这种特性让它无论是在罕见病中对缺陷基因的精准调控，还是在慢性病甚至CNS中针对不可成药靶点的有效干预，都展现出独特优势。 更关键的是，随着化学修饰与递送技术的成熟，小核酸药物的稳定性与靶向性大幅提升。 GalNAc偶联技术实现肝脏高效富集，LNP系统助力突破血脑屏障，而通过化学修饰进一步降低了潜在的毒性问题，多种技术优化得到的“平台”，让新一代产品不断涌现。 其次，先行者的商业化爆发，也在推动小核酸药物进入新阶段。 目前全球小核酸药物获批总数增至22款（其中3款已退市），从罕见病领域向慢性病、常见病跨越的趋势已经展现，商业化成果则更为亮眼。 典型如前文提及的Vutrisiran，自2022年上市以来，销售额持续攀升，2024年销售额接近10亿美元，而随着今年3月ATTR-CM适应症获批，Vutrisiran更是快速放量，二季度的销售额达到了4.92亿美元，同比增长114%。这也带动了Alnylam整体收入的超预期增长。 同样快速增长的还有诺华的Leqvio。2025年上半年，Leqvio销售额再同比大增66%，达到5.55亿美元，在诺华心血管板块新增收入中的占比已接近1/3。更重要的意义在于，Leqvio验证了小核酸药物在大规模慢性病市场（如高血脂）的显著疗效、可负担性与长效依从性优势。 当“技术的无限潜能”与“商业的规模化兑现”相交汇，小核酸已不再是“未来可期”，而是进入了实质化放量与价值重估的新周期。 当然，热度之下绝非坦途：长期的安全性需不断验证；全球范围内日趋激烈的专利布局博弈也成为关键卡位点。能否跨越这些门槛，也关系着企业在新周期中的座次。 但毋庸置疑的是，凭借独特的治疗优势与不断成熟的平台技术，小核酸之风，必将愈吹愈劲。 PS：欢迎扫描下方二维码，添加氨基君微信号交流。

Sep 09, 2025 CAMBRIDGE, Mass. --(BUSINESS WIRE)--Sep. 9, 2025-- Alnylam Pharmaceuticals, Inc. (“Alnylam”) (Nasdaq: ALNY), the leading RNAi therapeutics company, announced today the pricing of its previously announced private offering of $575 million aggregate principal amount of 0.00% convertible senior notes due 2028 (the “notes”) to persons reasonably believed to be qualified institutional buyers pursuant to Rule 144A under the Securities Act of 1933, as amended (the “Securities Act”). The size of the offering was increased from the previously announced offering of $500 million aggregate principal amount of notes. In addition, Alnylam granted the initial purchasers of the notes an option to purchase, for settlement within a 13-day period beginning on, and including, the date on which the notes are first issued, up to an additional $86.25 million aggregate principal amount of the notes. The offering is expected to close on September 12, 2025 , subject to customary closing conditions. The notes will be senior, unsecured obligations of Alnylam and will not bear regular interest, and the principal amount of the notes will not accrete. The notes will mature on September 15, 2028 , unless earlier converted, redeemed or repurchased. Before June 15, 2028 , noteholders will have the right to convert their notes in certain circumstances and during specified periods. From and after June 15, 2028 , noteholders may convert their notes at any time at their election until the close of business on the second scheduled trading day immediately before the maturity date. Alnylam will settle conversions by paying or delivering, as applicable, cash, shares of its common stock, par value $0.01 per share (“common stock”), or a combination of cash and shares of its common stock, at Alnylam’s election. The initial conversion rate is 1.4923 shares of common stock per $1,000 principal amount of the notes, which represents an initial conversion price of approximately $670.11 per share of Alnylam’s common stock. The initial conversion price represents a premium of approximately 40% above the U.S. composite volume weighted average price of Alnylam's common stock from 12:30 p.m. through 4:00 p.m. Eastern Daylight Time on September 9, 2025 , which was $478.6327 per share. The conversion rate and conversion price will be subject to adjustment upon the occurrence of certain events. The notes will be redeemable, in whole or in part (subject to certain limitations), for cash at Alnylam’s option at any time, and from time to time, on or after September 20, 2027 and on or before the 21st scheduled trading day immediately preceding the maturity date, if the last reported sale price per share of Alnylam’s common stock equals or exceeds 130% of the conversion price for a specified period of time. The redemption price will be equal to the principal amount of the notes to be redeemed, plus accrued and unpaid special interest, if any, to, but excluding, the redemption date. In connection with the pricing of the notes, Alnylam entered into privately negotiated capped call transactions with certain of the initial purchasers or their respective affiliates and certain other financial institutions (the “option counterparties”). The capped call transactions are expected generally to reduce potential dilution to Alnylam’s common stock upon conversion of any notes and/or offset any potential cash payments Alnylam is required to make in excess of the principal amount of converted notes, as the case may be, with such reduction and/or offset subject to a cap. The cap price of the capped call transactions will initially be approximately $837.61 per share of Alnylam’s common stock, which represents a premium of approximately 75% over the U.S. composite volume weighted average price of Alnylam’s common stock from 12:30 p.m. through 4:00 p.m. Eastern Daylight Time on September 9, 2025 . Alnylam has been advised that, in connection with establishing their initial hedges of the capped call transactions, the option counterparties or their respective affiliates expect to purchase shares of Alnylam’s common stock and/or enter into various derivative transactions with respect to Alnylam’s common stock concurrently with or shortly after the pricing of the notes. This activity could increase (or reduce the size of any decrease in) the market price of Alnylam’s common stock or the notes at that time. In addition, the option counterparties and/or their respective affiliates may modify their hedge positions by entering into or unwinding various derivatives with respect to Alnylam’s common stock and/or purchasing or selling Alnylam’s common stock or other securities of Alnylam in secondary market transactions from time to time prior to the maturity of the notes (and are likely to do so during any observation period related to a conversion of notes or following certain repurchases or redemptions of the notes). This activity could cause or avoid an increase or a decrease in the market price of Alnylam’s common stock or the notes, which could affect the ability of holders to convert the notes and, to the extent the activity occurs following conversion or during any observation period related to a conversion of notes, it could affect the amount and value of the consideration that holders will receive upon conversion of such notes. Alnylam estimates that the net proceeds from the offering of the notes will be approximately $561.6 million (or approximately $645.9 million if the initial purchasers exercise their option to purchase additional notes in full), after deducting the initial purchasers’ discounts and estimated offering expenses payable by Alnylam . Alnylam intends to use approximately $30.7 million of the net proceeds from the offering to pay the cost of the capped call transactions. If the initial purchasers exercise their option to purchase additional notes, Alnylam expects to use a portion of the net proceeds from the sale of the additional notes to enter into additional capped call transactions. In addition, Alnylam intends to use the remainder of the net proceeds from the offering, together with cash on hand, to repurchase for cash approximately $637.8 million aggregate principal amount of Alnylam’s 1.00% convertible senior notes due 2027 (the “existing notes”) through privately negotiated transactions entered into concurrently with the pricing of the notes. Concurrently with the pricing of the notes, Alnylam entered into privately negotiated transactions (the “note repurchase transactions”) with certain holders of the existing notes to repurchase for cash approximately $637.8 million aggregate principal amount of the existing notes for a total repurchase cost (including accrued and unpaid interest) of approximately $1,105.8 million . The terms of the note repurchase transactions were individually negotiated with certain holders of the existing notes and depended on a variety of factors, including the market price of Alnylam’s common stock and the trading price of the existing notes at the time of the note repurchase transactions. This press release is not an offer to repurchase the existing notes, and the offering of the notes is not contingent upon the repurchase of the existing notes. In connection with the note repurchase transactions, Alnylam expects that holders of the existing notes who have agreed to have their existing notes repurchased and who have hedged their equity price risk with respect to such existing notes (the “hedged holders”) will unwind all or part of their hedge positions by buying Alnylam’s common stock and/or entering into or unwinding various derivative transactions with respect to Alnylam’s common stock. The amount of Alnylam’s common stock to be purchased by the hedged holders or the notional number of shares of Alnylam’s common stock underlying such derivative transactions may be substantial in relation to the historic average daily trading volume of Alnylam’s common stock. This activity by the hedged holders could increase (or reduce the size of any decrease in) the market price of Alnylam’s common stock, including concurrently with the pricing of the notes, resulting in a higher effective conversion price of the notes. Alnylam cannot predict the magnitude of such market activity or the overall effect it will have on the price of the notes or Alnylam’s common stock and the corresponding effect on the initial conversion price of the notes. The notes were offered only to persons reasonably believed to be qualified institutional buyers pursuant to Rule 144A under the Securities Act. The offer and sale of the notes and any shares of common stock issuable upon conversion of the notes have not been, and will not be, registered under the Securities Act or any other securities laws, and the notes and any such shares cannot be offered or sold absent registration or except pursuant to an applicable exemption from, or in a transaction not subject to, the registration requirements of the Securities Act and any other applicable securities laws. This press release does not constitute an offer to sell, or the solicitation of an offer to buy, the notes or any shares of common stock issuable upon conversion of the notes, nor will there be any sale of the notes or any such shares, in any state or other jurisdiction in which such offer, sale or solicitation would be unlawful. About Alnylam Pharmaceuticals Alnylam (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding in 2002, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products include AMVUTTRA® (vutrisiran), ONPATTRO® (patisiran), GIVLAARI® (givosiran), and OXLUMO® (lumasiran), which are being developed and commercialized by Alnylam , and Leqvio® (inclisiran) and Qfitlia™ (fitusiran), which are being developed and commercialized by Alnylam’s partners, Novartis and Sanofi, respectively. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. Alnylam Forward Looking Statements Various statements in this release concerning Alnylam’s future expectations, plans and prospects, including, without limitation, statements regarding: whether Alnylam will issue the notes; whether the note repurchase transactions will settle; the anticipated use of the net proceeds from the offering; expectations regarding the effect of the capped call transactions; expectations regarding actions of the hedged holders, the option counterparties and their respective affiliates; and whether the capped call transactions will become effective, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results and future plans may differ materially from those indicated by these forward-looking statements as a result of various important risks, uncertainties and other factors, including, without limitation, risks and uncertainties relating to Alnylam’s ability to successfully execute on its “Alnylam P5x25” strategy; Alnylam’s ability to discover and develop novel drug candidates and delivery approaches and successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates; or advice of regulatory agencies and Alnylam’s ability to obtain and maintain regulatory approval for its product candidates, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; delays, interruptions or failures in the manufacture and supply of its product candidates or its marketed products; obtaining, maintaining and protecting intellectual property; Alnylam’s ability to manage its growth and operating expenses through disciplined investment in operations and its ability to achieve a self-sustainable financial profile in the future; Alnylam’s ability to maintain strategic business collaborations; Alnylam’s dependence on third parties for the development and commercialization of certain products; the outcome of litigation; the potential risk of future government investigations; and unexpected expenditures; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s most recent Annual Report on Form 10-K filed with the Securities and Exchange Commission (“SEC”), as may be updated from time to time in Alnylam’s subsequent Quarterly Reports on Form 10-Q, and in other filings that Alnylam makes with the SEC . In addition, any forward-looking statements represent Alnylam’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam explicitly disclaims any obligation, except to the extent required by law, to update any forward-looking statements. View source version on businesswire.com: https://www.businesswire.com/news/home/20250909474901/en/ Alnylam Pharmaceuticals, Inc. Christine Akinc (Investors and Media) +1-617-682-4340 Josh Brodsky (Investors) +1-617-551-8276 Source: Alnylam Pharmaceuticals, Inc.