Givosiran Sodium

− Achieved 28% and 33% Reduction in Composite of All-Cause Mortality and Recurrent Cardiovascular Events in the Overall and Monotherapy Populations, Respectively – − Reduced All-Cause Mortality by 36% and 35% in the Overall and Monotherapy Populations, Respectively, in a Pre-Specified Secondary Endpoint – − Demonstrated Clinically Significant Benefits on 6-Minute Walk Test, Kansas City Cardiomyopathy Questionnaire and NYHA Class – Key Measures of Disease Progression – − Observed Consistent Effects in All Key Subgroups, Including Baseline Tafamidis – − Demonstrated Encouraging Safety, Consistent with Established Profile – − Alnylam to File a U.S. Supplemental New Drug Application Using a Priority Review Voucher – − Alnylam to Host Conference Call Today at 8:00 am ET – CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced positive topline results from its HELIOS-B Phase 3 study of vutrisiran, an investigational RNAi therapeutic in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM). The study met the primary endpoint, demonstrating a statistically significant reduction in the composite of all-cause mortality and recurrent cardiovascular (CV) events during the double-blind period in both the overall population (HR 0.718, p-value 0.0118; n=654) and in the monotherapy population (patients not receiving tafamidis at baseline; HR 0.672, p-value 0.0162; n=395). The study also demonstrated statistically significant improvements across all secondary endpoints in both the overall and monotherapy populations. This includes key measures of disease progression: 6-minute walk test (6-MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ) and New York Heart Association (NYHA) Class at Month 30 (p<0.025 for all). Importantly, treatment with vutrisiran also reduced all-cause mortality in the overall population (HR 0.645, p<0.025) and in the monotherapy population (HR 0.655, p<0.05) up to Month 42. This was a pre-specified, intent-to-treat analysis that included up to six months of data from the open-label extension. “I’m thrilled by these overwhelmingly positive data from the HELIOS-B study, which suggest that vutrisiran has the potential to address the needs of patients with ATTR amyloidosis with cardiomyopathy, a steadily progressive, debilitating, and ultimately fatal disease,” said Pushkal Garg, M.D., Chief Medical Officer of Alnylam. “The results showed that vutrisiran improved cardiovascular outcomes, including survival, function and quality of life in all patient groups with ATTR cardiomyopathy. We are moving with urgency to compelling data with regulators to bring this medicine to patients around the world.” In addition, vutrisiran demonstrated consistent effects on the primary composite endpoint and all secondary endpoints across all key subgroups, including baseline tafamidis use, ATTR disease type and measures of disease severity. In the HELIOS-B study, vutrisiran demonstrated encouraging safety and tolerability, consistent with its established profile. Rates of adverse events (AEs), serious AEs and AEs leading to study drug discontinuation were similar between the vutrisiran and placebo arms. No AEs were seen ≥3% more frequently in the vutrisiran arm compared to the placebo arm. “I am overjoyed by the results of the HELIOS-B study, which suggest the potential for vutrisiran to be a transformative medicine for patients with ATTR amyloidosis with cardiomyopathy,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam. “Assuming favorable regulatory review, vutrisiran has the potential to become the new standard of care for the treatment of this disease, driving Alnylam’s next era of substantial growth.” HELIOS-B (NCT: NCT04153149) is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed and powered to evaluate the efficacy and safety of vutrisiran on the reduction of all-cause mortality and recurrent cardiovascular events as a primary composite endpoint in patients with ATTR amyloidosis with cardiomyopathy in the overall and monotherapy populations. The study randomized 655 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy. Patients were randomized 1:1 to receive vutrisiran 25mg or placebo subcutaneously once every three months during a double-blind treatment period of up to 36 months. After the double-blind period, all eligible patients remaining on the study may receive vutrisiran in an open-label extension period. Detailed results from the HELIOS-B study have been submitted as a late-breaking abstract to the European Society of Cardiology for presentation. The Company plans to proceed with global regulatory submissions starting later this year, including filing a supplemental New Drug Application with the U.S. Food and Drug Administration using a Priority Review Voucher. Investor Webcast Information Management will discuss the HELIOS-B topline results via conference call on Monday, June 24, 2024, at 8:00 am ET. To access the call, please register online at . Participants are requested to register at a minimum of 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same web page for six months. A live audio webcast of the call will be available on the Investors section of the Company’s website at . An archived webcast will be available on the Company’s website approximately two hours after the event. IMPORTANT SAFETY INFORMATION Reduced Serum Vitamin A Levels and Recommended Supplementation AMVUTTRA® (vutrisiran) treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking AMVUTTRA. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with AMVUTTRA, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness). Adverse Reactions The most common adverse reactions that occurred in patients treated with AMVUTTRA for polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) were arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). For additional information about AMVUTTRA, please see the full Prescribing Information. About ATTR Transthyretin amyloidosis (ATTR) is an underdiagnosed, rapidly progressive, debilitating and fatal disease caused by misfolded transthyretin (TTR) proteins, which accumulate as amyloid deposits in various parts of the body, including the nerves, heart and gastrointestinal tract. Patients may present with polyneuropathy, cardiomyopathy, or both manifestations of disease. There are two different forms of ATTR – hereditary ATTR (hATTR), which is caused by a TTR gene variant and affects approximately 50,000 people worldwide, and wild-type ATTR (wtATTR), which occurs without a TTR gene variant and impacts an estimated 200,000 – 300,000 people worldwide. About AMVUTTRA® (vutrisiran) AMVUTTRA® (vutrisiran) is an RNAi therapeutic that delivers rapid knockdown of mutant and wild‑type transthyretin (TTR), addressing the underlying cause of transthyretin (ATTR) amyloidosis. Administered quarterly via subcutaneous injection, AMVUTTRA is approved and marketed in more than 15 countries for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN) in adults. Vutrisiran is also in development for the treatment of ATTR amyloidosis with cardiomyopathy (ATTR-CM), which encompasses both wild-type and hereditary forms of the disease. For more information about AMVUTTRA, including the full U.S. Prescribing Information, visit AMVUTTRA.com. About RNAi RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines known as RNAi therapeutics is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by potently silencing messenger RNA (mRNA) – the genetic precursors that encode for disease-causing or disease pathway proteins – thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases. 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 are ONPATTRO® (patisiran), AMVUTTRA® (vutrisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), and Leqvio® (inclisiran), which is being developed and commercialized by Alnylam’s partner, Novartis. 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. For more information about our people, science and pipeline, please visit and engage with us on X (formerly Twitter) at @Alnylam, or on LinkedIn, Facebook, or Instagram. Alnylam Forward-Looking Statements This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, Alnylam’s expectations regarding the safety and efficacy of vutrisiran for the treatment of ATTR amyloidosis with cardiomyopathy, including its potential to be a transformative medicine for patients with ATTR amyloidosis with cardiomyopathy; the potential for vutrisiran to become the new standard of care for the treatment of ATTR amyloidosis with cardiomyopathy; the potential for vutrisiran to obtain regulatory approval for the treatment of ATTR amyloidosis with cardiomyopathy; the potential for vutrisiran to drive Alnylam’s next era of substantial growth; the expected timing of the presentation of full data from the HELIOS-B clinical trial and the filing of a U.S. Supplemental New Drug Application for vutrisiran; Alnylam’s plans to use a Priority Review Voucher in connection with the Supplemental New Drug Application for vutrisiran; the potential for vutrisiran’s clinical pro support first-line positioning in newly diagnosed patients and in those patients who continue to experience disease progression with stabilizers; and the potential for Alnylam to achieve its Alnylam P5x25 vision of becoming a leading biopharma company should be considered forward-looking statements. 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 successfully demonstrate the efficacy and safety of its product candidates; the pre-clinical and clinical results for Alnylam’s product candidates, including vutrisiran; actions or advice of regulatory agencies and Alnylam’s ability to obtain regulatory approval for its product candidates, including vutrisiran, as well as favorable pricing and reimbursement; successfully launching, marketing and selling Alnylam’s approved products globally; and any delays, interruptions or failures in the manufacture and supply of Alnylam’s product candidates or its marketed products; as well as those risks more fully discussed in the “Risk Factors” filed with Alnylam’s 2023 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 its other SEC filings. 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.

自1998年RNA干扰（RNAi）现象的发现以来，25年里这一技术已从发现走向了临床应用，为遗传性疾病治疗提供了新的可能性。突破RNAi药物从发现到临床应用1998年，RNA干扰（RNA interference，RNAi）现象首次被发现。这是一种转录后水平的基因表达调控技术，能够使与之同源的靶基因mRNA特异性降解或翻译受阻，从而达到基因沉默的效果。RNAi技术的发现为基因表达调控提供了新的机制，特别是在治疗遗传性疾病方面，被授予了2006年诺贝尔生理学或医学奖。小干扰RNA(small interference RNA, siRNA）药物正是基于RNAi技术的一种新型治疗方法，具有特异性沉默几乎任何治疗靶点的潜力，拥有前所未有的效力和持久性。2018年，FDA批准了首款siRNA药物——Onpattro（Patisiran），由Alnylam公司开发用于治疗hATTR患者，代表了一种治疗疾病的全新方法。该药基于脂质纳米颗粒（LNPs）递送，这也是目前市场上唯一利用这一技术平台的siRNA药物。此后，肝脏递送的主要平台由更有效的GalNAc偶联技术取代。目前，全球已有6个siRNA药物获批上市。表1. 全球已上市的6个siRNA药物通用名（商品名），公司靶点（适应症）上市日期2022年销售额（亿美元）2023年销售额（亿美元）Patisiran (Onpattro), Alnylam PharmaTTR （遗传性转甲状腺素淀粉样变性，多发性神经病变）2018.085.583.55Givosiran (Givlaari), Alnylam PharmaALAS1 （急性肝脏卟啉症）2019.111.732.19Lumasiran (Oxlumo)， Alnylam Pharma1型原发性高草酸尿症2020.110.71.1Inclisiran (Leqvio), Alnylam Pharma诺华PCSK9（动脉硬化性心血管疾病和家族性高胆固醇血症2021.121.123.55Vutrisiran (Amvuttra), Alnylam Pharma转甲状腺素蛋白家族性淀粉样多发性神经病2022.060.945.58Nedosiran(Rivfloza) 诺和诺德1型原发性高草酸尿症2023.095.583.55资料来源：FDA官网、博药整理图1：Patisiran (Onpattro)结构式（2018年） 图片来源：博药图2：Rivfloza结构式（2023年）图片来源：ChenFJMU然而，siRNA药物仍面临诸多挑战，尤其是递送问题。目前已获批上市的siRNA药物全部都靶向肝内组织，治疗肝外疾病的效用仍然有限，还需要持续的创新。挑战与创新影响siRNA药物疗效的因素尽管siRNA药物展现出巨大潜力，但其在体内的稳定性和生物利用度仍是主要挑战。化学修饰、计算机辅助设计和生物筛选、优化递送策略等方面的创新，为siRNA药物研发带来了新的希望和突破点。化学修饰由于siRNA药物是基于RNA结构进行设计的，而人体内又存在很多水解RNA的酶，因此在人的循环系统中，siRNA药物非常容易被水解掉，其表现为稳定性不足；另外一方面，siRNA药物是带有负电荷的核酸大分子，原则上很难通过细胞膜进入细胞内部发生作用；并且，siRNA还可以触发先天免疫反应并引起脱靶效应。对 siRNA 进行化学修饰，可以提高其在血液中的化学稳定性、增加半衰期、降低免疫效应和脱靶效应。还可以在药物上连接一些配体，当配体与特定组织上的受体结合时，会引起特定细胞的内吞作用，使得 RNAi 药物具有靶向运输能力。磷酸修饰：裸siRNA的核苷酸之间通过3',5'-磷酸二酯键连接，带有负电荷，容易被血液中的磷酸酶降解。最常见的修饰是将易被水解的磷酸二酯（phosphodiester，PO）替换为硫代磷酸酯（phosphorothioate，PS），可以显著地稳定 RNA 对核酸酶的降解，但过多的 PS 修饰可能导致毒性增加。除此之外，还可以将硼酸磷酸酯（BP）取代 ，效力更高，但目前缺乏大规模合成的优化方法。核糖修饰：最常见的核糖修饰位点为核苷酸的 2'位，包括 2'-O-Me 和 2'-F，可以提高核酸酶抗性和结合亲和力，延长半衰期，使 siRNA 稳定性增强。此外，还可以引入锁核酸（LNA）修饰，即核糖的 2'-O 与 4'-C 之间形成共价键。将 LNA 插入 siRNA 序列可以增加生物稳定性和靶标结合亲和力。碱基修饰：siRNA与mRNA 通过碱基互补形成氢键发挥作用，因此对碱基进行修饰会对 siRNA 的性能产生影响。常见的碱基修饰方法是用 5'-溴尿嘧啶、假尿嘧啶、2'-硫尿嘧啶、5'-碘尿嘧啶取代碱基，可以促进核苷酸之间氢键的形成，一定程度上提高稳定性。综合考虑不同方面的化学结构调整，可以优化siRNA的靶向性和安全性，为其在治疗应用中的应用提供更广阔的前景。图3. siRNA结构修饰策略图片来源：参考资料1计算机辅助设计和生物筛选siRNA的设计和生物筛选对疗效和安全性至关重要。通过计算机辅助设计，研究人员可以利用算法预测siRNA序列的功效和特异性。这些算法综合考虑了目标mRNA的可及性、热力学稳定性和非靶效应等因素。随后，潜在的siRNA候选序列还需要通过生物筛选来验证其活性和选择性。siRNA的修饰策略对其体内功能性具有显著影响。但目前大多数公开可用的siRNA预测算法是基于未修饰的siRNA数据集，这限制了它们对修饰siRNA的预测能力。在体外识别siRNA的活性较为简单，但体外效力并不总是能够直接转化为体内活性。因此，需要综合考虑体外和体内效力，并持续创新以提高预测准确性。靶点特异性是设计siRNA时需要考虑的另一个关键因素。由于脱靶而产生的毒性在体内与体外仍然存在差异，这也是需要考虑的因素。跨物种的siRNA设计可以简化临床前开发过程，但需要对人类和其他物种的靶序列同源性进行分析。在跨物种活性差异方面，仍然缺乏深入的生物学机制解释，需要更多的研究和创新。递送策略递送siRNA至目标细胞是RNAi疗法中不可忽视的一关。为了克服siRNA递送的挑战，科学家们开发了各种递送方法，主要可分为病毒载体和非病毒载体；前者通常使用逆转录病毒、腺病毒等作为递送载体，具有较高的递送效率，但免疫反应风险和毒性等问题，限制了其临床应用。相比之下，非病毒载体以其低毒性而具有更大的开发潜力，比如基于脂质体的纳米递送系统 和偶联介导的递送系统。目前，LNP（脂质纳米颗粒）平台与GalNAc共轭连接递送系统平台已有产品获批上市。另外，Dicerna公司（已被诺和诺德收购）肝脏靶向的GalXC™递送平台可实现RNAi疗法的皮下给药，基于该平台开发的Nedosiran (Rivfloza）已于2023年获批上市，用于原发性高草酸尿症（PH）。在肝外递送方面，Alnylam公司开发了十六烷基C16偶联技术，以鞘内给药方式尝试向中枢神经系统和眼部的递送，以及IKARIA™平台，对肺部、肌肉和脂肪组织的siRNA递送方法进行了改进。Codiak公司开发了外泌体递送平台。此外，近年来无载体递送系统成为一种具有潜力的递送策略，将纳米药物递送与自组装技术相结合，在不借助载体材料的情况下，siRNA 之间自组装或与其他药物共组装，形成均匀稳定的纳米粒，这些纳米粒具有自递送能力，即同时作为递送载体和被递送的对象，包括脂质 siRNA 偶联物、抗体-siRNA 偶联物、多肽 siRNA 偶联物、核酸适配体-siRNA 结合物以及siRNA 与其他药物的共组装。随着新材料、新技术和新策略的不断发展，siRNA的递送将会更加高效和安全，以实现siRNA药物的广泛应用。未来siRNA药物前景辽阔siRNA药物具有明显的优势，包括“不可成药”的靶点、相对较短的开发周期以及长期稳定的临床疗效，这些优势使其已成为药物研发领域的一大亮点。展望未来，siRNA药物的应用范围预计将实现大幅扩展。目前，多项使用脂质和抗体-蛋白质共轭物递送siRNA的临床项目已展现出显著的疾病治疗效果，这一进步可能预示着下一轮siRNA药物批准的浪潮即将到来。图4. 临床适应症和靶标选择图片来源：参考资料1在治疗肝病领域，siRNA药物已被视为一种首选的治疗策略，并已经获得临床验证。siRNA药物因其较低的用药频率和便利性，有望取代某些传统药物siRNA药物的持久性和安全性可能基因编辑方法获得临床接受的先决条件。例如，针对乙型肝炎的siRNA药物已进入了临床验证阶段。此外，siRNA还可以作为长非编码RNA的治疗靶点，为治疗特定疾病提供新的选择。尽管目前对于针对长非编码RNA的药物研发仍处于初级阶段，但siRNA和其他寡核苷酸为基础的治疗方法在这一领域展现出了极高的潜力，未来有望在这一领域取得突破。最后，siRNA与其他药物模式结合可能产生协同效应，为治疗复杂疾病带来新的可能性。例如，Alnylam的靶向C5补体siRNA药物cemdisiran与Regeneron的C5补体抑制剂pozelimab联合疗法在治疗阵发性夜间血红蛋白尿（PNH）显示出潜力。未来，siRNA药物在临床应用中的潜力将继续被挖掘和拓展，我们有望看到更多具有广泛应用前景的RNAi药物问世。参考资料https://doi-org.libproxy1.nus.edu.sg/10.1038/s41573-024-00912-9刘珂瑶，罗应楠，胡一雪，王东纳，张列峰．siRNA 无载体递送研究进展[J/OL]．南京师大学报自然科学版.黄新新. RNAi药物研究进展 [J]. 中国处方药, 2021, 19 (09): 19-20.来源 | 博药（药智网获取授权转载）撰稿 | metallic责任编辑 | 八角声明：本文系药智网转载内容，图片、文字版权归原作者所有，转载目的在于传递更多信息，并不代表本平台观点。如涉及作品内容、版权和其它问题，请在本平台留言，我们将在第一时间删除。商务合作 | 王存星 19922864877（同微信） 阅读原文，是昨天最受欢迎的文章哦