Plozasiran

▎药明康德编者按：在刚刚结束的2025上半年，降血脂新药研发领域迎来一系列新进展，小分子、寡核苷酸、基因疗法等同步突破，展现出新的潜力和前景。其中寡核苷酸疗法以潜在长效优势成为行业关注重点。为满足行业持续增长的研发需求，药明康德旗下WuXi TIDES的寡核苷酸平台为寡核苷酸原料药和制剂提供从药物发现到商业化生产的一体化CRDMO服务，更好地赋能全球合作伙伴，加速创新转化，造福全球病患。2025年6月，礼来（Eli Lilly and Company）宣布以约13亿美元收购Verve Therapeutics，后者拥有三款体内基因编辑在研管线，这些产品主要靶向PCSK9、ANGPTL3和LPA等与血脂调控密切相关的基因。2025年3月，恒瑞医药就其口服脂蛋白(a)[Lp(a)]小分子抑制剂HRS-5346与默沙东（MSD）达成19.7亿美元合作。该药物目前处于2期临床，拟用于治疗高脂蛋白(a)血症。此外在今年4月，在知名媒体Drug Hunter发布的2024年度明星分子榜单中，阿斯利康（AstraZeneca）在研的口服PCSK9抑制剂AZD0780入选，这是一款小分子降脂疗法。这些产业新动向，提示行业对降脂疗法的持续关注。高血脂，也称血脂异常，通常指血浆中甘油三酯(TG)或总胆固醇（TC）升高，也包括低密度脂蛋白胆固醇(LDL-C，常被称为“坏胆固醇”）升高。高血脂作为心血管疾病的重要危险因素，其治疗一直是医药研发的重点领域。现有降脂疗法已形成多层次的解决方案：从经典的他汀类药物，到选择性胆固醇吸收抑制剂、贝特类药物、新型PCSK9抑制剂以及siRNA药物（一年注射两次）等，为患者提供了多样化选择。然而，现有疗法在药物局限性、患者依从性和可及性等方面仍存在不足，推动着产业界持续探索更优解决方案。根据公开资料，目前全球范围内有近百款在研降脂疗法处于积极的临床研究阶段，覆盖小分子、抗体、寡核苷酸、以及基因编辑疗法等多种类型，涉及PCSK、ANGPTL3、APOC3、ANGPTL4、APOA、Lp(a)等热门靶点。其中，基于寡核苷酸和基因编辑的降脂疗法，通过靶向肝脏中与血脂生成相关基因，有望带来疗效更持久，甚至“只需一次给药，终生降血脂”的治疗方法。寡核苷酸疗法快速发展，20多款临床在研管线在降脂疗法的临床管线中，寡核苷酸药物占据重要地位，目前已有20多款临床在研产品，主要包括反义寡核苷酸（ASO）疗法和siRNA疗法。这类药物普遍具有长效性，单次给药后疗效可持续数月甚至半年，可显著简化患者的血脂管理流程，提高治疗依从性。2025年上半年，寡核苷酸降脂领域迎来多项重要进展：1月，Arrowhead Pharmaceuticals宣布FDA受理其siRNA疗法plozasiran的新药申请（NDA），用于治疗家族性乳糜微粒血症综合征（FCS）。这类患者的甘油三酯（TG）水平极高，易引发严重临床症状。Plozasiran通过下调载脂蛋白C-III(APOC3)降低甘油三酯水平，使脂质恢复到正常水平。该产品在中国也已提交上市申请并纳入优先审评。3月，礼来公司公布其siRNA疗法lepodisiran的一项2期研究数据，显示在血清Lp(a)浓度较高的患者中，该产品可有效降低Lp(a)浓度，效果维持至少1年；基线和第180天使用lepodisiran 400 mg剂量时，在第240-第360天的降幅可高达95%，且安全性良好。该研究结果同步发表于《新英格兰医学杂志》。同期，安进（Amgen）在JAMA Cardiology发表其靶向载脂蛋白(a) [ApoA]的siRNA疗法olpasiran的2期临床数据，显示每12周给药一次，高剂量组在治疗36周时Lp(a)降低超90%，效果持续至48周。目前该疗法针对动脉粥样硬化性心血管疾病（ASCVD）的3期试验正在进行中。5月，Ionis Pharmaceuticals宣布其靶向APOC3基因的ASO疗法Tryngolza（olezarsen）在3期临床中取得积极的顶线结果。Olezarsen在治疗6个月后显著降低了患者的甘油三酯水平，达到主要终点。该产品已于2024年底获FDA批准上市。此外，更多在研寡核苷酸降脂疗法持续推进，例如：礼来旗下靶向ANGPTL3的siRNA疗法solbinsiran的一项2期临床研究积极结果今年3月发表于《柳叶刀》，表现出降脂效果和良好耐受性。Lipigon Pharmaceuticals靶向ANGPTL4的ASO疗法lipisense于今年3月完成了2期临床试验患者招募，针对高脂血症患者，预计年底公布初步结果。石药集团靶向Lp(a)的siRNA疗法SYH2068注射液、鼎乐新为研发的PCSK9靶向siRNA疗法DNV001、靖因药业靶向LPA基因的siRNA疗法SRSD216注射液等多款寡核苷酸疗法均在上半年获批IND，进入临床阶段。创新技术推动，GalNAc发挥重要作用在治疗变革的发展中，创新技术往往是重要驱动因素。在寡核苷酸降脂疗法中，递送技术的发展发挥着重要作用。例如在目前在研的寡核苷酸降脂疗法中，大多采用GalNAc偶联技术。GalNAc偶联技术因其卓越的肝脏靶向性，成为肝脏靶向寡核苷酸药物的主流递送策略。在降脂领域，肝脏在脂质代谢中处于核心调控地位，直接影响血液中胆固醇和甘油三酯水平。降脂疗法靶蛋白如Lp(a)、ANGPTL3均是由肝脏合成或分泌的蛋白。GalNAc技术通过增强寡核苷酸分子的肝脏特异性递送，有望带来疗效、安全性更优以及更长效的治疗方案。尽管GalNAc偶联技术在肝脏特异性递送寡核苷酸药物方面表现突出，但药物实现规模化应用，还需要强有力的全方位技术整合能力作为支撑。作为医药创新的赋能者，药明康德旗下WuXi TIDES寡核苷酸平台为寡核苷酸原料药和制剂提供从药物发现到商业化生产的一体化CRDMO服务，更好地赋能全球合作伙伴。公开信息显示，围绕GalNAc等复杂分子，WuXi TIDES平台已打造了涵盖定制合成、工艺开发及生产的一站式服务平台，更好地满足全球合作伙伴的寡核苷酸及各类化学偶联物的研发需求。例如，在定制化GalNAc方面，WuXi TIDES团队已经生产过涵盖不同类型、总数超过100款的GalNAc化合物，覆盖不同类型的GalNAc分子；通过优化GalNAc树脂负载工艺，将固相合成的收率提高50%。同时，借助流动化学平台，加速高纯度GalNAc的规模化生产。需要注意的是，GalNAc单体寡核苷酸偶联化合物的快速推进，对于研发生产平台的集成能力要求极高。WuXi TIDES平台已建立全面的寡核苷酸偶联能力，涵盖各类偶联类型，以及各类偶联化学和化学修饰策略；并通过一体化CMC服务涵盖寡核苷酸原料药、制剂分析等全流程。在某真实案例中，WuXi TIDES多个团队凭借一体化平台优势，研发多线并行，生产无缝衔接，在10个月内将一个用于治疗siRNA-GalNAc候选化合物顺利推进至IND阶段。多元化降脂疗法齐头并进，造福病患除寡核苷酸疗法外，全球降脂药物研发管线呈现多元化发展态势，涵盖肽类、小分子、抗体、基因疗法等多种技术路径，靶向PCSK9、ANGPTL3、Lp(a)等关键靶点。今年上半年，更多创新降脂疗法领域取得新进展。例如，默沙东6月宣布其大环肽类口服PCSK9抑制剂enlicitide decanoate在三项3期临床试验中的前两项的积极结果。该药物有望成为获FDA批准的首款口服PCSK9抑制剂降脂疗法。CRISPR Therapeutics在5月公布其ANGPTL3靶向体内肝脏基因编辑疗法CTX310在1期临床中的积极结果，1例杂合子家族性高胆固醇血症（HeFH）患者LDL-C水平在第90天下降81%。Verve Therapeutics 在4月公布其靶向PCSK9基因的碱基编辑疗法VERVE-102在1b期试验中的初步积极数据，单次输注VERVE-102可导致血液中PCSK9蛋白水平和LDL-C呈剂量依赖性下降；尧唐生物同月公布其靶向PCSK9基因的体内碱基编辑药物YOLT-101治疗家族性高胆固醇血症（FH）的临床数据，实现PCSK9持续降低70%以上，最大降幅达87%。《自然-医学》今年1月发文指出，未来胆固醇和血脂的控制手段可能更为灵活，从每日服用的药片，到只需几个月一针的注射疗法，甚至“一劳永逸”的基因编辑疗法，为临床提供多元化选择。科学创新的脚步始终在向前。当前降脂领域已突破“他汀时代”的局限，形成“百花齐放”的创新格局。这些持续涌现的新疗法，将推动降脂治疗向更便捷、更持久、更个性化的方向发展。参考资料：[1] RNA gene therapies offer hope for millions with high cholesterol. Retrieved February 10, 2025, from https://www.nature.com/articles/d41591-025-00002-2版权说明：本文欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权或其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。

PASADENA, Calif.--(BUSINESS WIRE)--Arrowhead Pharmaceuticals, Inc. (NASDAQ: ARWR) today announced that it has dosed the first subject in the YOSEMITE Phase 3 clinical trial of zodasiran, the company’s investigational RNA interference (RNAi) therapeutic being developed as a potential treatment for homozygous familial hypercholesterolemia (HoFH), a rare genetic condition that leads to severely elevated LDL-cholesterol and early onset cardiovascular disease. Zodasiran is the fourth investigational RNAi-based candidate developed by Arrowhead to reach late-stage pivotal studies, after investigational drugs plozasiran, fazirsiran (licensed to Takeda) and olpasiran (licensed to Amgen). As an RNAi-based therapeutic targeting ANGPTL3, investigational zodasiran has the potential to treat HoFH in a fundamentally different manner from traditional LDL-C–lowering therapies. “Patients living with HoFH are difficult to adequately treat and have a very high risk of developing atherosclerotic cardiovascular disease due to severely elevated LDL-C, often exceeding 500 mg/dL. As an RNAi-based therapeutic targeting ANGPTL3, investigational zodasiran has the potential to treat HoFH in a fundamentally different manner from traditional LDL-C–lowering therapies,” said James Hamilton, M.D., Chief Medical Officer and head of R&D at Arrowhead. “In Phase 2 clinical studies, patients with HoFH receiving zodasiran achieved reductions from baseline in LDL-C, ApoB, non-HDL-C, and triglycerides, supporting its potential therapeutic role for the treatment of HoFH patients.” About Homozygous Familial Hypercholesterolemia Homozygous Familial Hypercholesterolemia (HoFH) is an ultra-rare treatment‐resistant genetic condition characterized by elevated low density lipoprotein cholesterol (LDL-C) and early-onset cardiovascular disease. Most cases of HoFH are due to mutations in the low-density lipoprotein receptor gene (LDLR) coding for the LDL receptor (LDLR). Thus, HoFH represents a unique case where LDL-C lowering therapies not requiring functional LDL receptors may have benefit. If left untreated, individuals with HoFH can have median LDL-C levels above 500 mg/dL (13 mmol/L), leading to early clinical manifestations of coronary artery disease1. Patients with HoFH may also have cholesterol deposits under the skin (xanthomas), around the eyes (xanthelasmas), or around the cornea (corneal arcus), but physical signs are not always present, particularly in children. HoFH remains challenging to treat and currently only patients with the more severe HoFH phenotypes get diagnosed and treated early. The estimated prevalence of HoFH globally is between 1:360,000 and 1:250,0001. About YOSEMITE Phase 3 Study YOSEMITE (NCT07037771) is a Phase 3 multicenter, randomized, placebo-controlled study to evaluate the efficacy and safety of zodasiran in adolescent and adult patients with genetically or clinically diagnosed homozygous familial hypercholesterolemia (HoFH) on maximally tolerated lipid lowering therapy. Approximately 60 subjects over the age of 12 will be randomized (2:1) to receive 4 doses (once every 3 months) of 200 mg zodasiran or placebo. The primary endpoint is the percent change from baseline to month 12 in fasting LDL-C. After month 12, eligible participants will be offered an opportunity to continue in an optional open-label extension. About Zodasiran Zodasiran, previously called ARO-ANG3, is a first-in-class investigational RNA interference (RNAi) therapeutic designed to reduce production of angiopoietin-like protein (ANGPTL3), which is a hepatocyte expressed regulator of lipid and lipoprotein metabolism with multiple potential modes of action, including inhibition of lipoprotein lipase (LPL) and endothelial lipase (EL)5,6. ANGPTL3 is an emerging therapeutic target with relevance to hypercholesterolemia, hypertriglyceridemia, and mixed hyperlipidemia. Genetic studies suggest that individuals with ANGPTL3 loss-of-function variants have enhanced lipoprotein lipase and endothelial lipase activity, resulting in lower levels of atherogenic lipoproteins and a reduced risk of ASCVD2-4. In prior clinical studies, investigational zodasiran was associated with dose-dependent reductions in triglycerides, triglyceride rich lipoprotein remnants, and total atherogenic lipoproteins, including LDL-C, in patients with homozygous (HoFH) and heterozygous (HeFH) familial hypercholesterolemia and mixed hyperlipidemia. Zodasiran also showed a favorable safety profile. In the Phase 2 GATEWAY study in patients with HoFH, there were no drug discontinuations, drug-related serious adverse events, or deaths. The most frequent adverse events were COVID-19, nasopharyngitis, upper respiratory tract infection, and dizziness. About Arrowhead Pharmaceuticals, Inc. Arrowhead Pharmaceuticals, Inc. develops medicines that treat intractable diseases by silencing the genes that cause them. Using a broad portfolio of RNA chemistries and efficient modes of delivery, Arrowhead therapies trigger the RNA interference mechanism to induce rapid, deep, and durable knockdown of target genes. RNA interference, or RNAi, is a mechanism present in living cells that inhibits the expression of a specific gene, thereby affecting the production of a specific protein. Arrowhead’s RNAi-based therapeutics leverage this natural pathway of gene silencing. For more information, please visit www.arrowheadpharma.com, or follow us on X (formerly Twitter) at @ArrowheadPharma, LinkedIn, Facebook, and Instagram. To be added to the Company's email list and receive news directly, please visit http://ir.arrowheadpharma.com/email-alerts. Safe Harbor Statement under the Private Securities Litigation Reform Act: This news release contains forward-looking statements within the meaning of the "safe harbor" provisions of the Private Securities Litigation Reform Act of 1995. Any statements contained in this release except for historical information may be deemed to be forward-looking statements. Without limiting the generality of the foregoing, words such as “may,” “might,” “will,” “expect,” “believe,” “anticipate,” “goal,” “endeavor,” “strive,” “hope,” “intend,” “plan,” “project,” “could,” “estimate,” “potential,” “target,” “forecast” or “continue” or the negative of these words or other variations thereof or comparable terminology are intended to identify such forward-looking statements. In addition, any statements that refer to projections of our future financial performance, trends in our business, expectations for our product pipeline or product candidates, including anticipated regulatory submissions and clinical program results, prospects or benefits of our collaborations with other companies, or other characterizations of future events or circumstances are forward-looking statements. These forward-looking statements include, but are not limited to, statements about the initiation, timing, progress and results of our preclinical studies and clinical trials, and our research and development programs; our expectations regarding regulatory approval for and commercial launch of plozasiran; our expectations regarding the potential benefits of the partnership, licensing and/or collaboration arrangements and other strategic arrangements and transactions we have entered into or may enter into in the future; our beliefs and expectations regarding milestone, royalty or other payments that could be due to or from third parties under existing agreements; and our estimates regarding future revenues, research and development expenses, capital requirements and payments to third parties. These statements are based upon our current expectations and speak only as of the date hereof. Our actual results may differ materially and adversely from those expressed in any forward-looking statements as a result of numerous factors and uncertainties, including the safety and efficacy of our product candidates, decisions of regulatory authorities and the timing thereof, the duration and impact of regulatory delays in our clinical programs, our ability to finance our operations, the likelihood and timing of the receipt of future milestone and licensing fees, the future success of our scientific studies, our ability to successfully develop and commercialize drug candidates, the timing for starting and completing clinical trials, rapid technological change in our markets, the enforcement of our intellectual property rights, and the other risks and uncertainties described in our most recent Annual Report on Form 10-K, subsequent Quarterly Reports on Form 10-Q and other documents filed with the Securities and Exchange Commission from time to time. We assume no obligation to update or revise forward-looking statements to reflect new events or circumstances. Source: Arrowhead Pharmaceuticals, Inc. ________________ 1. Cuchel, et al. Eur Heart J. 2023;44(25):2277-91 2. Dewey, et al. N Engl J Med. 2017;377 (3):211-21. 3. Minicocci, et al. J Lipid Res. 2013;54(12): 3481-90 4. Musunuru, et al. N Engl J Med. 2010; 363(23):2220-7 5. Adam, et al. J Lipid Res. 2020;61(9): 1271-86. 6. Rosenson. J Lipid Res. 2021:62:100060.