Tafamidis

Pictured (from left): Pfizer and Alnylam signs/Taylor Tieden for BioSpace Unveiled late last month, topline results from a Phase III trial of Alnylam’s RNAi therapy Amvuttra in ATTR amyloidosis with cardiomyopathy are turning some heads. The treatment showed a statistically significant reduction in all-cause mortality and recurrent cardiovascular events. “I expected this readout to be positive, but this was extremely positive,” said Kostas Biliouris, director and equity research analyst at Bank of Montreal Capital Markets. “I think the results reflect the best-case scenario.” The initial results appear promising, but a clearer picture will emerge when the full data come out later this summer. Further details of the HELIOS-B study will be presented as an abstract at the European Society of Cardiology’s congress in London, taking place Aug. 30 to Sept. 2. Paul Matteis, head of the therapeutics research team at Stifel, told BioSpace that not having those details is one of the biggest open questions at the moment. Amvuttra will have to face competition from Pfizer, whose ATTR-CM oral drugs Vyndamax and Vyndaqel were approved in 2019. The Vyndaqel family of drugs has earned blockbuster status, bringing in $1.1 billion in sales in the first quarter of 2024, a 66% boost from Q1 2023. Research Outlook and the ATTR-CM Space In the HELIOS-B trial, Amvuttra reduced the risk of mortality and recurrent cardiovascular events by 28% in patients also taking Pfizer’s Vyndamax compared to a placebo. Those only taking Amvuttra saw the risk drop by 33%. The risk of death from all causes, one of the secondary endpoints, was lowered by 36% in patients also taking Vyndamax, while it was reduced by 35% in those on Amvuttra monotherapy. Patients on Amvuttra also showed statistically significant improvements in other metrics, such as the six-minute walk test. “Given the data we have right now, the totality of the data and the limited information . . . I believe this is potentially the best pro ATTR cardiomyopathy,” Biliouris told BioSpace. Matteis said Amvuttra is at least “tied at the top” based on the topline data but noted that the most significant caveat in comparing Amvuttra to Vyndamax or BridgeBio’s investigational drug acoramidis is that the duration of Alnylam’s study is longer, and the interest will be in what the data at 30 months look like. However, he noted it is unlikely that the 30-month data will suggest Amvuttra is worse than its competition. “[Alnylam is] probably tied for first, in terms of the overall product offering and how compelling it is under the impetus to prescribe it,” he said. Some experts have reservations about whether Amvuttra can challenge Pfizer, however. Myles Minter, a research analyst at William Blair, told BioSpace that Alnylam has “more work to do” as it is going up against Vyndamax, a safe drug with an “impressive” hazard ratio that has benefits in cardiovascular outcomes. He also claims that the “knock” on Amvuttra is that the clinical trials were done in patients who had much more severe cardiovascular events, which differs from when the drug would actually be prescribed. “That’s not how the diagnosis is done today. So, we don’t have control data, like proper industry-standard control data against placebo in the patient population that we’re currently treating, which is early on in the treatment course,” Minter said. He noted that the detailed data expected at the European Society of Cardiology’s congress later this summer will also help determine whether Amvuttra is competitive against the industry standard. Amvuttra’s Financial Outlook Minter said that right now, Amvuttra, which is only approved in polyneuropathy, is generating over $900 million in sales and growing 18% year over year from a patient population of between 30,000 and 60,000. The cardiomyopathy opportunity may allow Amvuttra’s population to expand 10-fold as more noninvasive diagnosis techniques are available for ATTR-CM, he said. Minter estimates that the combined polyneuropathy and ATTR-CM peak sales of Amvuttra would be $3.7 billion in the U.S. and $1.8 billion in the European Union. Matteis projected peak drug sales of around $5 billion to $6 billion, but noted that the competition with Vyndamax will remain and said Pfizer’s drug will maintain its blockbuster status. Another element of the financial equation is pricing. Amvuttra is currently priced much higher than Vyndamax, but Matteis said there is a “general expectation” that it will be lowered to some degree. He also added that there may be other “economic drivers” to Amvuttra, as a practice could make more money prescribing the drug because it is an in-office injection. “There’s a chance where [Alnylam is] in pole position,” Matteis said. “But it is a little bit premature to draw that conclusion without seeing the full data.” Tyler Patchen is a staff writer at BioSpace. You can reach him at tyler.patchen@biospace.com. Follow him on LinkedIn.

关注并星标CPHI制药在线 近日，美国Alnylam Pharmaceuticals公布了其自研新药Amvuttra（Vutrisiran）用于治疗转甲状腺素蛋白淀粉样变心肌病（ATTR-CM）的HELIOS-B临床Ⅲ期研究的积极顶线结果。 Vutrisiran是一款皮下给药的RNAi（RNA干扰）疗法，通过靶向和沉默特定的mRNA，阻断野生型和变体转甲状腺素蛋白（TTR）的产生。基于Alnylam的增强稳定化学（ESC）-GalNAc偶联递送平台，Vutrisiran增加了效力和代谢稳定性。 HELIOS-B是一项全球多中心、随机、双盲、安慰剂对照的III期临床研究，旨在评估Vutrisiran在ATTR-CM患者中减少全因死亡率和复发性心血管事件的效果和安全性（主要终点）。 研究表明，每季度给予患者Vutrisiran可能有助于减少组织中的沉积，促进TTR淀粉样沉积物的清除，并有望恢复这些组织的功能。具体来说，在双盲期间，总人群（N=654）和单药治疗人群(N=395）的全因死亡率和复发性心血管（CV）事件的复合发生率在统计学上显著降低。 另外在总体和单药治疗人群中，所有次要终点均获得统计学显著改善。包括6分钟步行测试（6-MWT），堪萨斯城心肌病问卷调查（KCCQ）和第30个月纽约心功能分级（NYHA），p均小于0.025。 在安全性方面，Vutrisiran组不良事件（AE）、严重AE和因AE导致研究药物停药的发生率与安慰剂组相似。 2022年6月，FDA批准vutrisiran上市（商品名Amvuttra），用于治疗hATTR淀粉样变性成人患者的多发性神经病。 基于HELIOS-B III期临床研究结果，Alnylam 计划于今年晚些时候开始向监管机构提交申请，并将使用优先审查凭证向FDA提交补充新药申请（sBLA）。 Vutrisiran将与辉瑞重磅药物正面刚 ATTR-CM是一种罕见的心肌疾病，由转甲状腺素蛋白（TTR）聚集引起，通常见于老年患者。TTR是人体中一种重要的功能蛋白。正常情况下，TTR是一种稳定的蛋白质，但当TTR分解为单体后，会导致淀粉变性病（ATTR）。根据影响器官不同，ATTR在临床上可分为转甲状腺素蛋白淀粉样变性心肌病（ATTR-CM）和转甲状腺素蛋白淀粉样多发性神经病（ATTR-PN）两类。 其中ATTR-CM是一种罕见的致死性心肌病，患者被称为“淀粉人”，平均而言，患者在确诊后只能存活2-5年。就是这么一种严重的疾病，到目前为止，针对ATTR-CM适应症获批的药物仅有辉瑞的tafamidis一款。 tafamidis于2019年获批，批准基于的主要终点是患者30个月的全因死亡率和心血管疾病住院时间，Ⅲ期临床试验直接证明了患者只要使用tafamidis，就可以延长寿命，并降低住院风险。tafamidis成为FDA批准的第一种ATTR-CM治疗方法，去年全球销售额超过33亿美元。 由于存在较大的临床未满足需求，分析人士预测，到2028年，ATTR-CM药物的全球销售额将达到100亿~150亿美元。 未来，一旦Alnylam的vutrisiran获批上市，将与辉瑞直接竞争市场份额。 争夺增量市场，后来者来势汹汹 据统计，ATTR-CM市场正在以环比15%的速度增长，在这个增量市场，后来者依然有很大的空间争取。因此，多家大药企入局ATTR-CM赛道。 阿斯利康的ALXN2220是一款在研人源化抗ATTR单克隆抗体，原由Neurimmune公司研发，2022年3月，阿斯利康与Neurimmune公司达成协议，在I期临床试验结束后，阿斯利康将负责ALXN2220进一步的临床开发和商业化。 ALXN2220可特异性靶向错误折叠的TTR，通过清除心脏中的淀粉样纤维沉积物，针对ATTR-CM的致病原因，有望治疗晚期ATTR-CM患者。I期临床研究显示，ALXN2220的安全性在最高测试剂量下依然良好。药代动力学特征与IgG抗体一致，未检测到抗药抗体。在至少10mg/kg的剂量下，患者心脏淀粉样蛋白沉积在12个月内显著减少。ALXN2220的国际多中心III期临床研究（计划入组1000例受试者）预计于2028年完成。 拜耳的Acoramidis原由BridgeBio研发，今年3月，拜耳与BridgeBio达成协议，将获得其核心产品Acoramidis在欧洲的独家商业化权益。 Acoramidis是下一代口服转甲状腺素蛋白稳定剂，能够与TTR四聚体结合，在T119M突变位点形成强分子键，使TTR更加稳定。去年，Acoramidis已经提交上市申请，用于治疗ATTR-CM，PDUFA日期为2024年11月29日。 再生元也加入了战局，再生元与Intellia Therapeutics正在开发ATTR-CM的基因编辑药物NTLA-2001，目前处于临床III期。 由于没有足够高效的临床解决方案，ATTR一直是各大药企研发的热点，除了传统药物外，小核酸药物、基因治疗等方案齐上阵，用药便利性也正在成为后来者竞争的主要方向之一。从辉瑞的tafamidis销售业绩来看，ATTR-CM是一个重磅炸弹辈出的赛道，未来竞争格局如何，市场很快将给出答案。 参考来源：        1.Transthyretin Amyloidosis Treatment Market Size, Share & Trends Analysis Report By Type (ATTR-PN, ATTR-CM), By Therapy, By Disease Type, By Distribution Channel, By Region, And Segment Forecasts, 2022 - 2030. 2.Pablo Garcia-Pavia. et al. (2023)Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid.N Engl J Med. DOI: 10.1056/NEJMoa2303765. 来源：CPHI制药在线 声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。 投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~