Eplontersen

▎药明康德内容团队编辑 今天，Alnylam Pharmaceuticals公布其HELIOS-B临床3期研究的积极顶线结果。分析显示，其皮下注射RNAi疗法Amvuttra（vutrisiran）作为单药，可降低伴有心肌病的转甲状腺素蛋白介导的淀粉样变性（ATTR-CM）患者因任何原因死亡或发生复发性心血管事件的风险达33%。根据此积极结果，Alnylam将使用优先审评券（PRV）向美国FDA递交补充新药申请（sNDA）。 HELIOS-B是一项全球多中心、随机、双盲、安慰剂对照的3期研究，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）。研究共招募了655名包含遗传性或野生型的成人ATTR-CM患者，按照1：1的比例随机接受每三个月一次25 mg的vutrisiran或安慰剂皮下注射，双盲治疗期最长达36个月。双盲期结束后，所有符合条件的试验患者可在开放标签扩展期接受vutrisiran治疗。 研究达到主要终点，分析显示在双盲期间，总体患者（n=654；HR：0.718，p=0.0118）和接受单药治疗患者（即基线时未接受ATTR-CM获批疗法tafamidis治疗的患者，n=395；HR：0.672，p=0.0162）分别实现了全因死亡率和复发性心血管事件综合指标28%和33%的降低。 ▲HELIOS-B试验疗效结果摘要（图片来源：参考资料[2]） 研究还显示，总体和单药治疗患者在所有次要终点均有显著改善，包括疾病进展的关键指标：6分钟步行测试（6-MWT）、堪萨斯城心肌病问卷（KCCQ）和第30个月时纽约心脏协会（NYHA）分级（皆p<0.025）。重要的是，使用vutrisiran治疗还降低了总体患者（HR：0.645，p<0.025）和单药治疗患者（HR：0.655，p<0.05）第42个月时的全因死亡率，这是一项预定的意向性治疗分析，包括来自开放标签扩展阶段最长六个月的数据。 此外，在所有关键亚组患者中，vutrisiran在主要终点和所有次要终点均表现出一致的效果，包括基线tafamidis使用情况、ATTR疾病类型和疾病严重程度。 在HELIOS-B研究中，vutrisiran显示了令人鼓舞的安全性和耐受性，与其已知的安全特性一致。Vutrisiran和安慰剂组的不良事件（AE）、严重不良事件（SAE）和导致停药的不良事件的发生率相似。Vutrisiran组中没有任何不良事件的发生率比安慰剂组高出3%以上。 ▲HELIOS-B试验安全性结果摘要（图片来源：参考资料[2]） 转甲状腺素蛋白淀粉样变性（ATTR）是一种未被充分诊断、进展迅速、使人衰弱的致命疾病，由错误折叠的转甲状腺素蛋白（TTR）引起，这些蛋白会以淀粉样沉积物的形式在身体包括神经、心脏和胃肠道等各个部位积聚。患者可能出现多发性神经病、心肌病或两种疾病的表现。ATTR有两种不同形式：遗传性ATTR（hATTR），是由于TTR基因变异引起，影响全球约5万人；野生型ATTR（wtATTR），不伴有TTR基因变异，影响全球约20-30万人。 Vutrisiran是一款皮下给药的RNAi疗法，正在开发用于治疗ATTR淀粉样变性，包括hATTR和wtATTR淀粉样变性。它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。Vutrisiran基于Alnylam的增强稳定化学（ESC）-GalNAc偶联递送平台设计，增加了效力和代谢稳定性，可能允许不频繁的皮下注射。此前研究数据表明，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。2022年6月，美国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（polyneuropathy）。 目前产业界有多款针对ATTR-CM的在研疗法处于临床阶段。BridgeBio Pharma已向美国FDA递交其所研发的新一代、口服、高效TTR小分子稳定剂acoramidis的新药申请（NDA）。此前公布的3期试验数据显示，acoramidis组治疗期间的生存率为81%（安慰剂组为74%），该值开始接近无ATTR-CM人群的预期寿命估算（根据历史记录，该人群的生存率为85%）。绝对风险降低6.43%，相对风险降低25%。 阿斯利康（AstraZeneca）与Ionis Pharmaceuticals共同合作的反义寡核苷酸（ASO）疗法eplontersen用于治疗ATTR-CM目前处于临床3期试验阶段，该疗法在去年12月获批用以治疗TTR介导的淀粉样变性的多发性神经病成人患者。2022年，阿斯利康与Neurimmune就一款用以治疗ATTR-CM的人源化单抗NI006达成超7亿美元的合作。去年公布的1期临床试验结果显示，在至少10 mg/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。此外，患者的N末端B型钠尿肽原和肌钙蛋白T的水平也有所降低，这是一种用于测量心脏压力的和心肌细胞死亡的生物标志物。锐正基因（Accuredit）在今年5月公布其基因编辑药物ART001用以治疗ATTR患者的最新24周临床研究数据。结果显示，给药后4周，高剂量组受试者外周TTR蛋白较基线即可平均下降90%以上；给药24周后，高剂量组受试者ART001药效稳定在90%以上，并初步显示出一次性给药即可获得长期持续药效的潜力。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放 参考资料： [1] Alnylam Reports Positive Topline Results from HELIOS-B Phase 3 Study of Vutrisiran, Achieving Statistical Significance on Primary and All Secondary Endpoints in Both Overall and Monotherapy Populations. Retrieved June 24, 2024 from https://investors.alnylam.com/press-release?id=28231 [2] Positive Topline Results from HELIOS-B Phase 3 Study of Vutrisiran. Retrieved June 24, 2024 from https://alnylampharmaceuticalsinc.gcs-web.com/static-files/7bd799e2-0673-4ce5-8cd5-9a3a749d844e 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。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。 版权说明：本文来自药明康德内容团队，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。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。 分享，点赞，在看，聚焦全球生物医药健康创新

An experimental medicine helped people with a deadly heart disease stay out of the hospital and live longer in a closely watched clinical trial, a finding that could pave the way for a regulatory approval and help its developer, Alnylam Pharmaceuticals, rebound from a significant setback.Trial data released Monday showed trial participants with the disease, transthyretin amyloidosis cardiomyopathy, and treated with Alnylams drug had a 28% lower risk of death from any cause or recurrent cardiovascular event, compared to those given a placebo. Alnylam said its drug was associated with a 33% risk reduction verus placebo among people who werent on another drug for the condition, Pfizers tafamidis, at the studys start.Both comparisons were parallel main study goals after statistical changes Alnylam made to the study in February.Treatment with the medicine, called vutrisiran and sold as Amvuttra for a different form of the disease, was also associated with significant improvements in secondary measures of heart health, Alnylam said.Researchers also analyzed vutrisirans impact on survival alone, indicating treatment led to a 36% reduction in the risk of death in the overall study population up through 42 months. That figure was 35% for study volunteers not on tafamidis.Alnylam said the benefits of treatment were consistent across major subgroups of trial participants, including those with different levels of disease severity. Rates of adverse events, serious adverse events and side effects leading to study discontinuation were similar between drug and placebo arms. Among volunteers receiving vutrisiran, no adverse events were at least 3% more common than placebo, the company said.Alnylam didnt provide full trial details, leaving some questions about the drug and its benefits unanswered. Full study data will be disclosed at the European Society of Cardiology meeting at the end of August.Alnylam plans to submit the results to regulators for approval and use a so-called priority review voucher to speed up its evaluation.The results suggest the potential for vutrisiran to be a transformative medicine for patients with ATTR amyloidosis with cardiomyopathy, said CEO Yvonne Greenstreet, in a statement. Assuming favorable regulatory review, vutrisiran has the potential to become the new standard of care for the treatment of this disease, driving Alnylams next era of substantial growth.The data are highly positive and support vutrisiran becoming a blockbuster in TTR-cardiomyopathy, wrote Stifel analyst Paul Matteis, in a note to investors on Monday. Shares surged nearly 40% in pre-market trading Monday, to levels the company hasnt hit since late 2022.The results are a needed boost for Alnylam, one of the biotechnology sectors largest companies and a pioneering developer of a drugmaking method called RNA interference. Though Alnylam has brought four rare disease drugs to market and discovered a cholesterol-lowering medicine now sold by Novartis, it hasnt been consistently profitable. The company lost $440 million in 2023 and $1.1 billion the year prior.Success in transthyretin amyloidosis cardiomyopathy could change that. While Alnylam already sells vutrisiran and a similar, earlier medicine called Onpattro for the rarer polyneuropathy form of the disease that affects the nerves, the type that causes heart damage is more prevalent. Alnylam has estimated that more than 250,000 worldwide have the cardiomyopathy form, compared to between 30,000 to 50,000 in the U.S. and Europe who have polyneuropathy. The only available drug for the condition, tafamidis, generated $3.3 billion last year, making it a top-selling medicine for Pfizer, which sells it as Vyndamax.Alnylam has sought to top Vyndamax, first with Onpattro and now vutrisiran. It came close with Onpattro, reporting success in a Phase 3 study in 2022. But the Food and Drug Administration rejected its application last year, arguing the companys study results werent meaningful enough to warrant approval.Alnylam later abandoned plans to seek approval of Onpattro in cardiomyopathy. In the meantime, a pill similar to Pfizers and developed by BridgeBio Pharma succeeded in testing, adding another potential competitor to the mix. The FDA could approve that drug by November.Still, Alnylam coulc recover with vutrisiran, which works similarly to Onpattro but is administered via a subcutaneous injection rather than in infusion. Unlike the shorter study of Onpattro, Alnylam ran vutrisirans trial long enough to tell whether the drug could extend lives and prevent hospital stays the kind of benefits that supported the approval of Vyndamax.Analysts expectations were high because of Onpattros performance in clinical testing and the potential that drugs like it may be superior to Pfizers and BridgeBios pills. Whereas those oral medicines are designed to stabilize the misfolded protein, transthyretin, that causes the disease, RNA interference therapies stop it from being made.Though the debate rages on, experts interviewed by the investment bank Stifel believe the silencer mechanism should be superior, Matteis wrote earlier this year.Debate will likely intensify further following Alnylams results. BridgeBios drug was associated with a 25% relative reduction in the risk of death in its Phase 3 trial, and a 50% relative risk reduction in hospitalizations. Comparing drugs across trials can be misleading, though. And in transthyretin amyloidosis cardiomyopathy, there are varying patient demographics, making comparisons tougher, Matteis wrote.Still, vutrisiran at the very least looks like it will be the go-to second-line drug for the condition, while also fighting for first-line use, he wrote.What stands out the most is the highly robust benefit on top of tafamidis, Matteis added. BridgeBio shares fell by about 8% in pre-market trading Monday.The next big readout for TTR cardiomyopathy will come in 2025, when AstraZeneca and Ionis Pharmaceuticals are expected to reveal the results of a Phase 3 study testing another type of silencer called eplontersen.Intellia Therapeutics and partner Regeneron also have a gene editing treatment for the disease thats in late-stage testing. '