Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial

The study objective was to assess the effect of vutrisiran, an RNA interference therapeutic that reduces transthyretin (TTR) production, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. HELIOS-A was a phase 3, global, open-label study comparing the efficacy and safety of vutrisiran with an external placebo group (APOLLO study). Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months (Q3M) or intravenous patisiran 0.3 mg/kg every 3 weeks (Q3W) for 18 months. HELIOS-A enrolled 164 patients (vutrisiran, n = 122; patisiran reference group, n = 42); external placebo, n = 77. Vutrisiran met the primary endpoint of change from baseline in modified Neuropathy Impairment Score +7 (mNIS+7) at 9 months (p = 3.54 × 10−12), and all secondary efficacy endpoints; significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran Q3M was non-inferior to within-study patisiran Q3W. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. Vutrisiran significantly improved multiple disease-relevant outcomes for ATTRv amyloidosis versus external placebo, with an acceptable safety profile. NCT03759379

本研究旨在评估维特西兰（vutrisiran）——一种可降低运甲状腺素蛋白（transthyretin, TTR）生成的RNA干扰（RNA interference）治疗药物——在伴多发性神经病的遗传性运甲状腺素蛋白淀粉样变性（ATTRv型）患者中的疗效。HELIOS-A是一项3期全球开放标签临床试验，旨在对比维特西兰与外部安慰剂组（来源于APOLLO研究）的疗效与安全性。研究按3:1的比例将受试者随机分配至两个组别：每3个月（Q3M）皮下注射25mg维特西兰组，或每3周（Q3W）静脉注射0.3mg/kg帕提西兰（patisiran）组，治疗周期为18个月。HELIOS-A共纳入164例受试者，其中维特西兰组122例、帕提西兰对照组42例，外部安慰剂组77例。维特西兰达成了主要疗效终点：治疗9个月时改良神经病变损伤评分+7（modified Neuropathy Impairment Score +7, mNIS+7）较基线的变化（p=3.54×10⁻¹²），且所有次要疗效终点均达标；与外部安慰剂组相比，受试者在诺福克糖尿病神经病生活质量量表、10米步行试验（均于9个月及18个月时评估）、mNIS+7、改良体质量指数及拉斯奇整体残疾量表（均于18个月时评估）中均获得显著改善。每3个月给药方案下的维特西兰对TTR的降低效果非劣于本研究内每3周给药的帕提西兰。多数不良事件严重程度为轻中度，与ATTRv型淀粉样变性的自然病程相符。本研究未出现药物相关停药或死亡病例。与外部安慰剂组相比，维特西兰可显著改善ATTRv型淀粉样变性的多项疾病相关结局，且安全性特征良好。本临床试验注册号为NCT03759379