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）——一种可降低转甲状腺素蛋白（transthyretin, TTR）生成的RNA干扰（RNAi）治疗药物——在伴多发性神经病的遗传性转甲状腺素蛋白淀粉样变性（ATTRv）患者中的疗效。HELIOS-A是一项3期全球开放标签研究，对比维特西兰与源自APOLLO研究的外部安慰剂队列的有效性与安全性。患者按3:1比例随机分配至两个治疗组：皮下注射25mg维特西兰、每3个月一次（Q3M）组，或静脉输注0.3mg/kg帕西西兰（patisiran）、每3周一次（Q3W）组，治疗周期均为18个月。本研究共纳入164例患者，分为维特西兰组（n=122）与帕西西兰对照组（n=42）；另设源自APOLLO研究的外部安慰剂对照队列，共77例。维特西兰达成了主要终点：9个月时改良神经病损害评分+7（modified Neuropathy Impairment Score +7, mNIS+7）较基线的变化（p=3.54×10⁻¹²），且所有次要有效性终点均达标；与外部安慰剂组相比，诺福克糖尿病神经病生活质量量表、10米步行试验（均在9个月和18个月时）、mNIS+7、改良体质量指数以及拉施构建整体残疾量表（Rasch-built Overall Disability Scale）均观察到显著改善，上述改善均在18个月时显现。每3个月给药的维特西兰在降低TTR水平方面非劣于本研究内的每3周给药帕西西兰组。大多数不良事件为轻至中度，与ATTRv淀粉样变性的自然病程相符。未出现与研究药物相关的停药或死亡病例。相较于外部安慰剂组，维特西兰可显著改善ATTRv淀粉样变性的多项疾病相关转归，且安全性可接受。本研究临床试验注册号为NCT03759379