Impact of patisiran on polyneuropathy of hereditary transthyretin amyloidosis in patients with a V122I or T60A variant: a phase IV multicenter study

This study assessed the effectiveness and safety of patisiran in patients with V122I/T60A variant transthyretin (ATTRv) amyloidosis with polyneuropathy. These variants have been under-represented in previous trials of gene-silencing agents. This was a multicenter, phase IV study conducted at 27 sites in the USA. Patients were ≥ 18 years, diagnosed with ATTRv amyloidosis with polyneuropathy and a documented V122I or T60A variant. Patisiran-treated patients were enrolled prospectively, ambispectively, and retrospectively. The primary endpoint was the proportion of patients with a stable or improved polyneuropathy disability (PND) score at 12 months vs. baseline. Safety was monitored throughout the trial. Sixty-seven patients were enrolled, of whom 58 received ≥ 1 dose of patisiran. In the efficacy population, 42/45 (93.3%) patients demonstrated stable or improved PND scores from baseline to Month 12. Patients also showed stable or improved quality of life, health status, autonomic symptoms, and cardiac function vs. baseline. Adverse events occurred in 13/42 (31.0%) patients in the prospective and ambispective cohorts; most were mild or moderate. No deaths or cardiac hospitalizations were considered related to patisiran. Patisiran demonstrated a consistent positive effect across multiple endpoints in patients with V122I/T60A ATTRv amyloidosis, including polyneuropathy manifestations.

本研究评估了帕蒂萨兰(Patisiran)在携带V122I/T60A变异型转甲状腺素蛋白（ATTRv）淀粉样变性合并多发性神经病患者中的有效性与安全性。此类变异型在既往基因沉默类药物的临床试验中入组比例偏低。本研究为一项多中心IV期临床试验，在美国27家研究中心开展。入组患者年龄≥18岁，确诊为ATTRv淀粉样变性合并多发性神经病，且经证实携带V122I或T60A变异。接受帕蒂萨兰治疗的患者通过前瞻性、双向回顾性及回顾性三种方式入组。本研究的主要终点为治疗12个月时，患者的多发性神经病残疾（PND）评分较基线保持稳定或改善的患者比例。整个试验过程中均对安全性进行监测。本研究共入组67例患者，其中58例接受了至少1剂帕蒂萨兰治疗。在有效性分析人群中，42/45（93.3%）的患者从基线至第12个月时，PND评分保持稳定或有所改善。与基线相比，患者的生活质量、健康状况、自主神经症状及心功能也均保持稳定或得到改善。前瞻性及双向回顾性队列中，13/42（31.0%）的患者出现不良事件，且多数不良事件程度为轻中度。未出现被认定与帕蒂萨兰相关的死亡事件或心脏相关住院事件。帕蒂萨兰在V122I/T60A型ATTRv淀粉样变性患者的多项终点中均展现出一致的正向获益，其中包括多发性神经病相关表现。