Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy
Marianna Fontana, John L. Berk, Julian D. Gillmore, et al
N Engl J Med 2025;392:33-44
DOI: 10.1056/NEJMoa2409134
Abstract
BACKGROUND
Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease. Vutrisiran, a subcutaneously administered RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.
转甲状腺素蛋白淀粉样变性伴心肌病（ATTR-CM）是一种不断进展的致死性疾病。vutrisiran是一种皮下注射的RNA干扰治疗剂，可抑制肝脏内转甲状腺素蛋白的生成。
METHODS
In this double-blind, randomized trial, we assigned patients with ATTR-CM in a 1:1 ratio to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically.
在这项双盲随机试验中，我们以1:1比例分配ATTR-CM患者接受vutrisiran（25 mg）或安慰剂治疗，每12周一次，最长持续36个月。主要终点是由全因死亡和复发性心血管事件构成的复合终点。次要终点包括全因死亡、6分钟步行距离与基线相比的变化，以及堪萨斯城心肌病问卷总分（KCCQ-OS，Kansas City Cardiomyopathy Questionnaire– Overall Summary）与基线相比的变化。疗效终点在总体人群和单药治疗人群（基线时未接受tafamidis治疗的患者）中评估，并进行序贯检验。
RESULTS
A total of 655 patients underwent randomization; 326 were assigned to receive vutrisiran and 329 to receive placebo. Vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P=0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P=0.02) and a lower risk of death from any cause through 42 months (hazard ratio in the overall population, 0.65; 95% CI, 0.46 to 0.90; P=0.01). Among the patients in the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least one primary end-point event. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group.
共计655例患者接受了随机分组，其中326人被分配接受vutrisiran治疗，329人被分配接受安慰剂治疗。vutrisiran与安慰剂相比降低了42个月时的全因死亡和复发性心血管事件风险（总体人群中的风险比，0.72；95%置信区间[CI]，0.56~0.93；P=0.01；单药治疗人群中的风险比，0.67；95% CI，0.49~0.93；P=0.02），也降低了全因死亡风险（风险比，0.65；95% CI，0.46~0.90；P=0.01）。vutrisiran组163例患者和安慰剂组202例患者发生了主要终点事件。在总体人群中，vutrisiran与安慰剂相比减小了6分钟步行距离的缩短幅度（最小二乘平均差异，26.5 m；95% CI，13.4~39.6；P<0.001），也减小了KCCQ-OS评分下降幅度（最小二乘平均差异，5.8分；95% CI，2.4~9.2；P<0.001）。 在单药治疗人群中也观察到类似益处。两组的不良事件发生率相似（vutrisiran组99%，安慰剂组98%）；vutrisiran组严重不良事件发生率为62%，安慰剂组为67%。
CONCLUSIONS
Among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life. (Funded by Alnylam Pharmaceuticals; HELIOS-B ClinicalTrials.gov number, NCT04153149.)
在ATTR-CM患者中，与安慰剂相比，vutrisiran治疗可降低全因死亡和心血管事件风险，并有助于患者保持功能能力和生活质量。（由Alnylam Pharmaceuticals资助；HELIOS-B在ClinicalTrials.gov注册号为NCT04153149）。
