Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy

N Engl J Med. 2025 Jan 2;392(1):33-44. doi: 10.1056/NEJMoa2409134. Epub 2024 Aug 30.

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.

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.

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.

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.).

Publication types

  • Randomized Controlled Trial
  • Multicenter Study
  • Clinical Trial, Phase III

MeSH terms

  • Aged
  • Aged, 80 and over
  • Amyloid Neuropathies, Familial* / complications
  • Amyloid Neuropathies, Familial* / drug therapy
  • Amyloid Neuropathies, Familial* / genetics
  • Amyloid Neuropathies, Familial* / mortality
  • Cardiomyopathies* / drug therapy
  • Cardiomyopathies* / genetics
  • Cardiomyopathies* / mortality
  • Double-Blind Method
  • Female
  • Humans
  • Injections, Subcutaneous
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Prealbumin* / antagonists & inhibitors
  • Prealbumin* / genetics
  • Quality of Life
  • RNA, Small Interfering* / administration & dosage
  • RNAi Therapeutics
  • Treatment Outcome
  • Walk Test

Substances

  • Prealbumin
  • RNA, Small Interfering
  • TTR protein, human

Supplementary concepts

  • Amyloidosis, Hereditary, Transthyretin-Related

Associated data

  • ClinicalTrials.gov/NCT04153149