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Findings from the Phase III HELIOS-B trial (NCT04153149) show that patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) administered Amvuttra (vutrisiran) achieved a significant reduction in the risk of death and recurrent cardiovascular events. Further, the drug was found to stop the deterioration of heart failure symptoms while helping patients to maintain functional capacity and quality of life compared to placebo, according to the study, published by The New England Journal of Medicine.1,2
“These benefits were observed in both the overall population and the monotherapy population and are particularly meaningful for patients whose quality of life and functional capacity are impaired by this disease,” the study authors wrote. “These data suggest that reducing levels of the circulating amyloidogenic TTR protein with vutrisiran in patients with ATTR-CM leads to a reduction in the risk of death from any cause and cardiovascular events.”1
Amvuttra is a double‑stranded small interfering RNA designed to target mutant and wild‑type transthyretin (TTR) messenger RNA (mRNA). It was approved by the FDA in June 2022 for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adult patients.3
The regulatory action was based on findings from the Phase III HELIOS-A trial (NCT03759379), in which Amvuttra was found to produce a significant improvement in the signs and symptoms of polyneuropathy. Investigators reported that more than 50% of patients administered the drug had their disease manifestations stop or reversed.3
Trial Design
The double-blind, randomized HELIOS-B trial enrolled patients aged 18 to 85 years. Enrollment criteria included a diagnosis of ATTR-CM of either variant or wild-type ATTR amyloidosis); evidence of cardiac involvement as per transthoracic echocardiography; a clinical history of heart failure with at least one prior hospitalization or clinical evidence of heart failure, and signs and symptoms of volume overload or increased intracardiac pressures that required diuretic treatment.
A total of 655 patients with ATTR-CM were randomly assigned in a 1:1 ratio to receive Amvuttra at a dose of 25 mg (n = 326) or placebo (n = 329) every 12 weeks for up to 36 months. The trial’s primary endpoint was composite of death from any cause and recurrent cardiovascular events, with secondary endpoints that included death from any cause, change from baseline in distance covered on a six-minute walk test, and change from baseline in Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score. Investigators evaluated the efficacy endpoints among the overall patient population and in a monotherapy population of patients who were not being treated with tafamidis (Vyndaqel; Vyndamax) at baseline and who were tested hierarchically.
Trial Results
Amvuttra was found to reduce the risk of death from any cause and recurrent cardiovascular events compared to 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 reduced the 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).
In the overall population, 125 patients in the Amvuttra cohort and 159 patients in the placebo cohort achieved at least one primary endpoint event. Among the overall patient population, patients treated with Amvuttra showed a lesser reduction in distance covered on the six-minute walk test compared to placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and a lesser reduction in KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). These findings were also similar to what was observed in the monotherapy population.
In terms of safety, adverse events (AEs) were similar between both cohorts, with 99% of patients in the Amvuttra cohort and 98% in the placebo cohort reporting an AE, respectively. Serious AEs were reported in 62% of patients in the Amvuttra cohort compared to 67% of patients in the placebo cohort.
“In patients with ATTR-CM, treatment with vutrisiran resulted in a lower risk of death from any cause and recurrent cardiovascular events than placebo,” the study authors concluded. “Vutrisiran also preserved functional capacity and quality of life and prevented worsening of heart failure symptoms. These effects were consistent across all prespecified subgroups, including patients who were receiving background tafamidis. Collectively, these data suggest that rapid knockdown of TTR by vutrisiran reduces morbidity and mortality among patients with ATTR-CM.”1
References
1. Fontana, M., et al. Vutrisiran in Patients with Transthyretin Amyloidosis with Cardiomyopathy. N Engl J Med 2025;392:33-44. DOI: 10.1056/NEJMoa2409134 Vol. 392 No. 1.
2. HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy. ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04153149
3. Alnylam Announces FDA Approval of AMVUTTRA™ (vutrisiran), an RNAi Therapeutic for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults. News release. Alnylam Pharmaceuticals, Inc. June 13, 2022. Accessed January 20, 2025. https://investors.alnylam.com/press-release?id=26776