Vutrisiran Cuts Risk of Advanced ATTR-CM, Improves Outcomes in Those Who Progress

New analyses from the phase 3 HELIOS-B trial (NCT04153149) offer a more in-depth picture of vutrisiran's (Amvuttra; Alnylam) impact in transthyretin amyloid cardiomyopathy (ATTR-CM), showing the RNA interference therapeutic reduced the likelihood of patients reaching advanced stages of heart failure (HF) and, for those who did progress, meaningfully improved clinical outcomes.¹

The findings, presented at the American College of Cardiology 2026 Annual Scientific Session, examined patients from both the overall HELIOS-B population and a monotherapy subgroup. The aim of the study was to evaluate whether vutrisiran prevented progression to advanced disease and if it improved outcomes in patients who ultimately reached that advanced threshold.

Advanced disease was defined as transitioning to either New York Heart Association (NYHA) class III concurrent with National Amyloidosis Centre stage III or NYHA class IV—criteria that reflect a well-recognized inflection point in ATTR-CM's natural history. Patients meeting these thresholds at screening were excluded from HELIOS-B, making this analysis a prospective look at in-trial progression.

During the double-blind period, 10.7% of patients who received placebo in the overall population developed advanced disease compared with 8.0% of those receiving vutrisiran. In the monotherapy subgroup, the gap was similar: 11.1% vs 8.2%, respectively. Progression specifically to NYHA class IV was notably rarer in the vutrisiran arm: 3.0% vs 0.9% in the overall population and 2.5% vs 0.5% in the monotherapy cohort.

Among the 61 patients who developed advanced disease (35 on placebo, 26 on vutrisiran), outcomes still favored the active treatment arm, despite vutrisiran-treated patients in this subgroup entering with somewhat worse baseline characteristics, including higher N-terminal pro-B-type natriuretic peptide levels and a greater prevalence of prior HF hospitalizations.

Vutrisiran numerically reduced the risk of the primary composite end point of all-cause mortality and recurrent cardiovascular events by 40% in the overall advanced-disease population (HR, 0.604; 95% CI, 0.287-1.274) and by 46% in the monotherapy subgroup (HR, 0.542; 95% CI, 0.240-1.223).

The impact on all-cause mortality alone was more pronounced. In the overall advanced-disease group, vutrisiran was associated with a 56% reduction in mortality risk (HR, 0.442; 95% CI, 0.148-1.323), and in the monotherapy population, a 77% reduction (HR, 0.226; 95% CI, 0.054-0.940).

At the time of advanced disease development, patients who received placebo appeared clinically worse across multiple measures, including 6-minute walk test distance, Kansas City Cardiomyopathy Questionnaire-Overall Summary scores, and NYHA class distribution, with 20% reaching class IV compared with 8% of those on vutrisiran.

Moreover, the safety profile of vutrisiran in patients with advanced disease was broadly consistent with the overall trial. Rates of serious adverse events, severe adverse events, and treatment discontinuation were comparable to or lower in the vutrisiran group relative to placebo. Deaths in this subgroup numbered 9 (26%) in the placebo arm vs 4 (15%) in the vutrisiran arm.

Despite the availability of transthyretin stabilizers, ATTR-CM continues to carry a substantial mortality burden.² Real-world data suggest that approximately 2 in 5 patients with ATTR-CM treated with tafamidis can be expected to die in less than 4 years. These findings underscore the unmet need for more potent interventions capable of further reducing mortality in this population and provide important context for the clinical significance of the survival benefits observed with vutrisiran in the HELIOS-B trial.

References

1. Gillmore JD, Tsujita K, Shah Z, et al. Vutrisiran reduces the risk of developing advanced disease and demonstrates benefits in patients who do develop advanced disease in ATTR-CM: analysis from the HELIOS-B study. Presented at: American College of Cardiology Annual Scientific Session; March 28-30, 2026; New Orleans, LA.

2. O’Riordan M. Even on tafamidis, ATTR-CM patients face high mortality over time. tctMD. February 13, 2025. Accessed April 9, 2026. https://www.tctmd.com/news/even-tafamidis-attr-cm-patients-face-high-mortality-over-time