Long-Term Safety of Vutrisiran Confirmed in ATTR Amyloidosis Analysis

Vutrisiran (Amvuttra; Alnylam Pharmaceuticals) maintains a favorable long-term safety profile in patients with transthyretin amyloidosis (ATTR), supporting its use across both hereditary and wild-type forms of the disease, according to a pooled safety analysis of the phase 3 HELIOS-A (NCT03759379) and HELIOS-B (NCT04153149) trials, published in JACC Advances.¹

“By combining data from both studies in this pooled analysis, we demonstrate that in a large group of patients who have extensive exposure to the therapy, vutrisiran is well tolerated and has an acceptable safety profile,” wrote the researchers of the study.

ATTR is a progressive disease caused by misfolded transthyretin proteins that aggregate into amyloid fibrils and deposit in organs such as the heart and peripheral nerves, commonly leading to polyneuropathy or infiltrative cardiomyopathy that can significantly impair quality of life and survival.² RNA interference therapies, including vutrisiran, reduce hepatic production of transthyretin, lowering circulating protein levels and limiting amyloid deposition.

Vutrisiran has previously demonstrated efficacy in treating ATTR with polyneuropathy in the HELIOS-A study and ATTR with cardiomyopathy in the HELIOS-B study.¹ The investigators conducted a pooled safety analysis of both trials to better understand the long-term safety of the therapy in a larger population and with extended follow-up.

The analysis included all patients who received at least 1 dose of vutrisiran during either trial. For comparison, investigators also evaluated data from placebo groups drawn from the HELIOS-B trial and the external placebo arm from the APOLLO (NCT01960348) study used in HELIOS-A. Adverse event (AE) rates were adjusted for exposure and calculated per 100 patient-years.

In total, 707 patients received vutrisiran across both trials, including 160 participants from HELIOS-A and 547 from HELIOS-B. The mean (SD) age at symptom onset was 68.5 (12.6) years, and approximately 30.3% of patients had hereditary ATTR, while the remainder had wild-type disease. Patients were treated for a median (IQR) duration of 33.4 (0.0-57.8) months, with some receiving therapy for nearly 58 months. The total cumulative exposure to vutrisiran reached 1518.9 patient-years.

Overall, the therapy was well tolerated over the extended treatment period. Exposure-adjusted AE rates and serious AE rates were comparable to those observed in placebo groups and were consistent with findings reported during the original randomized phases of both studies.

Cardiac failure was the most commonly reported AE among vutrisiran-treated patients, excluding COVID-19-related events. However, investigators noted that exposure-adjusted rates of cardiac failure were lower in the vutrisiran groups compared with the corresponding placebo groups in both trials.

Injection-site reactions occurred infrequently and were generally mild or moderate in severity. Importantly, investigators found no evidence of new safety concerns involving ocular, hepatic, or renal function—areas that are often monitored closely in therapies targeting transthyretin production.

The findings are notable given the progressive nature of ATTR amyloidosis and the need for long-term treatment strategies that maintain both efficacy and tolerability. By pooling data from 2 large phase 3 trials, the analysis provides a more comprehensive assessment of safety across a broader patient population, including individuals with both neuropathic and cardiac manifestations of the disease.

The results reinforce previous clinical findings supporting the safety profile of vutrisiran and suggest that the therapy remains well tolerated during extended treatment periods approaching 5 years. For clinicians managing ATTR amyloidosis, these data offer additional reassurance about the long-term safety of RNA interference–based approaches targeting transthyretin production.

As treatments for ATTR continue to evolve, long-term safety data will remain essential for guiding treatment decisions in a condition that often requires sustained therapy to manage disease progression.

“This pooled analysis, in a large and heterogeneous population of patients with ATTR who had up to 58 months of treatment, demonstrates that vutrisiran is well tolerated and has an acceptable safety profile,” wrote the researchers.

References

1. Witteles RM, Garcia-Pavia P, Morbach C, et al. Vutrisiran in transthyretin amyloidosis: a pooled safety analysis of HELIOS-A and HELIOS-B. JACC Adv. 2025;4(9):102066. doi:10.1016/j

2. Lim GB. Benefit of vutrisiran in transthyretin amyloidosis with cardiomyopathy. Nat Rev Cardiol. doi.org/10.1038/s41569-024-01086-y