New subgroup data from the HELIOS-B Phase III trial show that vutrisiran (Amvuttra) maintained consistent treatment effects on mortality and recurrent cardiovascular events regardless of baseline tafamidis use, adding evidence to the unresolved question of whether combining TTR silencing with stabilization can provide additional clinical benefit in transthyretin amyloid cardiomyopathy (ATTR-CM). The data were by Cambridge, Massachusetts-based Alnylam Pharmaceuticals (Nasdaq: ALNY) at the European Society of Cardiology (ESC) Congress 2026 and simultaneously published in the Journal of the American College of Cardiology.
Among the 654 randomized and treated patients in HELIOS-B, 259 (40%) were receiving tafamidis at baseline. The prespecified subgroup analysis showed that vutrisiran's effect on the primary composite endpoint — all-cause mortality and recurrent cardiovascular events through 33–36 months — was consistent across both the combination population (vutrisiran plus tafamidis) and the monotherapy population. In the overall and monotherapy populations, vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 28.2% and 32.8%, respectively, versus placebo through 36 months. Functional capacity, measured by 6-minute walk distance, was preserved versus placebo in both populations. Health status improvement measured by the Kansas City Cardiomyopathy Questionnaire overall summary score was observed in both populations, though the effect was attenuated in patients receiving background tafamidis. The trial was not powered to establish benefit specifically within the tafamidis-treated subgroup, and the findings warrant further evaluation of TTR silencing and stabilization combination strategies.
Two post hoc analyses from HELIOS-B extended the efficacy picture beyond standard cardiac endpoints. In the first, patients treated with vutrisiran demonstrated 25% less decline from baseline in intrinsic capacity — a composite measure of locomotion, cognition, vitality, psychological well-being, and sensory function aligned with the World Health Organization Integrated Care for Older People framework — and a 52% reduction in the risk of decline versus placebo. In the second, vutrisiran-treated patients had lower overall adverse event rates compared with placebo, with gastrointestinal disorders 42% lower, nervous system disorders 41% lower, and eye disorders 46% lower. A pooled analysis of 1,402 patients across four Phase III studies of vutrisiran — including 203 females and 1,199 males — showed consistent treatment effects across sexes in both ATTR-CM and the polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN).
Vutrisiran is a GalNAc-conjugated small interfering RNA that exploits the RNA interference pathway to degrade TTR messenger RNA in hepatocytes, reducing TTR protein production at its source. It is administered once quarterly by subcutaneous injection. Patisiran, the earlier approved RNAi agent in the same class, requires intravenous infusion every three weeks; inotersen (Tegsedi), an antisense oligonucleotide targeting TTR mRNA, is administered weekly by subcutaneous injection.
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