Gene silencing versus protein stabilization in transthyretin amyloid cardiomyopathy: contextualizing the HELIOS-B results and the road to precision agent selection

Transthyretin amyloid cardiomyopathy (ATTR-CM) now has three approved disease-modifying agents: tafamidis, acoramidis, and vutrisiran, representing two mechanistically distinct classes: TTR tetramer stabilizers and RNA interference (RNAi) gene silencers. The phase 3 HELIOS-B trial, published in the New England Journal of Medicine, demonstrated that vutrisiran, a subcutaneous RNAi therapeutic, reduced the composite of all-cause mortality and recurrent cardiovascular events compared with placebo (hazard ratio 0.72; P = 0.01) in 655 patients with ATTR-CM over 33–36 months. These results supported the March 2025 FDA approval of vutrisiran for this indication. This letter contextualizes the mechanistic shift from stabilization to silencing, discusses the limitations of the HELIOS-B trial design, and examines the implications of an expanding therapeutic landscape for which patient-level selection criteria remain undefined. The ongoing CARDIO-TTRansform trial of the antisense oligonucleotide eplontersen will provide further comparative data, but head-to-head evidence across existing approved agents is absent. The question of how to sequence or select between mechanistically distinct agents for individual patients represents the central unresolved issue in ATTR-CM management.