CONGRESS ABSTRACT

Introduction : Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive and systemic disease, caused by accumulation of misfolded transthyretin (TTR) proteins. This can involve extracardiac organs, leading to gastrointestinal (GI) and neuropathic symptoms that negatively impact quality of life. In the phase 3 HELIOS-B study of ATTR-CM patients, vutrisiran, an RNA interference therapeutic, significantly reduced all-cause mortality and cardiovascular events. However, it remains unclear whether GI manifestations are affected by vutrisiran. Hypothesis : In the HELIOS-B study, vutrisiran is associated with a reduction in GI events compared to placebo. Methods : Adverse events (AEs) classified under the GI disorders system organ class and reported during the double-blind period of HELIOS-B study (up to 36 months), were compared between the vutrisiran and placebo arms of the overall and monotherapy populations, and the prespecified baseline tafamidis subgroup of HELIOS-B. Results : Treatment with vutrisiran was associated with 37-49% lower rates of GI AEs compared with placebo (rate ratios [RR]: 0.58, 0.63, 0.51 in overall, monotherapy, and baseline tafamidis groups, respectively). In vutrisiran treated patients, a lower rate was observed for most GI AEs, including the commonly reported AEs nausea (RR: 0.35, 0.17, 0.48 in overall, monotherapy, and baseline tafamidis groups, respectively), vomiting (RR: 0.16, 0.25, 0), diarrhoea (RR: 0.46, 0.48, 0.44), and constipation (RR: 0.61, 0.80, 0.39) (Table). The reduction in the mean cumulative GI AEs per patient with vutrisiran treatment, was observed as early as the 3 rd month of the double-blind period versus placebo (Figure). Out of 529 GI AEs reported, 10 were deemed by the PI to be related to treatment (8 placebo and 2 vutrisiran). Conclusions : In this analysis of ATTR-CM patients, we observed a considerable number of GI events suggesting possible GI involvement in this patient population. Treatment with vutrisiran was associated with early and substantial reductions in GI events compared to placebo. The benefit was observed in both the monotherapy population and baseline tafamidis subgroup of HELIOS-B. These results suggest extracardiac manifestations attributable to transthyretin amyloid infiltration that may improve with vutrisiran therapy.