Fewer adverse events reported in ATTR-CM patients treated with vutrisiran versus placebo: Post hoc safety analysis from HELIOS-B

Background Transthyretin (TTR) amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, fatal disease caused by misfolded wild-type (wt) or variant (v) TTR protein accumulating in the heart and other systems. Patients with ATTR-CM often experience a substantial burden of adverse events (AEs) across multiple system organ classes (SOCs), negatively impacting quality of life. In the Phase 3 HELIOS-B study, vutrisiran, an RNA interference therapeutic targeting TTR, significantly reduced all-cause mortality and cardiovascular events in patients with ATTR-CM and had an acceptable safety profile. However, the impact of vutrisiran on overall AE incidence and SOC-specific AEs has not been described. Purpose To assess the impact of vutrisiran treatment on overall and SOC-specific adverse event rates in patients with ATTR-CM from HELIOS-B. Methods Exposure-adjusted event rates (per 100 patient-years [PY]) of AEs reported during the double-blind period (up to 36 months) of HELIOS-B were compared between vutrisiran and placebo arms in the overall and monotherapy populations (patients not receiving tafamidis at baseline), and baseline tafamidis subgroup. AEs (coded using MedDRA v23.0 preferred terms) were analysed by SOC for the 10 SOCs with the most frequent AEs during the double-blind period. Additional subgroup analyses were conducted by disease type (ATTRwt-CM vs ATTRv-CM). Adjusted rate ratios (ARRs) were calculated using Poisson regression models with follow-up time as an offset variable, adjusting for treatment group and baseline characteristics. Results Vutrisiran treatment was associated with 25% relative risk reduction of all AEs vs placebo in the overall study population (ARR: 0.75; Figure 1). Lower AE event rates were consistently observed with vutrisiran vs placebo across all 10 most frequent SOCs (ARRs 0.58–0.96 in the overall population; Figure 1), the greatest being gastrointestinal (GI) and nervous system (peripheral and central) disorders (42% and 41% lower reported AE rates), likely improving quality of life. Notably, lower AE rates were also reported for a SOC of interest concerning eye disorders (ARR: 0.54 in the overall population). Mean cumulative events analysis showed lower rates of all AEs with vutrisiran vs placebo as early as 3 months in the overall population (Figure 2). Results in the monotherapy population, baseline tafamidis subgroup, and across patients with ATTRv-CM or ATTRwt-CM were generally consistent with those in the overall population. Conclusion This post hoc analysis demonstrated that while patients with ATTR-CM experienced multiple AEs across SOCs, vutrisiran-treated patients had fewer AEs overall and across multiple systems. Among SOCs with the most frequent AEs, GI and nervous system disorders had the greatest difference with 42% and 41% fewer AEs in patients treated with vutrisiran, suggesting vutrisiran benefits extending beyond cardiac manifestations of ATTR.