Abstract 4362795: Vutrisiran Improved Outcomes Versus Placebo in Patients with Transthyretin Amyloidosis with Cardiomyopathy and Severe Chronic Kidney Disease: Post Hoc Analysis of HELIOS-B

Background: Decline in renal function is common in patients (pts) with transthyretin amyloidosis (ATTR) and is a marker of disease progression associated with mortality in ATTR with cardiomyopathy (ATTR-CM). The TTR-silencing RNAi therapeutic vutrisiran reduced risk of all-cause mortality (ACM) and cardiovascular (CV) events vs placebo (PBO) in pts with ATTR-CM in the Phase 3 HELIOS-B study (NCT04153149). Aims: To assess the potential impact of vutrisiran on renal function and efficacy/safety of vutrisiran in pts who advanced to CKD Stage 4 during the HELIOS-B double-blind (DB) period. Methods: HELIOS-B eligibility criteria included eGFR ≥30 mL/min/1.73m 2 . Pts were randomized 1:1 to vutrisiran 25 mg or PBO Q3M. In this post hoc analysis of the DB period (up to 33–36 months), the proportion of pts with eGFR decline ≥40% from baseline was assessed. The primary composite endpoint of ACM and CV events, as well as ACM, CV events, and safety, were also assessed in pts who progressed to CKD Stage 4 (eGFR <30 mL/min/1.73m 2 ) during the DB period. Outcomes were assessed overall and by baseline tafamidis use (monotherapy and baseline tafamidis subgroups). Results: Median (IQR) eGFR at baseline in pts receiving vutrisiran and PBO was 64 (50–81) and 65 (53–81) mL/min/1.73m 2 , respectively. In the overall population, fewer pts in the vutrisiran group experienced a ≥40% decline in eGFR from baseline vs PBO (12.7% vs 21.2%, respectively); results were consistent in monotherapy and baseline tafamidis subgroups ( Figure 1 ). Among pts who advanced to CKD Stage 4, in the overall population, vutrisiran reduced the risk of composite ACM and CV events vs PBO (HR [95% CI] 0.47 [0.26, 0.85]); similar results were seen in ACM and CV events, separately, and in the monotherapy and baseline tafamidis subgroups ( Figure 2 ; CV-related death: 34.3% with PBO; 9.7% with vutrisiran in the overall population). The safety profile of vutrisiran in pts who advanced to CKD Stage 4 was comparable with PBO. No new safety signals were reported. Conclusion: Vutrisiran appeared to preserve renal function in pts with ATTR-CM. Consistent with results from the overall population, vutrisiran reduced the risk of ACM and CV events vs PBO in pts with ATTR-CM and advanced CKD in HELIOS-B; results require corroboration in a larger pt population.