Efficacy of Acoramidis on All-Cause Mortality and Cardiovascular Hospitalization in Transthyretin Amyloid Cardiomyopathy.

Abstract

Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed chronic disease associated with progressive heart failure that results in impaired quality of life, repeated hospitalizations, and premature death. Acoramidis is a selective, oral transthyretin stabilizer recently approved by the U.S. Food and Drug Administration for the treatment of ATTR-CM. In a phase 3, randomized, double-blind study (ATTRibute-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]), acoramidis was well tolerated and showed clinical efficacy in improving the primary endpoint, a hierarchical combination of all-cause mortality (ACM), cardiovascular-related hospitalization (CVH), N-terminal pro-B-type natriuretic peptide level, and 6-minute walk distance. The goal of this study was to characterize the efficacy of acoramidis on ACM and CVH. In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to receive acoramidis hydrochloride (800 mg twice daily) or placebo for 30 months. Efficacy analyses were conducted in the modified intention-to-treat population (participants with a baseline estimated glomerular filtration rate ≥30 mL/min/1.73 m). CVH and the composite of ACM or first CVH were plotted by using Kaplan-Meier curves and summarized with a stratified Cox proportional hazards model. The annualized frequency of CVH was analyzed by using a negative binomial regression model. Subgroup analyses were conducted for the composite of ACM or first CVH. Of the 632 participants randomized to treatment, 611 (97%) were included in efficacy analyses (acoramidis, n = 409; placebo, n = 202). Compared with placebo, acoramidis reduced the occurrence of the composite of ACM or first CVH (acoramidis, 35.9%; placebo, 50.5%; HR: 0.64; 95% CI: 0.50-0.83; P = 0.0008) and of first CVH (acoramidis, 26.7%; placebo, 42.6%; HR: 0.60; 95% CI: 0.45-0.80; P = 0.0005), with Kaplan-Meier curves separating at month 3 and continuing to diverge through month 30. Annualized frequency of CVH was reduced with acoramidis compared with placebo (acoramidis, 0.22; placebo, 0.45; relative risk ratio: 50%; 95% CI: 0.36-0.70; P < 0.0001). The efficacy of acoramidis on the composite of ACM or first CVH was consistent across subgroups. Acoramidis was well tolerated, with no safety signals of potential clinical concern identified. In participants with ATTR-CM, acoramidis reduced the composite of ACM or first CVH vs placebo, with an early effect driven by a reduction in CVH. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).