Efficacy of Acoramidis on All-Cause Mortality and Cardiovascular Hospitalization in Transthyretin Amyloid Cardiomyopathy
- PMID: 40074465
- DOI: 10.1016/j.jacc.2024.11.042
Efficacy of Acoramidis on All-Cause Mortality and Cardiovascular Hospitalization in Transthyretin Amyloid Cardiomyopathy
Abstract
Background: 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.
Objectives: The goal of this study was to characterize the efficacy of acoramidis on ACM and CVH.
Methods: 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 m2). 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.
Results: 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.
Conclusions: 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).
Keywords: ATTR-CM; acoramidis; all-cause mortality; cardiovascular-related hospitalization; transthyretin.
Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Funding Support and Author Disclosures The ATTRibute-CM study was funded by BridgeBio Pharma, Inc. Dr Judge has received consultancy fees from Alexion Pharmaceuticals, Alleviant Medical, Alnylam Pharmaceuticals, Attralus, Cytokinetics, Lexeo Therapeutics, Novo Nordisk, Pfizer, Renovacor, and Tenaya Therapeutics; and his institution has received clinical trial funding from Array Biopharma, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), MyoKardia, and Pfizer. Dr Alexander has served as a consultant, advisor, or speaker for Arbor Biotechnologies, Attralus, Intellia Therapeutics, and Prothena. Dr Cappelli has served as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, Amicus Therapeutics, AstraZeneca, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Novo Nordisk, and Pfizer. Dr Fontana has served as a consultant, advisor, or speaker for Akcea Therapeutics, Alexion Pharmaceuticals, Alnylam Pharmaceuticals, AstraZeneca, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Intellia Therapeutics, Ionis Pharmaceuticals, Janssen Global Services, Novo Nordisk, and Pfizer; and has received research grants from BridgeBio Pharma, Inc (formerly Eidos Therapeutics) and Pfizer. Dr Garcia-Pavia has served as a consultant, advisor, or speaker for Alexion Pharmaceuticals, Alnylam Pharmaceuticals, AstraZeneca, Attralus, Bayer, BridgeBio (formerly Eidos Therapeutics), Intellia Therapeutics, Ionis Pharmaceuticals, Neuroimmune, Novo Nordisk, and Pfizer; and his institution has received research and/or educational funding from Alnylam Pharmaceuticals, AstraZeneca, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Intellia Therapeutics, Novo Nordisk, and Pfizer. Dr Gibbs is an employee of BridgeBio Pharma, Inc; and has served as a speaker, advisory board member, or steering committee member for AbbVie, Alnylam Pharmaceuticals, Bristol Myers Squibb, Intellia Therapeutics, Ionis Pharmaceuticals, Janssen Pharmaceuticals, Pfizer, and Takeda. Dr Grogan has served as a researcher for Alnylam Pharmaceuticals, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Intellia Therapeutics, Novo Nordisk, Janssen Pharmaceuticals, and Pfizer; and has served as a consultant, advisor, or speaker for Alnylam, BridgeBio, Pfizer, Janssen Pharmaceuticals, and Novo Nordisk. Dr Hanna has served as a consultant, advisor, or speaker for Alexion Pharmaceuticals, Alnylam Pharmaceuticals, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Ionis Pharmaceuticals, and Pfizer. Dr Masri has served as a researcher for Attralus, Cytokinetics, Ionis Pharmaceuticals, and Pfizer; and has served as a consultant, advisor, or speaker for Akros Pharma, Alexion Pharmaceuticals, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BioMarin Pharmaceutical, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Bristol Myers Squibb, Cytokinetics, Haya Therapeutics, Ionis Pharmaceuticals, Lexicon Pharmaceuticals, Pfizer, Prothena Biosciences, and Tenaya Therapeutics. Dr Maurer has served as a researcher for the National Institutes of Health (R01HL139671 and R01AG081582-01), Alnylam Pharmaceuticals, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Ionis Pharmaceuticals, Pfizer, Attralus, and Intellia Therapeutics; and has served as a consultant or advisor for Akcea Therapeutics, Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Intellia Therapeutics, Ionis Pharmaceuticals, Novo Nordisk, and Pfizer. Dr Obici has served as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, AstraZeneca, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), Ionis Pharmaceuticals, Novo Nordisk, Pfizer, and Sobi–Swedish Orphan Biovitrum. Dr Soman has served as a researcher for Pfizer; and has served as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, BridgeBio Pharma, Inc (formerly Eidos Therapeutics), and Pfizer. Drs Cao, Lystig, Tamby, Siddhanti, Castaño, Katz, and Fox are employees and stockholders of BridgeBio Pharma, Inc. Dr Mahaffey has received research support from the American Heart Association, Apple, Inc, Bayer, California Institute Regenerative Medicine, CSL Behring, Eidos, Ferring, Gilead, Google, Idorsia, Johnson and Johnson, Luitpold, Novartis, PAC-12, Precordior, and Sanifit; has served as a consultant for Applied Therapeutics, Bayer, Bristol Myers Squibb, BridgeBio, CSL Behring, Elsevier, Fosun Pharma, Human, Johnson and Johnson, Moderna, Myokardia, Novartis, Novo Nordisk, Otsuka, Phasebio, Portola, Quidel, and Theravance; and has equity in Human, Medeloop, Precordior, and Regencor. Dr Gillmore has served as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio Pharma, Inc, Intellia Therapeutics, Ionis Pharmaceuticals, Lycia, and Pfizer.
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