Early Increase in Serum Transthyretin by Acoramidis Independently Predicts Improved Survival in TTR Amyloid Cardiomyopathy
- PMID: 40398971
- DOI: 10.1016/j.jacc.2025.03.542
Early Increase in Serum Transthyretin by Acoramidis Independently Predicts Improved Survival in TTR Amyloid Cardiomyopathy
Abstract
Background: Acoramidis is a novel, high-affinity stabilizer that achieves ≥90% transthyretin (TTR) stabilization. The phase 3 study, ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), met its primary hierarchical efficacy endpoint with mortality, morbidity, and functional components at 30 months. Stabilization of TTR (prealbumin) by acoramidis results in an immediate and sustained rise in serum transthyretin (sTTR) levels, but the association between this pharmacodynamic effect and all-cause mortality (ACM) has not been elucidated.
Objectives: The purpose of this study was to assess the prognostic implication of acoramidis-mediated early change in sTTR and its relationship to ACM.
Methods: We evaluated sTTR levels in 557 participants with ATTR-CM from the ATTRibute-CM study population. For the Kaplan-Meier overall survival assessment, univariate and multivariate modeling were used to evaluate factors associated with ACM. Modeling and simulation analyses described acoramidis population pharmacokinetics.
Results: Treatment with acoramidis resulted in a sharp and significant early rise in sTTR levels (mean 9.1 mg/dL) within 28 days which was sustained throughout the 30-month treatment period. Participants with ≥20 mg/dL sTTR at baseline had significantly (P < 0.0001) greater overall survival probability than those with <20 mg/dL. An early increase in sTTR levels on day 28 of dosing (early ΔTTR) was associated with reduced ACM in univariate analysis (HR: 0.96 per 1 mg/dL increase in early ΔTTR; 95% CI: 0.93-0.98; P = 0.002). In the multivariate analysis, after adjusting for TTR variant status, baseline New York Heart Association functional class, baseline National Amyloidosis Centre stage, and baseline sTTR level, early ΔTTR remained independently associated with reduced ACM (P < 0.001). Bootstrap mediation analyses showed that early ΔTTR fully mediates the effect of acoramidis treatment on ACM probability (average causal mediation effect = -0.117; P = 0.002; average direct effect = 0.0366; P = 0.448). Logistic modeling demonstrated that among participants treated with acoramidis, early ΔTTR was associated with reduced ACM, whereas no such association was observed in participants treated with placebo. For every 5 mg/dL increase in sTTR levels, a logistic model predicted a 31.6% relative reduction in odds of ACM.
Conclusions: Acoramidis-mediated early ΔTTR is independently associated with improved survival after adjusting for known predictors. This provides strong evidence for a direct association between a prompt and sustained increase in sTTR upon initiation of treatment with acoramidis and survival. Early changes in sTTR could be used as a marker of the degree of TTR stabilization. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).
Keywords: ATTR-CM; TTR stabilization; acoramidis; all-cause mortality; serum TTR; 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 Maurer has acted as a researcher for National Institutes of Health R01HL139671 and R01AG081582-01, Alnylam Pharmaceuticals, BridgeBio (formerly Eidos Therapeutics), Ionis Pharmaceuticals, Pfizer, Attralus, Intellia, and Prothena Biosciences; and has served as a consultant or advisor for Alnylam Pharmaceuticals, AstraZeneca, Attralus, BridgeBio (formerly Eidos Therapeutics), Intellia Therapeutics, Ionis Pharmaceuticals, Novo Nordisk, and Pfizer. Dr Judge has received consultancy fees from Alnylam Pharmaceuticals, Attralus, Cytokinetics, Lexeo Therapeutics, Novo Nordisk, and Tenaya Therapeutics. Dr Gillmore has received consultancy fees from Pfizer, Ionis, Attralus, Eidos Therapeutics/BridgeBio, Alnylam Pharmaceuticals, Alexion, AstraZeneca, and Intellia. Dr Garcia-Pavia has received speaker fees from Alnylam Pharmaceuticals, AstraZeneca, BridgeBio, Intellia Therapeutics, Ionis Pharmaceuticals, Novo Nordisk, and Pfizer; has received consulting fees from Alexion, Alnylam Pharmaceuticals, AstraZeneca, Attralus, Bayer, BridgeBio, Intellia Therapeutics, Ionis Pharmaceuticals, Pfizer, Neuroimmune, and Novo Nordisk; and has received research/educational support to his institution from Pfizer, BridgeBio, Novo Nordisk, AstraZeneca, Intellia Therapeutics, and Alnylam Pharmaceuticals. Dr Masri has received research grants from Pfizer, Ionis Pharmaceuticals, Attralus, and Cytokinetics; and has received consulting fees from Cytokinetics, Bristol Myers Squibb, Eidos Therapeutics/BridgeBio, Pfizer, Ionis Pharmaceuticals, Lexicon, Attralus, Alnylam Pharmaceuticals, Haya, Alexion, Akros, Lexeo, Prothena Biosciences, BioMarin, AstraZeneca, and Tenaya. Dr Cappelli has acted as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, Amicus Therapeutics, AstraZeneca, BridgeBio (formerly Eidos Therapeutics), Novo Nordisk, and Pfizer. Dr Alexander has acted as a consultant, advisor, or speaker for Arbor Biotechnologies, Attralus, Intellia Therapeutics, and Prothena Biosciences. Dr Sarswat has received research funding from Pfizer, BridgeBio, Novo Nordisk, AstraZeneca, and Alnylam Pharmaceuticals. Dr Grogan has acted as a researcher for Alnylam Pharmaceuticals, BridgeBio (formerly Eidos Therapeutics), Intellia Therapeutics, Novo Nordisk, Janssen Pharmaceuticals, and Pfizer; and has served as a consultant, advisor, or speaker for Alnylam Pharmaceuticals, BridgeBio, Pfizer, Janssen Pharmaceuticals, and Novo Nordisk. Dr Ducharme has received research support from Abbott, AstraZeneca, Bayer, BridgeBio, Merck, and Novo Nordisk. Dr Poulsen has received consulting fees from BridgeBio, Pfizer, and Bayer; and has received research support from Novo Nordisk. Dr Lam has received consultancy fees from Pfizer; and has received honorariums from Menarini. Dr Obici has acted as a consultant, advisor, and speaker for Alnylam Pharmaceuticals, AstraZeneca, BridgeBio, Ionis Pharmaceuticals, Novo Nordisk, Pfizer, and Sobi, Inc. Dr Soman has received institutional research grants from Pfizer; and has received consultation fees for advisory boards from Pfizer, BridgeBio, and Alnylam Pharmaceuticals. Drs Rao, Tamby, Castaño, Fox, and Sinha are employees and stockholders of BridgeBio. Drs Adam and Poland are employees and stockholders of Certara. Dr Chepyala was an employee and stockholder of Certara at the time of writing of this paper. Dr Fontana has acted as a consultant, advisor, or speaker for Akcea Therapeutics, Alexion Pharmaceuticals, Alnylam Pharmaceuticals, AstraZeneca, BridgeBio (formerly Eidos Therapeutics), Intellia Therapeutics, Ionis Pharmaceuticals, Janssen Global Services, Novo Nordisk, and Pfizer; and has received research grants from BridgeBio (formerly Eidos Therapeutics) and Pfizer. Dr Ambardekar has reported that he has no relationships relevant to the contents of this paper to disclose.
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