Early Increase in Serum Transthyretin by Acoramidis Independently Predicts Improved Survival in TTR Amyloid Cardiomyopathy

作者：Mathew S. Maurer, Daniel P. Judge, Julian D. Gillmore, Pablo García‐Pavía, Ahmad Masri, Francesco Cappelli, Kevin Alexander, Nitasha Sarswat, Martha Grogan, Amrut V. Ambardekar, Anique Ducharme, Steen Hvitfeldt Poulsen, Kaitlyn Lam, Laura Obici, Prem Soman, Satish Rao, Jean‐François Tamby, Adam Castaño, Jonathan C. Fox, Brian Adam, Surendhar Reddy Chepyala, Bill Poland, Uma Sinha, Marianna Fontana · 发表于：Journal of the American College of Cardiology · 年份：2025 · DOI：10.1016/j.jacc.2025.03.542 · 被引用次数：37 · 研究领域：Amyloidosis: Diagnosis, Treatment, Outcomes、Parathyroid Disorders and Treatments、Dermatological and Skeletal Disorders

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 uni...