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

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)