Amrut V. Ambardekar, NITASHA SARSWAT, RICHARD WRIGHT, John Berk, Margot K. Davis, PABLO GARCIA-PAVIA, JULIAN D. GILLMORE, JUSTIN L. GRODIN, Joshua D. Mitchell, DEIRDRE MOONEY, JOSE NATIVI-NICOLAU, STEEN H. POULSEN, Frederick L. Ruberg, Chris Chen, ALAN JI, Suresh Siddhanti, JEAN-FRANÇOIS TAMBY, ADAM CASTAÑO, Leonid Katz, UMA SINHA, JONATHAN C. FOX, MATHEW S. MAURER, RICHARD K. CHENG
BACKGROUND: Transthyretin amyloid cardiomyopathy (ATTR-CM) causes heart failure, often leading to death, and it may be associated with low serum transthyretin (sTTR) levels. Acoramidis, a near-complete (≥90%) TTR stabilizer, increases sTTR levels and has demonstrated clinical efficacy in ATTR-CM. This report evaluates the association between the acoramidis-related early change from baseline in sTTR (ΔTTR) and cardiovascular-specific outcomes. METHODS: The 611 participants in the phase 3 (ATTRibute-CM) trial (NCT03860935; Efficacy and Safety of Acoramidis in Participants With Transthyretin Amyloid Cardiomyopathy) (acoramidis [409], placebo [202]) received oral acoramidis hydrochloride (800 mg) or placebo twice daily. Outcomes through month 30 included time to cardiovascular mortality (CVM) or first cardiovascular-related hospitalization (CVH), CVM alone, ΔTTR (day 28 until month 30), and the association between early ΔTTR (at day 28) and cardiovascular risk, including a mediation analysis. RESULTS: Acoramidis reduced the risk of CVM or first CVH vs placebo (33.3% vs 48.5%; hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.48-0.80; P < .001). A trend toward lower CVM with acoramidis was observed (14.9% vs 21.3%; HR 0.71; 95% CI 0.47, 1.05; P = .09). Cardiovascular benefits appeared to be mediated by acoramidis-induced ΔTTR (mean [standard error], 9.2 [0.25] mg/dL). Each 1- and 5-mg/dL increase in acoramidis-mediated early ΔTTR was associated with a 5.5% and 24.5% reduction in CVM and a 4.1% and 19.0% reduction in first CVH, respectively, over 30 months. CONCLUSIONS: In ATTRibute-CM trial, acoramidis led to early ΔTTR, which mediated, in part, reduced risks of CVM and first CVH over 30 months. This suggests that sTTR may serve as a clinically informative biomarker for ATTR-CM cardiovascular risk assessment following stabilizer initiation. TWEET: #Acoramidis led to an early increase in serum TTR (sTTR) that reduced risk of cardiovascular (CV) #mortality and first #CV-hospitalization over 30 months, suggesting that #sTTR may be a clinically informative biomarker after stabilizer initiation. @BridgeBioPharma.