Acoramidis, Serum Transthyretin, and Cardiovascular Outcomes in Transthyretin Amyloid Cardiomyopathy: Insights From the ATTRibute-CM Trial

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.