Judge Daniel P, Alexander Kevin M, Cappelli Francesco, Fontana Marianna, Garcia-Pavia Pablo, Gibbs Simon D J, Grogan Martha, Hanna Mazen, Masri Ahmad, Maurer Mathew S, Obici Laura, Soman Prem, Cao Xiaofan, Lystig Ted, Tamby Jean-François, Siddhanti Suresh, Castaño Adam, Katz Leonid, Fox Jonathan C, Mahaffey Kenneth W, Gillmore Julian D
Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina, USA.
Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA; Stanford Center for Clinical Research, Stanford School of Medicine, Palo Alto, California, USA.
J Am Coll Cardiol. 2025 Mar 18;85(10):1003-1014. doi: 10.1016/j.jacc.2024.11.042.
Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed chronic disease associated with progressive heart failure that results in impaired quality of life, repeated hospitalizations, and premature death. Acoramidis is a selective, oral transthyretin stabilizer recently approved by the U.S. Food and Drug Administration for the treatment of ATTR-CM. In a phase 3, randomized, double-blind study (ATTRibute-CM [Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy]), acoramidis was well tolerated and showed clinical efficacy in improving the primary endpoint, a hierarchical combination of all-cause mortality (ACM), cardiovascular-related hospitalization (CVH), N-terminal pro-B-type natriuretic peptide level, and 6-minute walk distance.
The goal of this study was to characterize the efficacy of acoramidis on ACM and CVH.
In ATTRibute-CM, participants with ATTR-CM were randomized 2:1 to receive acoramidis hydrochloride (800 mg twice daily) or placebo for 30 months. Efficacy analyses were conducted in the modified intention-to-treat population (participants with a baseline estimated glomerular filtration rate ≥30 mL/min/1.73 m). CVH and the composite of ACM or first CVH were plotted by using Kaplan-Meier curves and summarized with a stratified Cox proportional hazards model. The annualized frequency of CVH was analyzed by using a negative binomial regression model. Subgroup analyses were conducted for the composite of ACM or first CVH.
Of the 632 participants randomized to treatment, 611 (97%) were included in efficacy analyses (acoramidis, n = 409; placebo, n = 202). Compared with placebo, acoramidis reduced the occurrence of the composite of ACM or first CVH (acoramidis, 35.9%; placebo, 50.5%; HR: 0.64; 95% CI: 0.50-0.83; P = 0.0008) and of first CVH (acoramidis, 26.7%; placebo, 42.6%; HR: 0.60; 95% CI: 0.45-0.80; P = 0.0005), with Kaplan-Meier curves separating at month 3 and continuing to diverge through month 30. Annualized frequency of CVH was reduced with acoramidis compared with placebo (acoramidis, 0.22; placebo, 0.45; relative risk ratio: 50%; 95% CI: 0.36-0.70; P < 0.0001). The efficacy of acoramidis on the composite of ACM or first CVH was consistent across subgroups. Acoramidis was well tolerated, with no safety signals of potential clinical concern identified.
In participants with ATTR-CM, acoramidis reduced the composite of ACM or first CVH vs placebo, with an early effect driven by a reduction in CVH. (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy [ATTRibute-CM]; NCT03860935).
转甲状腺素蛋白淀粉样心肌病（ATTR-CM）是一种诊断不足的慢性疾病，与进行性心力衰竭相关，会导致生活质量受损、反复住院和过早死亡。阿考米司是一种选择性口服转甲状腺素蛋白稳定剂，最近获得美国食品药品监督管理局批准用于治疗ATTR-CM。在一项3期随机双盲研究（ATTRibute-CM [AG10在转甲状腺素蛋白淀粉样心肌病患者中的疗效和安全性]）中，阿考米司耐受性良好，并在改善主要终点方面显示出临床疗效，该主要终点是全因死亡率（ACM）、心血管相关住院（CVH）、N末端B型利钠肽原水平和6分钟步行距离的分层组合。
本研究的目的是描述阿考米司对ACM和CVH的疗效。
在ATTRibute-CM研究中，将ATTR-CM患者按2:1随机分组，接受盐酸阿考米司（每日两次，每次800 mg）或安慰剂治疗30个月。在改良意向性治疗人群（基线估计肾小球滤过率≥30 mL/min/1.73 m²的参与者）中进行疗效分析。使用Kaplan-Meier曲线绘制CVH以及ACM或首次CVH的复合终点，并采用分层Cox比例风险模型进行总结。使用负二项回归模型分析CVH的年化频率。对ACM或首次CVH的复合终点进行亚组分析。
在随机分组接受治疗的632名参与者中，611名（97%）纳入疗效分析（阿考米司组，n = 409；安慰剂组，n = 202）。与安慰剂相比，阿考米司降低了ACM或首次CVH复合终点的发生率（阿考米司组为35.9%；安慰剂组为50.5%；HR：0.64；95%CI：0.50-0.83；P = 0.0008）以及首次CVH的发生率（阿考米司组为26.7%；安慰剂组为42.6%；HR：0.60；95%CI：0.45-0.80；P = 0.0005），Kaplan-Meier曲线在第3个月开始分离，并在第30个月持续分开。与安慰剂相比，阿考米司降低了CVH的年化频率（阿考米司组为0.22；安慰剂组为0.45；相对风险比：50%；95%CI：0.36-0.70；P < 0.0001）。阿考米司对ACM或首次CVH复合终点的疗效在各亚组中一致。阿考米司耐受性良好，未发现潜在临床关注的安全信号。
在ATTR-CM患者中，与安慰剂相比，阿考米司降低了ACM或首次CVH复合终点的发生率，早期效果由CVH的降低驱动。（AG10在转甲状腺素蛋白淀粉样心肌病患者中的疗效和安全性[ATTRibute-CM]；NCT03860935）
