From the National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London (J.D.G., M.F.); the Medical University of South Carolina, Charleston, SC (D.P.J.); Tuscan Regional Amyloidosis Centre, Careggi University Hospital, Florence (F.C.), and the Amyloidosis Research and Treatment Center, IRCCS Fondazione Policlinico San Matteo, Pavia (L.O.) - both in Italy; the Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, Centro de Investigacíon Biomédica en Red Enfermedades Cardiovaculares, and Centro Nacional de Investigaciones Cardiovasculares (P.G.-P.) - both in Madrid; European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart, Amsterdam (P.G.-P.); the Victorian and Tasmanian Amyloidosis Service, Department of Haematology, Monash University Eastern Health Clinical School, Box Hill, VIC, Australia (S.G.); the Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN (M.G.); the Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland (M.H.); the Sylvester Comprehensive Cancer Center, University of Miami, Miami (J.H.), and the Amyloidosis Program, Department of Transplant, Mayo Clinic, Jacksonville (J.N.-N.) - both in Florida; the Cardiac Amyloidosis Program, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (A.M.); the Cardiac Amyloidosis Program, Division of Cardiology, Columbia College of Physicians and Surgeons, New York (M.S.M.); the Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark (S.H.P.); Duke Clinical Research Institute (F.R., J.G., K.C., H.X.) and Duke University Medical Center (F.R.) - both in Durham, NC; the Pauley Heart Center, Virginia Commonwealth University, Richmond (K.B.S.); the Division of Cardiology, University of Pittsburgh Medical Center, Pittsburgh (P.S.); and Eidos Therapeutics affiliate of BridgeBio Pharma, San Francisco (X.C., T.L., U.S., J.C.F.).
N Engl J Med. 2024 Jan 11;390(2):132-142. doi: 10.1056/NEJMoa2305434.
Transthyretin amyloid cardiomyopathy is characterized by the deposition of misfolded monomeric transthyretin (TTR) in the heart. Acoramidis is a high-affinity TTR stabilizer that acts to inhibit dissociation of tetrameric TTR and leads to more than 90% stabilization across the dosing interval as measured ex vivo.
In this phase 3, double-blind trial, we randomly assigned patients with transthyretin amyloid cardiomyopathy in a 2:1 ratio to receive acoramidis hydrochloride at a dose of 800 mg twice daily or matching placebo for 30 months. Efficacy was assessed in the patients who had an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m of body-surface area. The four-step primary hierarchical analysis included death from any cause, cardiovascular-related hospitalization, the change from baseline in the N-terminal pro-B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6-minute walk distance. We used the Finkelstein-Schoenfeld method to compare all potential pairs of patients within strata to generate a P value. Key secondary outcomes were death from any cause, the 6-minute walk distance, the score on the Kansas City Cardiomyopathy Questionnaire-Overall Summary, and the serum TTR level.
A total of 632 patients underwent randomization. The primary analysis favored acoramidis over placebo (P<0.001); the corresponding win ratio was 1.8 (95% confidence interval [CI], 1.4 to 2.2), with 63.7% of pairwise comparisons favoring acoramidis and 35.9% favoring placebo. Together, death from any cause and cardiovascular-related hospitalization contributed more than half the wins and losses to the win ratio (58% of all pairwise comparisons); NT-proBNP pairwise comparisons yielded the highest ratio of wins to losses (23.3% vs. 7.0%). The overall incidence of adverse events was similar in the acoramidis group and the placebo group (98.1% and 97.6%, respectively); serious adverse events were reported in 54.6% and 64.9% of the patients.
In patients with transthyretin amyloid cardiomyopathy, the receipt of acoramidis resulted in a significantly better four-step primary hierarchical outcome containing components of mortality, morbidity, and function than placebo. Adverse events were similar in the two groups. (Funded by BridgeBio Pharma; ATTRibute-CM ClinicalTrials.gov number, NCT03860935.).
转甲状腺素蛋白淀粉样心肌病的特征是心脏中错误折叠的单体转甲状腺素蛋白（TTR）的沉积。Acoramidis 是一种高亲和力的 TTR 稳定剂，可抑制四聚体 TTR 的解离，在体外测量时，其半衰期超过 90%。
在这项 3 期、双盲试验中，我们以 2:1 的比例随机分配转甲状腺素蛋白淀粉样心肌病患者，接受 800 mg 盐酸 acoramidis 每日两次或匹配的安慰剂治疗 30 个月。在肾小球滤过率估计值至少为每分钟每 1.73 平方米体表面积 30 毫升的患者中评估疗效。四级主要分层分析包括任何原因导致的死亡、心血管相关住院治疗、基线时 N 端前 B 型利钠肽（NT-proBNP）水平的变化以及 6 分钟步行距离的变化。我们使用 Finkelstein-Schoenfeld 方法比较每个分层内所有潜在患者对来生成 P 值。主要次要终点是任何原因导致的死亡、6 分钟步行距离、堪萨斯城心肌病问卷总体摘要评分和血清 TTR 水平。
共有 632 名患者接受了随机分组。主要分析结果支持 acoramidis 优于安慰剂（P<0.001）；相应的优势比为 1.8（95%置信区间[CI]，1.4 至 2.2），63.7%的成对比较有利于 acoramidis，35.9%有利于安慰剂。总的来说，任何原因导致的死亡和心血管相关住院治疗对优势比的贡献超过了一半（所有成对比较的 58%）；NT-proBNP 成对比较的优势比最高（23.3%对 7.0%）。acoramidis 组和安慰剂组的不良事件总发生率相似（分别为 98.1%和 97.6%）；两组患者均报告了 54.6%和 64.9%的严重不良事件。
在转甲状腺素蛋白淀粉样心肌病患者中，与安慰剂相比，接受 acoramidis 治疗可显著改善包含死亡率、发病率和功能的四级主要分层结局。两组的不良事件相似。（由 BridgeBio Pharma 资助；ATTRibute-CM ClinicalTrials.gov 编号，NCT03860935。）
