Maharao Neha, Xu Donghong, Simkins Tyrell J, Bowles Owen, Liu Genzhou, Benattia Youcef, Griffith Adrienne, Heitner Stephen B, Kupfer Stuart, German Polina
Department of Clinical Pharmacology, Cytokinetics, Incorporated, South San Francisco, California, USA.
Department of Clinical Research, Cytokinetics, Incorporated, South San Francisco, California, USA.
Clin Transl Sci. 2025 Apr;18(4):e70218. doi: 10.1111/cts.70218.
Aficamten is a next-in-class, small-molecule, cardiac myosin inhibitor in development for treating hypertrophic cardiomyopathy (HCM). This 2-part study evaluated aficamten's impact on QTc interval in healthy participants. Part A (n = 10) was an open-label study to find the appropriate dose for thorough QT (TQT) evaluation in Part B. Part B (n = 34) was a double-blind, 3-way crossover TQT study conducted as per ICH E14 guidance using negative (placebo) and positive (moxifloxacin) controls. A single 50 mg aficamten dose achieved exposures (C range: 124-1660 ng/mL) comparable to the highest clinical dose (20 mg QD) in obstructive HCM patients (NCT05186818; [C range: 131-1230 ng/mL]) and was chosen for TQT evaluation. Using concentration-QT (C-QT) modeling, the placebo- and baseline-corrected QT interval using Fridericia's correction (ΔΔQTcF) was -1.82 msec (90% CI: -3.43, -0.214) at peak aficamten concentrations (298.3 ng/mL) following the 50 mg dose. The 90% CI upper bound of ΔΔQTcF for aficamten was < 10 msec at all post-dose time points. Assay sensitivity was established by the 90% CI lower bound for moxifloxacin (ΔΔQTcF) exceeding 5 msec. Aficamten did not cause QTc prolongation (using C-QT and by time point analyses) within observed plasma concentrations up to 1660 ng/mL (aficamten), 213 ng/mL (metabolite CK-3834282), and 343 ng/mL (metabolite CK-3834283). No clinically meaningful effect on electrocardiogram parameters, including absolute QTcF (≤ 450 msec) and change from baseline in QTcF (≤ 30 msec) was noted in aficamten-treated participants. Aficamten was generally well tolerated. In conclusion, there was no evidence of aficamten-mediated QTc prolongation across the therapeutic concentration range in a formal TQT study.
阿非卡坦是一种处于研发阶段的新型小分子心肌肌球蛋白抑制剂，用于治疗肥厚型心肌病（HCM）。这项分为两部分的研究评估了阿非卡坦对健康参与者QTc间期的影响。A部分（n = 10）是一项开放标签研究，旨在确定B部分进行全面QT（TQT）评估的合适剂量。B部分（n = 34）是一项双盲、三交叉TQT研究，按照ICH E14指南进行，使用阴性（安慰剂）和阳性（莫西沙星）对照。单次50 mg阿非卡坦剂量达到的暴露量（C范围：124 - 1660 ng/mL）与梗阻性HCM患者的最高临床剂量（20 mg QD）相当（NCT05186818；[C范围：131 - 1230 ng/mL]），并被选用于TQT评估。使用浓度 - QT（C - QT）模型，在50 mg剂量后阿非卡坦峰值浓度（298.3 ng/mL）时，使用弗里德里西亚校正法（ΔΔQTcF）校正的安慰剂和基线QT间期为 - 1.82毫秒（90% CI： - 3.43， - 0.214）。在所有给药后时间点，阿非卡坦的ΔΔQTcF的90% CI上限均<10毫秒。通过莫西沙星的90% CI下限（ΔΔQTcF）超过5毫秒确定了检测灵敏度。在观察到的血浆浓度高达1660 ng/mL（阿非卡坦）、213 ng/mL（代谢物CK - 3834282）和343 ng/mL（代谢物CK - 3834283）范围内，阿非卡坦未引起QTc延长（使用C - QT和时间点分析）。在接受阿非卡坦治疗的参与者中，未观察到对心电图参数有临床意义的影响，包括绝对QTcF（≤450毫秒）和QTcF相对于基线的变化（≤30毫秒）。阿非卡坦总体耐受性良好。总之，在一项正式的TQT研究中，没有证据表明在治疗浓度范围内阿非卡坦会介导QTc延长。
