School of Cardiovascular and Metabolic Health University of Glasgow United Kingdom.
Oregon Health and Science University Portland OR.
J Am Heart Assoc. 2024 Aug 6;13(15):e035993. doi: 10.1161/JAHA.124.035993. Epub 2024 Jul 26.
Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM).
A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation.
A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM.
URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.
新型心肌肌球蛋白抑制剂阿非卡肽可逆转梗阻性肥厚型心肌病患者的心肌过度收缩。我们预先分析了阿非卡肽在 SEQUOIA-HCM（梗阻性肥厚型心肌病中阿非卡肽的安全性、疗效和定量梗阻影响的理解）中的药代动力学、药效学和安全性。
共有 282 例梗阻性肥厚型心肌病患者随机分为 1:1 组，每日接受阿非卡肽（5-20mg）或安慰剂治疗，分组时间为 2022 年 2 月 1 日至 2023 年 5 月 15 日。阿非卡肽的给药剂量旨在实现最低有效剂量，以达到经部位解读的瓦尔萨尔瓦动作左心室流出道梯度<30mmHg，同时左心室射血分数（LVEF）≥50%。在滴定期（第 1 天至第 8 周）、维持期（第 8-24 周）和洗脱期（第 24-28 周）评估终点，包括主要不良心脏事件、新发心房颤动、植入式心律转复除颤器放电、LVEF<50%和治疗相关不良事件。在第 8 周时，分别有 3.6%、12.9%、35%和 48.6%的患者达到 5、10、15 和 20mg 的剂量。各组间的基线特征相似。阿非卡肽的浓度随剂量增加，并在维持期保持稳定。在治疗期间，LVEF 每 100ng/mL 阿非卡肽暴露降低-0.9%（95%CI，-1.3 至-0.6）。有 7（4.9%）名接受阿非卡肽治疗的患者因经部位解读的 LVEF<50%而按方案减少剂量。没有因 LVEF<50%而中断治疗或心力衰竭恶化的情况。与阿非卡肽相关的主要不良心血管事件为零，治疗组之间的治疗相关不良事件相似，包括心房颤动。
基于部位的给药算法以最低有效阿非卡肽剂量为目标，降低了左心室流出道梯度，在整个 SEQUOIA-HCM 期间具有良好的安全性。
