背景:非坎顿,一种新的心肌肌球蛋白抑制剂,在梗阻性肥厚型心肌病中可逆性地降低心脏收缩过度。我们提出了一个预定的药代动力学分析,药效学,和aficanten在Sequoia-HCM中的安全性(安全性,功效,以及对非卡丁在HCM中的阻塞影响的定量理解)。
结果:在2022年2月1日至2023年5月15日之间,共有282例梗阻性肥厚型心肌病患者以1:1的比例随机分配至每日非卡西汀(5-20mg)或安慰剂。Aficamten给药的目标是实现位点解释的Valsalva左心室流出道梯度<30mmHg且左心室射血分数(LVEF)≥50%的最低有效剂量。在滴定期间(第1天至第8周)评估终点,维护(第8-24周),和冲洗(第24-28周),并包括主要不良心脏事件,新发心房颤动,植入式心脏复律除颤器放电,LVEF<50%,和治疗引起的不良事件。在第8周,3.6%,12.9%,35%,48.6%的患者实现了5,10-,15-,和20毫克的剂量,分别。各组的基线特征相似。Aficamten浓度随剂量增加而增加,并在维持期间保持稳定。在治疗期间,每100ng/mLaficamten暴露,LVEF降低-0.9%(95%CI,-1.3至-0.6)。7名(4.9%)服用aficamten的患者因位点解释的LVEF<50%而接受了符合方案的剂量减少。LVEF<50%没有治疗中断或心力衰竭恶化。无主要不良心血管事件与aficamten相关,和治疗引起的不良事件在治疗组之间相似,包括心房颤动.
结论:以最低有效非卡明剂量为目标的基于部位的给药算法降低了左心室流出道梯度,在整个SEQUOIA-HCM中具有良好的安全性。
背景:URL:https://www。clinicaltrials.gov;唯一标识符:NCT05186818。
BACKGROUND: 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).
RESULTS: 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.
CONCLUSIONS: 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.
BACKGROUND: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.