Aficamten Treatment for Symptomatic Obstructive Hypertrophic Cardiomyopathy

IF 10.3 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

JACC. Heart failure Pub Date : 2025-06-19 DOI:10.1016/j.jchf.2025.03.040

Sara Saberi MD, MS , Theodore P. Abraham MD , Lubna Choudhury MD, MRCPI , Roberto Barriales-Villa MD, PhD , Perry M. Elliott MBBS, MD , Michael E. Nassif MD, MS , Artur Oreziak MD, PhD , Anjali T. Owens MD , Albree Tower-Rader MD , Florian Rader MD , Pablo Garcia-Pavia MD, PhD , Iacopo Olivotto MD , Caroline J. Coats MD, PhD , Michael A. Fifer MD , Mark V. Sherrid MD , Scott D. Solomon MD , Hugh Watkins MD, PhD , Stephen B. Heitner MD , Daniel L. Jacoby MD , Stuart Kupfer MD , Ahmad Masri MD MS

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Abstract

Background

Long-term safety and efficacy data for aficamten in symptomatic obstructive hypertrophic cardiomyopathy are needed.

Objectives

This study aims to evaluate 48-week experience from the ongoing FOREST-HCM (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy) study.

Methods

Obstructive hypertrophic cardiomyopathy participants in an aficamten study (REDWOOD-HCM [Dose-finding Study to Evaluate the Safety, Tolerability, PK, and PD of CK-3773274 in Adults With HCM; NCT04219826]; SEQUOIA-HCM [Aficamten vs Placebo in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy; NCT05186818]) could enroll in this phase 2/3, open-label, extension study. Participants received aficamten 5 mg once daily titrated ≤20 mg based on site-read echocardiographic assessments of Valsalva left ventricular outflow tract gradient and left ventricular ejection fraction.

Results

From May 2021 to October 2023, 213 participants enrolled; 46 participants with 48 weeks of follow-up were evaluated (mean age: 59.7 years; female: n = 26 [56.5%]). There were rapid, substantial, and sustained reductions in mean resting (−40 ± 34 mm Hg) and Valsalva peak left ventricular outflow tract gradient (−53 ± 39 mm Hg) from baseline to week 48. A total of 82% experienced ≥1 NYHA functional class improvement; 31% experienced a 20-point improvement in Kansas City Cardiomyopathy Questionnaire–Clinical Summary score. There were substantial reductions (mean change) in maximum left ventricular wall thickness (−1.2 ± 1.6 mm; P < 0.0001), left atrial volume index (−3.5 ± 6.6 mL/m²; P = 0.0008), lateral E/e′ (−2.2 ± 6.1; P = 0.02), and cardiac biomarkers (P ≤ 0.0031). Aficamten was well tolerated with 2 (4.3%) asymptomatic and transient instances of left ventricular ejection fraction <50% (range: 47%-49%), neither resulting in drug discontinuation, and no new-onset atrial fibrillation.

Conclusions

Aficamten treatment over 48 weeks was well tolerated and associated with substantial and durable relief of obstruction and symptom burden, lower cardiac biomarker levels, and cardiac phenotypic changes, which may indicate favorable cardiac remodeling. (A Follow-Up, Open-Label, Research Evaluation of Sustained Treatment With Aficamten [CK-3773274] in Hypertrophic Cardiomyopathy [FOREST-HCM]; NCT04848506)

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症状性梗阻性肥厚性心肌病的阿非康治疗

背景：aficamten治疗症状性梗阻性肥厚性心肌病的长期安全性和有效性数据有待研究。目的：本研究旨在评估正在进行的FOREST-HCM （Aficamten [CK-3773274]持续治疗肥厚性心肌病的随访，开放标签，研究评估）研究的48周经验。方法：在一项评估CK-3773274在成人HCM患者中的安全性、耐受性、PK和PD的剂量研究中，对梗阻性肥厚性心肌病患者进行了一项非洲研究（REDWOOD-HCM）；NCT04219826];SEQUOIA-HCM [Aficamten vs安慰剂]治疗成人症状性梗阻性肥厚性心肌病NCT05186818])可以入组该2/3期开放标签扩展研究。根据现场读取超声心动图Valsalva左心室流出道梯度和左心室射血分数评估，参与者接受aficamten 5mg，每日一次，滴定≤20mg。从2021年5月到2023年10月，213名参与者入组；对46名参与者进行了48周的随访评估(平均年龄：59.7岁；女性：n = 26[56.5%])。从基线到第48周，平均静息（- 40±34 mm Hg）和Valsalva峰值左室流出道梯度（- 53±39 mm Hg）快速、大量和持续降低。82%的患者NYHA功能分级改善≥1；31%的人在堪萨斯城心肌病问卷-临床总结评分中提高了20分。最大左室壁厚度显著降低（平均变化）(- 1.2±1.6 mm；P & lt;0.0001)，左房容积指数(−3.5±6.6 mL/m2；P = 0.0008)，侧位E/ E′(- 2.2±6.1；P = 0.02)，心脏生物标志物（P≤0.0031）。阿非卡坦耐受性良好，2例（4.3%）无症状和短暂性左心室射血分数为50%（范围：47%-49%），均未导致停药，也未出现新发心房颤动。结论替卡坦治疗48周耐受性良好，可显著缓解梗阻和症状负担，降低心脏生物标志物水平，改变心脏表型，这可能表明有利于心脏重构。Aficamten [CK-3773274]持续治疗肥厚性心肌病[FOREST-HCM]的随访、开放标签、研究评价；NCT04848506)

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来源期刊

JACC. Heart failure CARDIAC & CARDIOVASCULAR SYSTEMS-

CiteScore

21.20

自引率

2.30%

发文量

164

期刊介绍： JACC: Heart Failure publishes crucial findings on the pathophysiology, diagnosis, treatment, and care of heart failure patients. The goal is to enhance understanding through timely scientific communication on disease, clinical trials, outcomes, and therapeutic advances. The Journal fosters interdisciplinary connections with neuroscience, pulmonary medicine, nephrology, electrophysiology, and surgery related to heart failure. It also covers articles on pharmacogenetics, biomarkers, and metabolomics.