Saberi Sara, Abraham Theodore P, Choudhury Lubna, Barriales-Villa Roberto, Elliott Perry M, Nassif Michael E, Oreziak Artur, Owens Anjali T, Tower-Rader Albree, Rader Florian, Garcia-Pavia Pablo, Olivotto Iacopo, Coats Caroline J, Fifer Michael A, Sherrid Mark V, Solomon Scott D, Watkins Hugh, Heitner Stephen B, Jacoby Daniel L, Kupfer Stuart, Malik Fady I, Melloni Chiara, Meng Lisa, Wei Jenny, Maron Martin S, Masri Ahmad
University of Michigan, Ann Arbor, Michigan, USA.
University of California-San Francisco, San Francisco, California, USA.
JACC Heart Fail. 2025 Aug;13(8):102496. doi: 10.1016/j.jchf.2025.03.040. Epub 2025 Jun 19.
Long-term safety and efficacy data for aficamten in symptomatic obstructive hypertrophic cardiomyopathy are needed.
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.
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.
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/m; 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.
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).
需要有关于阿非卡坦治疗有症状的梗阻性肥厚型心肌病的长期安全性和有效性数据。
本研究旨在评估正在进行的FOREST-HCM（阿非卡坦[CK-3773274]在肥厚型心肌病中的持续治疗的随访、开放标签、研究评估）研究的48周经验。
参加阿非卡坦研究（红木-HCM[评估CK-3773274在成人肥厚型心肌病中的安全性、耐受性、药代动力学和药效学的剂量探索研究；NCT04219826]；红杉-HCM[阿非卡坦与安慰剂治疗有症状的梗阻性肥厚型心肌病成人患者；NCT05186818]）的梗阻性肥厚型心肌病参与者可以参加这项2/3期开放标签扩展研究。参与者每天一次服用5毫克阿非卡坦，并根据基于Valsalva左心室流出道梯度和左心室射血分数的现场读取超声心动图评估将剂量滴定至≤20毫克。
从2021年5月到2023年10月，213名参与者入组；对46名有48周随访的参与者进行了评估（平均年龄：59.7岁；女性：n = 26[56.5%]）。从基线到第48周，平均静息左心室流出道梯度（-40±34毫米汞柱）和Valsalva峰值左心室流出道梯度（-53±39毫米汞柱）迅速、显著且持续降低。共有82%的患者纽约心脏协会（NYHA）功能分级改善≥1级；31%的患者堪萨斯城心肌病问卷临床总结评分提高20分。最大左心室壁厚度（-1.2±1.6毫米；P<0.0001）、左心房容积指数（-3.5±6.6毫升/平方米；P = 0.0008）、侧壁E/e'（-2.2±6.1；P = 0.02）和心脏生物标志物（P≤0.0031）均有显著降低（平均变化）。阿非卡坦耐受性良好，有2例（4.3%）无症状且短暂的左心室射血分数<50%（范围：47%-49%），均未导致停药，也没有新发房颤。
48周的阿非卡坦治疗耐受性良好，与梗阻和症状负担的显著且持久缓解、较低的心脏生物标志物水平以及心脏表型变化相关，这可能表明心脏重塑良好。（阿非卡坦[CK-3773274]在肥厚型心肌病中的持续治疗的随访、开放标签、研究评估[FOREST-HCM]；NCT04848506）
