Highlight
– Aficamten, a selective cardiac myosin inhibitor, significantly reduces LVOT gradients in symptomatic obstructive hypertrophic cardiomyopathy (oHCM) with sustained effect over 96 weeks.
– Treatment is associated with meaningful clinical improvements including NYHA functional class and Kansas City Cardiomyopathy Questionnaire scores.
– Long-term aficamten therapy exhibits a favorable safety profile with low incidence of adverse cardiac events such as new-onset atrial fibrillation and minimal impact on left ventricular ejection fraction (LVEF).
– No treatment-related serious adverse events or mortality were observed during extended follow-up, underscoring therapeutic potential.
Study Background
Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by hypercontractility and left ventricular outflow tract (LVOT) obstruction, leading to symptoms such as dyspnea, chest pain, and exercise intolerance. This condition carries risks of morbidity related to heart failure and arrhythmias. Current pharmacologic options, mostly beta-blockers and calcium channel blockers, mainly provide symptom relief without targeting the underlying hypercontractile pathophysiology. The development of cardiac myosin inhibitors such as aficamten represents a novel mechanism aiming to attenuate myosin-actin crossbridge cycling and thus reduce hypercontractility, LVOT obstruction, and downstream clinical sequelae.
Study Design
The FOREST-HCM study (NCT04848506) was an open-label extension trial enrolling patients with symptomatic oHCM who had completed a parent aficamten study. A total of 296 patients (mean age 61±12.3 years; 44.3% female) participated from May 2021 through August 2024. The trial assessed long-term safety and efficacy of oral aficamten over a median follow-up of approximately 52 weeks, with cumulative exposure of 352 patient-years. Key endpoints included hemodynamic measures, especially Valsalva-induced LVOT gradient changes, left ventricular ejection fraction (LVEF), symptom status assessed by New York Heart Association (NYHA) functional class, and health-related quality of life via the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score. Safety outcomes encompassed treatment-emergent serious adverse events (TESAEs), changes in LVEF below thresholds (<50%, <40%), incidence of atrial fibrillation, and therapy discontinuations.
Key Findings
Hemodynamic Improvements
Aficamten treatment led to remarkable and sustained reductions in LVOT gradients. At 12 weeks, the mean gradient reduction was 56 ± 43 mmHg from baseline, further improving slightly to 62 ± 33 mmHg at 96 weeks. Both reductions were statistically significant (P < 0.0001). Importantly, these improvements were achieved with minimal impact on LVEF: a modest decrease of 3% ± 6% at 12 weeks and 5% ± 5% at 96 weeks, staying within a safe range without any events of LVEF dropping below 40%. LVEF<50% manifested in only 3.4% of patients, with non-serious mild or moderate dyspnea in two individuals, and did not require treatment interruption.
Clinical Symptom Relief and Quality of Life
Clinical benefits paralleled hemodynamic gains. At 12 weeks, 69% of patients improved at least one NYHA class; this proportion increased to 93% by 96 weeks, reflecting sustained symptom alleviation. Patient-reported quality of life measured by the KCCQ clinical summary score improved by 15 ± 16 points at Week 12 and 16 ± 16 points at Week 96, indicating enhanced physical function and symptom burden reduction that persisted long term.
Safety Profile
The incidence of treatment-emergent serious adverse events was low (12.2% of patients), and no deaths, heart failure episodes, or adverse events attributed to aficamten were reported. One patient (0.3%) discontinued therapy due to ischemic colitis unrelated to the drug. Notably, new-onset atrial fibrillation was rare, occurring in only 2.4% of patients (exposure-adjusted incidence rate 2.0 per 100 patient-years). This low incidence supports aficamten’s safety, particularly given the arrhythmia predisposition in oHCM.
Expert Commentary
The FOREST-HCM study provides compelling evidence that selective myosin inhibition with aficamten offers durable hemodynamic and symptomatic benefits for symptomatic oHCM patients with a reassuring safety margin. Reductions in LVOT obstruction translate into improved functional capacity and quality of life while preserving systolic function. Compared to earlier molecule classes like mavacamten, aficamten’s consistent long-term profile, including minimal LVEF decline and low atrial fibrillation risk, may represent a meaningful clinical advantage.
However, the open-label design and lack of a control arm in this extension study underscore the need for continued controlled phase 3 evaluations and post-marketing surveillance. Future investigations should explore patient subgroups, long-term cardiac remodeling effects, and combination strategies with adjunctive therapies.
Conclusion
Extended aficamten therapy in symptomatic obstructive hypertrophic cardiomyopathy leads to significant and sustained improvements in LVOT gradient, symptoms, and quality of life while maintaining a favorable safety profile. These findings endorse aficamten as a promising therapeutic option targeting the core disease mechanism in oHCM, marking a new era in pharmacologic management of this challenging condition.
Funding and ClinicalTrials.gov
The FOREST-HCM study was sponsored by MyoKardia, Inc. ClinicalTrials.gov identifier: NCT04848506.
References
1. Tower-Rader A, Masri A, Nassif ME, et al. Aficamten in symptomatic obstructive hypertrophic cardiomyopathy: the FOREST-HCM long-term study. Eur Heart J. 2026 Jun 23;47(24):3120-3131. PMID: 41780565.
2. Olivotto I, et al. Mavacamten for Treatment of Symptomatic Obstructive Hypertrophic Cardiomyopathy (EXPLORER-HCM): A Randomised, Double-Blind, Placebo-Controlled, Phase 3 Trial. Lancet. 2020.
3. Maron MS, et al. Secondary Prevention Strategies in Hypertrophic Cardiomyopathy. Circulation. 2017.