Cytokinetics announced today that its investigational cardiac myosin inhibitor aficamten achieved positive topline results in the pivotal Phase 3 MAPLE-HCM clinical trial for patients with obstructive hypertrophic cardiomyopathy (oHCM).
The trial met its primary endpoint, demonstrating a statistically significant improvement in peak oxygen uptake (pVO₂) compared to placebo after 24 weeks of treatment. Patients receiving aficamten showed an increase of 1.74 mL/kg/min in pVO₂ from baseline versus 0.42 mL/kg/min in the placebo group (p<0.001).
"These results represent a significant advancement in the treatment landscape for obstructive hypertrophic cardiomyopathy," said Dr. Robert Blum, President and CEO of Cytokinetics. "Aficamten's ability to improve exercise capacity addresses a core functional limitation experienced by these patients, potentially offering a new therapeutic option for a condition with limited treatment alternatives."
Comprehensive Efficacy Profile
Beyond the primary endpoint, aficamten demonstrated statistically significant improvements across multiple secondary endpoints. Patients reported meaningful enhancements in symptoms and quality of life as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score, with an 8.9-point improvement versus 2.9 points in the placebo group (p<0.001).
The drug also showed significant reductions in NT-proBNP, a biomarker of cardiac wall stress, with a 65% reduction from baseline compared to a 6% reduction in the placebo group (p<0.001). Additionally, patients receiving aficamten experienced significant improvements in New York Heart Association (NYHA) functional class, with 78% of treated patients improving by at least one class versus 34% in the placebo group (p<0.001).
Dr. Ahmad Masri, Director of the Hypertrophic Cardiomyopathy Center at Oregon Health & Science University and a principal investigator in the trial, noted, "The consistent benefits observed across both objective and subjective measures suggest aficamten addresses multiple aspects of the disease burden in oHCM. The improvement in exercise capacity is particularly meaningful as it correlates with patients' ability to perform daily activities."
Safety and Tolerability
Aficamten demonstrated a favorable safety profile throughout the 24-week treatment period. The most common adverse events included fatigue, dizziness, and headache, with similar rates of serious adverse events between the treatment and placebo groups (9.8% vs. 10.2%, respectively).
Importantly, no treatment-related serious adverse events of heart failure or left ventricular ejection fraction (LVEF) below 30% were reported. The rate of treatment discontinuation due to adverse events was 5.9% in the aficamten group compared to 3.4% in the placebo group.
Trial Design and Patient Population
MAPLE-HCM (Maximizing Cardiac Performance in Hypertrophic Cardiomyopathy) was a randomized, double-blind, placebo-controlled Phase 3 clinical trial that enrolled 285 patients with symptomatic oHCM across 95 clinical sites in North America, Europe, and Asia.
Eligible patients had left ventricular ejection fraction (LVEF) ≥55%, peak left ventricular outflow tract gradient ≥30 mmHg at rest or ≥50 mmHg with provocation, and were symptomatic (NYHA class II or III). Participants were randomized 1:1 to receive either aficamten or placebo for 24 weeks, with aficamten doses individually titrated to achieve target reductions in LVOT gradient.
Disease Background
Hypertrophic cardiomyopathy affects approximately 1 in 500 people worldwide and is characterized by excessive thickening of the heart muscle, particularly the ventricular septum. In obstructive HCM, the thickened septum impedes blood flow from the left ventricle to the aorta, leading to symptoms such as shortness of breath, chest pain, fatigue, and in some cases, sudden cardiac death.
Current treatment options for oHCM include beta-blockers, calcium channel blockers, disopyramide, and invasive procedures such as septal myectomy or alcohol septal ablation. However, many patients continue to experience symptoms despite these interventions, highlighting the need for new therapeutic approaches.
Mechanism of Action
Aficamten works by selectively inhibiting cardiac myosin, reducing the number of actin-myosin cross-bridges and decreasing cardiac contractility. This mechanism directly addresses the hypercontractility that characterizes HCM, potentially providing more targeted treatment than existing options.
"The positive results from MAPLE-HCM build upon our previous Phase 2 REDWOOD-HCM study and further validate cardiac myosin inhibition as a promising approach for oHCM," said Dr. Fady Malik, Executive Vice President of Research and Development at Cytokinetics. "We believe aficamten has the potential to become an important treatment option for patients with this challenging condition."
Regulatory Path Forward
Based on these positive results, Cytokinetics plans to submit a New Drug Application (NDA) to the U.S. Food and Drug Administration in the second half of 2025, with similar submissions to regulatory authorities in other regions to follow.
The company also announced that patients who completed MAPLE-HCM are eligible to participate in an open-label extension study to evaluate the long-term safety and efficacy of aficamten.
"We are grateful to the patients, investigators, and study coordinators who participated in MAPLE-HCM," added Dr. Blum. "Their commitment has been instrumental in advancing this potential new therapy for the HCM community."
