Cytokinetics (Nasdaq: CYTK) reported that aficamten met both dual primary endpoints in the Phase III ACACIA-HCM trial in symptomatic non-obstructive hypertrophic cardiomyopathy, a patient population for which no disease-specific therapy is currently approved by the FDA or EMA. The aficamten hypertrophic cardiomyopathy data, drawn from 516 randomized participants, showed statistically significant improvements in both symptom burden and exercise capacity compared to placebo at 36 weeks — the first Phase III trial to demonstrate such improvements in this subtype.
ACACIA-HCM Trial Results: What the Data Show
The ACACIA-HCM trial is a Phase III, multi-center, randomized, double-blind, placebo-controlled study designed to evaluate aficamten against placebo in adults with symptomatic non-obstructive HCM, enrolling 516 participants outside Japan on a 1:1 basis.
On the dual primary endpoints, aficamten produced a least square mean change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) of 11.4 points from baseline versus 8.4 points for placebo, a treatment difference of 3.0 points (95% CI: 0.5–5.5; p=0.021). The KCCQ cardiac outcomes signal was consistent throughout the treatment period and reversed toward placebo levels following washout, suggesting an on-target pharmacological effect rather than a sustained structural change. On maximal exercise performance, peak oxygen consumption (pVO2) increased by 0.64 mL/kg/min with aficamten versus a decline of 0.03 mL/kg/min with placebo, a difference of 0.67 mL/kg/min (95% CI: 0.22–1.1; p=0.003).
Key secondary endpoints, each reaching p<0.001, included the proportion of participants achieving at least one class improvement in New York Heart Association functional class, a composite z-score of ventilatory efficiency and pVO2, and NT-proBNP reduction. The consistency of these findings across both patient-reported and physician-assessed measures strengthens the overall signal, though the magnitude of the KCCQ difference — 3.0 points — sits at the lower boundary of what is generally considered clinically meaningful in cardiomyopathy trials, a nuance that regulators are likely to weigh carefully.
Safety profile
No new safety signals were identified. Completion of planned dosing was similar between arms: 88.4% for aficamten and 90.3% for placebo. However, the reduction in left ventricular ejection fraction (LVEF) below 50% occurred in 10% of aficamten-treated participants compared to 1% on placebo, and two participants on aficamten experienced serious adverse events of heart failure associated with that LVEF decline. Treatment interruptions due to LVEF falling below 40% occurred in 3% of the aficamten group.
This safety pattern is consistent with the known pharmacology of cardiac myosin inhibitors and mirrors the profile established in obstructive HCM trials. Myqorzo (aficamten), already approved in the US, EU, and China for symptomatic obstructive HCM, carries a boxed warning for the risk of heart failure due to systolic dysfunction and is available only through a Risk Evaluation and Mitigation Strategy (REMS) program in the US.
The competitive context for aficamten in hypertrophic cardiomyopathy
Non-obstructive HCM accounts for approximately half of all HCM cases based on recent claims data analysis, representing an estimated 150,000 or more diagnosed patients in the US alone. Unlike obstructive HCM, where the left ventricular outflow tract gradient provides both a pathophysiological target and a measurable surrogate endpoint, non-obstructive disease is defined by the absence of that gradient — meaning the disease burden falls almost entirely on symptoms, diastolic dysfunction, and exercise intolerance, with no pharmacological intervention currently holding regulatory approval.