Aficamten improved function in nonobstructive HCM, with cardiac safety trade-offs

Aficamten improved symptoms and exercise capacity in adults with symptomatic nonobstructive hypertrophic cardiomyopathy in a large Phase 3 trial, while also increasing episodes of reduced heart-pumping function and serious adverse events. The results were presented Aug. 28 at the European Society of Cardiology Congress and published the same day in the New England Journal of Medicine.

The findings matter because nonobstructive hypertrophic cardiomyopathy can markedly limit daily activity even though it does not create the outflow blockage seen in the obstructive form. Aficamten is already FDA-approved for symptomatic obstructive disease, but the agency has not approved it for nonobstructive HCM. Developer Cytokinetics says it plans to seek the expanded U.S. indication in the fourth quarter of 2026.

What ACACIA-HCM tested

ACACIA-HCM was a multinational, randomized, double-blind, placebo-controlled trial funded by Cytokinetics. It assigned 517 adults with symptomatic nonobstructive HCM to aficamten or placebo. Participants had New York Heart Association class II or III symptoms, preserved left ventricular ejection fraction at screening and evidence of impaired exercise capacity and cardiac stress. Doses were adjusted using serial echocardiograms.

The two primary endpoints at 36 weeks were change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, a patient-reported measure of symptoms and physical limitations, and change in peak oxygen uptake during exercise testing.

The questionnaire score rose by 11.4 points with aficamten and 8.4 points with placebo. The adjusted between-group advantage was 3.0 points, with a 95% confidence interval of 0.5 to 5.5. Peak oxygen uptake increased by 0.64 milliliters per kilogram per minute with aficamten and declined by 0.03 with placebo, producing an adjusted difference of 0.67 milliliters per kilogram per minute.

Secondary findings supported a physiological effect. At 36 weeks, 41.9% of aficamten recipients improved by at least one NYHA functional class, compared with 27.8% on placebo. A cardiac-stress biomarker and a combined exercise-testing measure also favored aficamten. However, the trial did not show a significant difference in left atrial volume or time to a first cardiovascular event.

Benefit came with a cardiac safety signal

Aficamten inhibits cardiac myosin and reduces heart-muscle contraction. That mechanism can help an overly contractile heart, but it can also lower ejection fraction too far. In ACACIA-HCM, ejection fraction fell below 50% in 10.5% of participants receiving aficamten versus 0.8% receiving placebo. Serious adverse events occurred in 20.2% and 14.7%, respectively, while nonfatal adverse events leading to early discontinuation occurred in 7.0% and 1.9%.

Two aficamten recipients had serious heart-failure events associated with an ejection fraction below 50%. The study used intensive echocardiographic titration, and many low-ejection-fraction episodes were managed by holding or reducing treatment. That protocol is important context: the approved obstructive-HCM label carries a boxed warning for systolic heart failure and requires echocardiographic monitoring through a restricted FDA safety program.

What the evidence does—and does not—establish

This is strong evidence that aficamten can improve short-term functional endpoints in a selected, closely monitored nonobstructive-HCM population. The randomized design, objective exercise endpoint and concordant symptom and biomarker results strengthen the finding.

The practical gain was nevertheless modest on the two primary measures, and the placebo group also reported substantial symptom improvement. The trial was not powered to establish reductions in hospitalization, transplantation or death, and its cardiovascular-event endpoint was neutral. Longer follow-up is needed to clarify durability and the balance between functional benefit and systolic dysfunction.

For now, ACACIA-HCM supports regulatory review rather than off-label certainty. FDA evaluation will need to weigh whether the observed symptom and exercise gains justify the monitoring burden and higher frequency of reduced ejection fraction in this population.