MUNICH — For the first time in a controlled trial, meaningful clinical benefit has been achieved with a drug in nonobstructive hypertrophic cardiomyopathy, a disease for which so far there have been no approved therapies. 

Aficamten, which is already approved for obstructive hypertrophic cardiomyopathy, showed significant benefit for dual primary endpoints of reduced symptom burden and improved exercise capacity, said Ahmad Masri, MD, an associate professor of medicine in the division of cardiology at the Oregon Health & Science University in Portland.

The results of this multinational phase 3 trial, called ACACIA-HCM, were presented at the European Society of Cardiology (ESC) 2026 Congress and simultaneously published in The New England Journal of Medicine. 

By the Numbers

In ACACIA-HCM, 518 adults with nonobstructive HCM were randomized at 160 sites in 19 countries to receive a starting dose of 5 mg (titrated to a maximum dose of 20 mg) aficamten or placebo. Notable eligibility requirements included a left ventricular end-diastolic wall thickness ≥ 13 mm in the presence of a causative genetic mutation or ≥ 15 mm in others. They were also required to have a left ventricular outflow tract gradient < 30 mm Hg.

The dual primary endpoints were change from baseline to week 36 in Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (a patient-oriented measure of symptom burden) and peak oxygen uptake (a measure of exercise capacity). 

At 36 weeks, KCCQ score improved by a mean 11.4 points in the aficamten arm and 8.4 points in the placebo arm, providing a mean 3-point advantage (P = .02) for active treatment, which was clinically meaningful, Masri said.

The mean change in peak oxygen uptake at 36 weeks was an increase of 0.64 mL/kg/min with aficamten vs a reduction of 0.03 mL/kg/min with placebo, a mean difference of 0.67 mL/kg/min (P = .003), which was also clinically meaningful, Masri reported.

Improvements in these endpoints were observed as early as 12 weeks, and the curves continued to separate during treatment out to 72 weeks, when therapy was stopped. Both benefits were lost over the course of the washout period.

Five Secondary Endpoints All Positive

Five secondary endpoints were evaluated in hierarchical order: improvement by at least one class in New York Heart Association functional class; composite Z-score of peak oxygen uptake and ventilatory efficiency slope; change in N-terminal pro–B-type natriuretic peptide (NT-proBNP) concentration; left atrial volume index; and time to first composite cardiovascular event.

All of these endpoint results at least numerically favored aficamten over placebo, but a prespecified analysis by the ACACIA-HCM investigators, simultaneously published in Circulation, further support the clinical benefit of the cardiac myosin inhibitor.

“What happens if you put all of these together and define a clinical response as a positive result on three or more of these outcomes? That happened in 53% of those randomized to aficamten vs 13% of those on placebo, which was highly significant [P = .001],” Masri reported.

Aficamten was well tolerated overall, but Masri acknowledged that more patients in the experimental arm developed significant reductions in left ventricular ejection fraction. These reductions were generally reversible but might account for the higher rate of nonfatal adverse events that led to study discontinuation among aficamten-treated patients (7.0% vs 1.9%). Yet, all three of the deaths in this study occurred in the placebo arm.

Overall the findings “show that aficamten is an effective treatment for patients with nonobstructive HCM,” Masri said. However, he pointed out that the study also showed benefit across phenotypes that might not fully share disease pathways.

“Despite the phenotypic variety in patients with nonobstructive HCM, the prespecified subgroup analyses showed consistency of the treatment effects and the generalizability of these findings across the spectrum of patients,” Masri and colleagues pointed out in the published results.

 ESC-invited discussant Nosheen Reza, MD, MS, an assistant professor of medicine at the Center for Inherited Cardiovascular Disease, University of Pennsylvania, Philadelphia, agreed. 

Pointing out the “consistency across efficacy measures,” Reza said the study confirms that myosin inhibition in nonobstructive HCM — like obstructive HCM where this mechanism has become a standard therapy — “is biologically and clinically active.”

Effect More Modest in Nonobstructive HCM

In a side-by-side comparison of trial data for aficamten and mavacamten, another myosin inhibitor, in nonobstructive relative to obstructive HCM, she noted that benefits do appear to be generally less robust in nonobstructive HCM with a higher risk of reduced LVEF. But she agreed that the relatively modest benefits of aficamten in nonobstructive HCM can still be considered clinically meaningful.

Although the study is positive, Reza said more work is needed, not least because nonobstructive HCM “is not a single phenotype.” She identified three components of a series of next steps now that there is evidence that myosin inhibition does have a role in the disorder.

“As we move forward, more work is needed to define the phenotypes most likely to benefit — perhaps contractile dysfunction, perhaps diastolic function, or perhaps other mechanisms,” she said. 

“Second, we need to better align therapeutic targets with disease mechanisms,” she added, suggesting that there are likely many targets beyond myosin inhibition that might provide opportunities to build toward greater efficacy.

“And finally, we must look to inform myocardial therapies beyond HCM. The lessons we learned here from cardiac myosin inhibition might extend beyond this disease and may inform how we approach phenotypes,” she said. 

Masri has reported financial relationships with Attralus, Cytokinetics, and Janssen, and consulting fees from Cytokinetics, BridgeBio, Pfizer, Ionis, Lexicon, Attralus, Alnylam, Haya, Alexion, Akros, Edgewise, Rocket, Lexeo, Prothena, BioMarin, Intellia, Imbria, Braveheart, AstraZeneca, Avidity, and Neurimmune. Reza has reported financial relationships with American Regent, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Idorsia, Novo Nordisk, and Roche.

Ted Bosworth, a career medical writer based in New York City, has been covering advances in clinical medicine, including cardiology, for several decades.