Aficamten Improved Symptoms in a Form of Heart Disease That Had No Approved Treatment

CATEGORY: HEART & CIRCULATION

A year and a half ago, this story looked closed. Mavacamten, the first drug of its kind, had just failed in the nonobstructive form of hypertrophic cardiomyopathy, missing both of its main goals in a trial of 580 patients.² Its sister drug has now landed the other way. Among 517 patients randomized to aficamten or placebo, the drug improved symptom scores by about 3 points more than placebo on a 100-point questionnaire over nine months, a gap that widened to 7 points by 17 months, and 53% of patients met a broader five-part definition of meaningful response versus 13% on placebo.¹

The Form of the Disease That Had No Drug

Hypertrophic cardiomyopathy means the heart’s muscular walls grow abnormally thick and stiff. In the obstructive form, the overgrown muscle physically blocks blood on its way out, and two approved drugs now treat exactly that. The nonobstructive form is quieter but no kinder. Nothing is blocked, yet the stiff, over-muscled chamber can’t relax and fill properly between beats, and people live with breathlessness, chest pain and fatigue. “Despite this being a relatively common disorder, there are no effective therapies,” said Ahmad Masri, the trial’s lead investigator. Expectations were low here for a concrete reason. Mavacamten’s trial had measured the same two yardsticks, a symptom questionnaire and treadmill oxygen uptake, in 580 similar patients over 48 weeks, and it came up short on both.²

What 36 Weeks on the Capsules Changed

The new trial, called ACACIA-HCM, enrolled 517 symptomatic adults at 182 hospitals. Randomization software decided who got aficamten and who got identical placebo capsules; neither patients nor their doctors knew. Doses started at 5 mg daily and were stepped up as ultrasound checks allowed. After 36 weeks, symptom scores on the 100-point Kansas City questionnaire had risen 11.4 points with aficamten against 8.4 with placebo. Notice that placebo patients improved too. That’s routine in symptom trials, and it’s why the honest measure is the 3-point gap, not the 11.4. Peak oxygen uptake on a treadmill, a measure of what the heart can actually deliver, rose slightly on the drug while drifting down on placebo. Some 42% of aficamten patients climbed at least one class on the standard scale of heart-failure limitation, versus 28% on placebo. A blood marker of heart strain fell as well. The researchers also built a stricter test of success: improvement in at least three of five areas spanning symptoms, exercise capacity, heart-strain markers and measures of the heart’s filling. By that standard, 53% of drug patients responded and 13% of placebo patients did. And when the capsules were stopped at the trial’s end, symptoms returned in force, which is its own kind of evidence that the drug was doing the work.¹

A Fifth Had Serious Events, and the Squeeze Can Dip

Aficamten works by slightly relaxing an overworking heart, and it can overshoot. The heart’s pumping strength dipped below normal in about 10% of drug patients against under 1% on placebo, reversibly, with dose adjustment or a pause. Serious adverse events of any kind occurred in 20.2% on the drug and 14.7% on placebo, and heart-failure events, while uncommon, were more frequent with aficamten. The drug is already approved in the United States for the obstructive form. Whether regulators extend it to the nonobstructive form, where no approved drug exists at all, is the decision this trial now feeds. Longer-term questions, such as whether feeling better translates into fewer hospital stays or longer lives, remain open.¹

Key Takeaways

• The safety ledger is real: roughly 1 in 10 patients had a reversible drop in pumping strength, and serious adverse events were more common on the drug, so treatment came with ultrasound monitoring throughout.
• Aficamten beat placebo on symptoms, treadmill capacity and a five-part response measure (53% versus 13%) in the first successful large trial ever run in nonobstructive hypertrophic cardiomyopathy.
• The average symptom gain over placebo was modest at nine months, about 3 points on a 100-point scale, and grew to 7 points by 17 months; the trial did not measure hospitalizations or survival.

References

1. Masri A, Maron MS, Bhatia A, et al. Aficamten for symptomatic nonobstructive hypertrophic cardiomyopathy. N Engl J Med. 2026; published online August 28. doi:10.1056/NEJMoa2603021. link
2. Desai MY, Owens AT, Abraham T, et al. Mavacamten in symptomatic nonobstructive hypertrophic cardiomyopathy. N Engl J Med. 2025;393(10):961–972. link