A myosin inhibitor helped in the form of hypertrophic cardiomyopathy with no approved drug

Hypertrophic cardiomyopathy comes in two broad forms. In the obstructive kind, thickened muscle blocks blood leaving the heart, and the last few years have produced drugs aimed squarely at that blockage. In the non-obstructive kind there is no outflow gradient to relieve, patients are still breathless and limited, and — as the ACACIA-HCM investigators put it — there has been no proven medical therapy [s1].

ACACIA-HCM, published in the New England Journal of Medicine on 28 August and presented at ESC Congress 2026, is the first phase 3 trial to report a positive result in that group [s1] [s2].

What the trial did

ACACIA-HCM was a phase 3, multinational, double-blind trial [s1]. Adults with symptomatic non-obstructive HCM were randomly assigned 1:1 to aficamten — a cardiac myosin inhibitor, starting at 5 mg with a maximum of 20 mg — or to placebo, for up to 72 weeks [s1].

There were two primary endpoints, both measured as change from baseline to week 36: peak oxygen uptake on exercise testing, and the Kansas City Cardiomyopathy Questionnaire clinical summary score, a patient-reported measure running from 0 to 100 where higher scores mean better health status [s1].

Aficamten was assigned to 258 patients and placebo to 259 [s1]. Mean age was 55.1 years and 53.6% of participants were women [s1] — an unusually balanced trial population by cardiology standards.

What happened

Both primary endpoints favoured aficamten, and both by margins that need stating precisely.

On the questionnaire, the change at 36 weeks was 11.4 points (95% CI 9.6 to 13.2) with aficamten and 8.4 points (95% CI 6.6 to 10.2) with placebo — a least-squares mean difference of 3.0 points (95% CI 0.5 to 5.5, P = 0.02) [s1].

Two things are visible in those numbers. The drug arm improved by 11.4 points. So did the placebo arm, by 8.4 points [s1]. What aficamten added, over and above whatever produced the placebo-arm improvement, was 3.0 points on a 100-point scale, with a lower confidence bound of 0.5 [s1].

On exercise capacity, peak oxygen uptake changed by 0.64 ml per kilogram of body weight per minute (95% CI 0.32 to 0.95) with aficamten and by -0.03 ml per kilogram per minute (95% CI -0.35 to 0.28) with placebo, a difference of 0.67 ml per kilogram per minute (95% CI 0.22 to 1.11, P = 0.003) [s1]. Here the placebo arm did not improve, which makes the contrast cleaner even though the absolute quantity is small.

The safety signal is the part to read twice

Aficamten works by reducing excessive contraction of the heart muscle [s2]. Push that too far and the heart underpumps.

Reversible reductions in left ventricular ejection fraction to below 50% occurred in 27 patients (10.5%) receiving aficamten and 2 patients (0.8%) receiving placebo [s1]. Serious adverse events occurred in 52 patients (20.2%) on aficamten and 38 (14.7%) on placebo [s1].

The word doing work in that sentence is "reversible" — the reductions recovered. But 10.5% of treated patients had one against 0.8% on placebo [s1], which is a mechanism-linked effect rather than background noise, and it implies monitoring rather than a prescribe-and-forget drug.

What the trial does and does not establish

The authors' conclusion is narrow and worth quoting in its shape: among patients with symptomatic non-obstructive HCM, aficamten resulted in a significantly greater change in exercise capacity and patient-reported health status than placebo at 36 weeks [s1].

That is a symptom and function result at 36 weeks. It is not a result about death, about heart failure hospitalisation, or about whether the underlying disease progresses more slowly. The trial ran up to 72 weeks, so longer-term data exist to be reported, but the primary comparisons were made at 36 [s1].

Nor does it say anything about obstructive HCM, where the clinical problem, the comparator drugs and the outcome measures are all different.

The trial was funded by Cytokinetics and registered as NCT06081894 [s1].

What to watch

The immediate question for regulators and guideline writers is whether a 3.0-point questionnaire difference and a 0.67 ml per kilogram per minute difference in peak oxygen uptake clear the bar for a condition with no approved therapy [s1]. Historically that bar sits lower when the alternative is nothing, and higher when a drug carries an ejection-fraction signal of the size seen here.

The second question is durability: whether the 36-week separation widens, holds or narrows out to 72 weeks, and what the ejection-fraction events look like over the longer exposure [s1].

This article describes trial results. It is not advice about any medicine, and nothing here should be used to start, stop or change treatment.

Sources

• Aficamten for Symptomatic Nonobstructive Hypertrophic Cardiomyopathy, New England Journal of Medicine, 28 August 2026
• Hot Lines revealed - the trials that will make the headlines at ESC Congress 2026, European Society of Cardiology, 23 July 2026