Aficamten Is the First Drug to Benefit Patients With Nonobstructive HCM

Hypertrophic cardiomyopathy comes in two flavors, and for a long time only one of them had an approved treatment. The obstructive form — where the outflow tract is narrowed by the hypertrophied septum — gained mavacamten in 2022, a myosin inhibitor that reduces obstruction directly. The nonobstructive form, which affects roughly 30–40% of HCM patients, had nothing. No drug had ever demonstrated benefit in a randomized trial. That changed on August 28, 2026, when the ACACIA-HCM results were presented at the ESC Congress in Munich and published simultaneously in the New England Journal of Medicine.[1]

ACACIA-HCM enrolled 517 patients with symptomatic nonobstructive hypertrophic cardiomyopathy (LVOT gradient below 30 mmHg at rest and provocation) across multiple international sites. Patients were randomized to aficamten — a cardiac myosin inhibitor — or placebo for 36 weeks, on top of standard background therapy. The coprimary endpoints were change in peak oxygen uptake (peak VO₂) on cardiopulmonary exercise testing and change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS), a validated patient-reported symptom measure. Both were met. Peak VO₂ improved by 0.67 mL/kg/min more in the aficamten group than placebo (p=0.003), and KCCQ-CSS improved by 3.0 points more (p=0.021).[1]

The effect sizes are modest in absolute terms. A 0.67 mL/kg/min improvement in peak VO₂ is meaningful for a patient who is limited by exertional dyspnea — it represents an improvement in functional reserve — but it is not a dramatic reversal of exercise limitation. Similarly, a 3-point KCCQ improvement crosses the threshold for clinical significance (generally considered 5 points for minimal clinically important difference) only narrowly, though the trial was powered on the expectation that smaller differences matter in a chronically symptomatic population. The importance here is not magnitude; it is precedent. No drug has ever moved the needle in nonobstructive HCM in a placebo-controlled trial.

Clinical Context

Hypertrophic cardiomyopathy is the most common inherited cardiac condition, affecting roughly 1 in 500 adults. It is caused by mutations in sarcomere proteins — most commonly beta-myosin heavy chain and myosin-binding protein C — that cause the myocardium to hypercontract and hypertrophy. The obstructive phenotype produces a dynamic LVOT gradient that contributes directly to symptoms; the nonobstructive phenotype produces symptoms through impaired relaxation, elevated filling pressures, and microvascular ischemia, but without a gradient to target.[2]

Aficamten, like mavacamten, is a selective cardiac myosin inhibitor that reduces ATP hydrolysis, blunts myosin power stroke formation, and decreases the number of myosin heads actively engaged in cross-bridge cycling. In obstructive HCM, this mechanism reduces the outflow tract gradient. In nonobstructive HCM, the proposed mechanism is different: by reducing hypercontractility, aficamten may lower filling pressures, improve diastolic function, and reduce myocardial oxygen demand — ultimately translating to better exercise tolerance even without a gradient to abolish.[1]

The prior VALOR-HCM trial (2022, NEJM) established mavacamten for obstructive HCM, reducing LVOT gradient and improving symptoms in patients otherwise facing septal reduction therapy.[3] For nonobstructive HCM, beta-blockers and calcium channel blockers are used empirically, but evidence for their benefit is largely indirect. Disopyramide, which reduces contractility via sodium channel blockade, has been used, but it is not approved for HCM and carries QT prolongation risk. The ACACIA-HCM data now give clinicians a rationale for myosin inhibition in nonobstructive disease — and likely a pathway to FDA approval for aficamten in this indication.

Why It Matters Clinically

The echocardiographic safety data from ACACIA-HCM will be important to review. In obstructive HCM trials with myosin inhibitors, transient left ventricular systolic dysfunction has been observed — when the inhibitor reduces contractility too aggressively, LVEF can drop, requiring dose holds. The risk appears manageable with appropriate monitoring, but it argues for careful titration and LVEF surveillance in clinical practice.

ESC Congress 2026 was dominated by cardiology results that will reshape practice. The ACACIA-HCM trial is among the most significant: it opens an entirely new treatment frontier for a common inherited disease that has long had inadequate options for a third of its patients. For a condition diagnosed increasingly in young adults, the prospect of a drug that reliably reduces symptoms — even modestly — changes long-term management from watchful waiting to active intervention.

Limitations

The absolute effect sizes are small, raising questions about clinical meaningfulness in individual patients. KCCQ improvement of 3 points narrowly crosses the threshold for meaningful change. Whether peak VO₂ benefit translates to outcomes such as hospitalization or mortality is unknown. Longer-term safety data, particularly regarding LVEF surveillance requirements, are needed before widespread adoption.