Two late-breaking clinical trials presented at the ESC Congress 2025 and published in The New England Journal of Medicine have explored the efficacy of cardiac myosin inhibitors for the treatment of hypertrophic cardiomyopathy (HCM). First, although the cardiac myosin inhibitor mavacamten has been approved to treat symptomatic obstructive HCM, the ODYSSEY-HCM trial investigators now report that the drug does not improve peak oxygen uptake or reduce symptoms compared with placebo in patients with non-obstructive HCM. Moreover, the investigators in the MAPLE-HCM trial show that in patients with obstructive HCM, aficamten is superior to the β-blocker metoprolol in increasing peak oxygen uptake and reducing symptoms.

Non-obstructive HCM is characterized by left ventricular hypertrophy without an obstruction in the left ventricular outflow tract (LVOT). The treatment of affected patients remains a major unmet need, given the lack of approved therapies. Investigators in the ODYSSEY-HCM trial sought to assess whether mavacamten could improve functional capacity and patient-reported health status in patients with symptomatic, non-obstructive HCM.

Credit: V. Summersby/Springer Nature Limited

In this phase III, double-blind, multicentre, randomized, placebo-controlled trial, a total of 580 adult patients (mean age 56 years; 46% women) with non-obstructive HCM were randomly assigned to mavacamten treatment or placebo. From baseline to week 48, the difference between groups in peak oxygen uptake was not significant (0.47 ml/kg/min, 95% CI −0.03 to 0.98, P = 0.07). Furthermore, the between-group difference in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) was also not significant (2.7 points, 95% CI −0.1 to 5.6, P = 0.06). Given that the symptoms experienced by patients with non-obstructive HCM are related to diastolic dysfunction and impaired cellular energetics, the investigators propose that cardiac myosin inhibitors might have a limited effect in improving haemodynamics or energy efficiency. A secondary analysis of the ODYSSEY-HCM data published in the Journal of the American College of Cardiology revealed that mavacamten was associated with improvements in cardiac biomarkers and favourable cardiac remodelling compared with placebo; these findings warrant further investigation into the efficacy of mavacamten in this patient cohort.

In the multicentre, double-blind MAPLE-HCM trial, 175 adults with symptomatic, obstructive HCM were randomly assigned to receive aficamten plus placebo or metoprolol plus placebo. At 24 weeks, peak oxygen uptake changed by 1.1 ml/kg/min in the aficamten group compared with −1.2 ml/kg/min in the metoprolol group (P < 0.001). Furthermore, aficamten treatment was associated with greater improvements in NYHA class, KCCQ-CSS and LVOT gradient compared with metoprolol treatment. These findings have widespread clinical implications, given that myosin inhibitor therapy is currently recommended only as a second-line treatment for patients with persistent symptoms while receiving β-blocker therapy.