In one of two trials that substantially expand clinical evidence with myosin inhibitors in the treatment of hypertrophic cardiomyopathy (HCM), a next-in-class agent beat beta-blockers in first-line treatment for obstructive disease, while the other failed to show superiority of an established agent over placebo in patients with the non-obstructive form of the condition.

These phase 3 trials were presented today at the 2025 annual congress of the European Society of Cardiology. Results of both studies, MAPLE-HCM and ODYSSEY-HCM, were published simultaneously in the New England Journal of Medicine.

In the head-to-head MAPLE-HCM trial, aficamten became the first myosin inhibitor to demonstrate an efficacy advantage over beta-blockers, the traditional first-line therapy, in the setting of obstructive disease, according to Pablo Garcia-Pavia, MD, PhD, head of heart failure at the Hospital Universitario Puerta de Hierro de Majadahonda in Madrid, Spain.

The results of the head-to-head phase 3 trial challenge current guidelines, he added.

In the second trial, called ODYSSEY-HCM, mavacamten, the only approved myosin inhibitor, was tested in patients with non-obstructive hypertrophic cardiomyopathy, a subtype for which no approved therapies exist.

Primary Endpoints Missed

Despite favorable trends in ODYSSEY-HCM for mavacamten over placebo on both of the primary endpoints — (a) change from baseline in peak oxygen uptake and (b) quality of life as measured with the Kansas City Cardiomyopathy Questionnaire (KCCQ) — the predefined level of statistical significance was not met either.

In current European and US guidelines, mavacamten is recommended for patients with obstructive HCM who have not responded to beta-blockers, but its effectiveness relative to those drugs had never been tested. MAPLE-HCM is the first trial to compare a myosin inhibitor directly to beta-blocker therapy for first-line control of the condition. 

In the phase 3, double-blind, double-dummy trial, 175 patients with symptomatic HCM and a left ejection fraction of 60% or greater were randomly assigned at centers in North America, South America, Europe, the Middle East, and Asia. In the experimental group, a 5 mg dose of aficamten was administered daily with uptitration to 20 mg permitted. In the control arm, patients started on 50 mg of metoprolol with titration allowed to an upper limit of 200 mg. Patients in each group received a matching placebo.

The mean peak oxygen uptake from baseline, which was the primary endpoint, rose steadily in the aficamten arm but fell in the beta-blocker arm for an end-of-study difference favoring aficamten of 2.3 mL/kg/min (P < .001), according to Garcia-Pavia. A change of 1 mL/kg/min is generally considered clinically meaningful, he added.

Aficamten Beats BBs Across Major Endpoints

Consistent with this effect, the researchers reported a statistically and clinically significant advantage for aficamten over beta-blockers for most secondary endpoints, including improvement of at least one heart failure functional class (P < .001), improvement in KCCQ score (P = .002), an attenuated increase in NT-proBNP (P < .001), and favorable changes in hemodynamics, such as a reduced change in left ventricular outflow tract gradient after the Valsalva maneuver (P < .001).

Benefits were consistent across all subgroups evaluated, including those defined by age, sex, baseline NT-proBNP level, body mass index, and sarcomeric gene variant status.

The findings have the potential to change guidelines, according to Garcia-Pavia. Use of beta-blockers, although a traditional first-line therapy, is primarily supported by expert opinion. According to him, this new, controlled evidence of superiority for aficamten over beta-blockers warrants a change in practice if the drug receives regulatory approval. 

In ODYSSEY, 289 patients with symptomatic non-obstructive HCM were randomly assigned to mavacamten in a starting dose of 5 mg daily or placebo. A previous phase 2 study that linked the use of mavacamten with significant reductions in markers of wall stress provided the rationale for moving to a phase 3 trial, according to Desai.

After 48 weeks, the researchers observed a signal of potential benefit with mavacamten over placebo for the two primary endpoints of change in peak oxygen flow (P = .07) and the improvement in KCCQ (P = .06), but both fell short of statistical significance. 

Surrogate outcomes indicated the treatment was active in nonobstructive HCM. For example, levels of NT-proBNP fell in the mavacamten group but were unchanged in the placebo arm. An improvement of at least one level in heart function class was also slightly but nonsignificantly higher in the mavacamten arm (36.3% vs. 31.6%).

Mavacamten was reasonably well tolerated, but the proportion of patients with an interruption of treatment due to an adverse event was higher in the experimental arm (14.6%) than in the placebo group (5.2%), the researchers reported.

Desai said many hypotheses for why the study missed its primary endpoints are being explored. The adequacy of the power of the trial and the duration of treatment are being evaluated, and investigators are looking at whether treatment should be initiated at an earlier stage of disease. 

Non-obstructive HCM in Search of a Therapy

Despite the promise of mavacamten in nonobstructive HCM hinted at by prior, smaller studies, Carolyn Y. Ho, MD, medical director of the Cardiovascular Genetics Center at Brigham and Women’s Hospital in Boston, was not fully surprised by the lack of benefit in this HCM subtype. 

She called non-obstructive HCM “more complex and heterogeneous” than obstructive HCM and said myosin inhibitors may not hit targets meaningful to all or most patients with the condition. Exploratory analyses of the ODYSSEY data may yield more information about next strategies, she said. 

Ho, who was the invited discussant at the meeting for both trials, agreed the MAPLE-HCM data are compelling evidence and that “the sequence of drugs needs to change,” moving aficamten in front of beta-blockers for obstructive HCM.

The relative safety and efficacy of aficamten and mavacamten in obstructive HCM remain unknown. Garcia-Pavia listed several differences between these agents that might be clinically relevant. For example, the shorter half-life of aficamten might permit fast uptitration, but these drugs have yet to be compared. 

Garcia-Pavia reports financial relationships with Alexion, BioMarin, Bristol-Myers Squibb, Edgewise, Lexeo, Rocket, and Cytogenetics, which provided funding for MAPLE-HCM. Desai reports financial relationships with Edgewise, Viz AI, Tenaya, Cytokinetics, and Bristol-Myers Squibb, which provided funding for the ODYSSEY trial. Ho reports no relevant financial relationships.