Madrid, Spain – 30 August 2025. Mavacamten treatment at 48 weeks was not associated with significant improvements in patient-reported health status or peak oxygen consumption compared with placebo in patients with symptomatic nonobstructive hypertrophic cardiomyopathy, according to late-breaking research presented in a Hot Line session today at ESC Congress 2025 and simultaneously published in New England Journal of Medicine.1

Nonobstructive hypertrophic cardiomyopathy (HCM) is a condition where the heart muscle thickens, but this thickening does not significantly block blood flow out of the heart. In contrast, in obstructive HCM, the thickened part of the heart muscle blocks blood flow. Both forms of HCM can worsen over time, causing symptoms like shortness of breath, fatigue and chest pain. HCM can lead to heart failure, arrhythmias and also rarely, sudden cardiac death.

Principal Investigator, Professor Milind Desai from Cleveland Clinic, Cleveland, USA, explained why the ODYSSEY-HCM trial was carried out: “There are currently no approved medical therapies for patients with nonobstructive HCM, who experience a high burden of symptoms. The cardiac myosin inhibitor, mavacamten, is approved for the treatment of symptomatic obstructive HCM and results from a small phase II study suggested improvements in biomarkers in nonobstructive HCM.2 We conducted the phase III ODYSSEY-HCM trial to assess whether mavacamten improved patient-reported health status and functional capacity in patients with symptomatic nonobstructive HCM.”

This randomised, double-blind, parallel-group phase III trial was conducted at 201 sites in 22 countries. Symptomatic adult patients with nonobstructive HCM were enrolled with key inclusion including: peak left ventricular outflow tract gradient <30 mmHg at rest and <50 mmHg with provocation, New York Heart Association (NYHA) functional class II or III, Kansas City Cardiomyopathy Questionnaire 23-item Clinical Summary Score (KCCQ-23 CSS) ≤85, left ventricular ejection fraction (LVEF) ≥60% and elevated biomarkers. Patients were randomised 1:1 to receive mavacamten 5 mg (with blinded dose titration as needed based on LVEF) or placebo once daily for 48 weeks. The two primary endpoints were the change from baseline to week 48 in patient-reported health status (measured by the KCCQ-23 CSS) and in peak oxygen consumption.

Among 580 patients randomised, the mean age was 56 years and 46% were women. The average time from the initial diagnosis to randomisation was 10.3 years and 43.3% of patients had a family history of HCM.

There were no significant differences in the dual primary endpoints with mavacamten vs. placebo at week 48. KCCQ-23 CSS increased by 13.1 (95% confidence interval [CI] 10.7 to 15.5) in the mavacamten group and 10.4 (95% CI 8.0 to 12.8) in the placebo group (between-group difference 2.7; 95% CI –0.08 to 5.6; p=0.056). The least-squares mean increase in peak oxygen consumption was 0.52 (95% CI 0.09 to 0.95) in the mavacamten group and 0.05 (95% CI –0.38 to 0.47) in the placebo group (between group-difference 0.47 ml/kg/min; 95% CI –0.03 to 0.98; p=0.066). The secondary endpoints did not meet the requirement for further statistical testing.

Regarding safety, treatment-emergent adverse events resulting in study drug interruption or permanent treatment discontinuation occurred in 14.6% and 5.2% of patients, respectively, with mavacamten and 5.2% and 2.8% of patients, respectively, with placebo. LVEF <50% occurred in 21.5% of patients in the mavacamten group vs. 1.7% of patients in the placebo group, and all but 3 patients returned to LVEF ≥50% after study drug interruption.

Professor Desai concluded: “In this large trial including patients with longstanding nonobstructive HCM, significant improvements in patient-reported health status or peak oxygen consumption were not observed with mavacamten. Further analyses are being conducted, including two that will be presented at ESC Congress 2025 on Sunday,3,4 to understand more about the effects of mavacamten in nonobstructive HCM and whether any patient subgroups may benefit.”

ENDS