Mavacamten did not significantly improve exercise capacity as assessed by peak oxygen uptake or improve patient-reported health status compared with placebo in patients with symptomatic nonobstructive hypertrophic cardiomyopathy (HCM), based on findings from the ODYSSEY-HCM trial presented at ESC Congress 2025 and simultaneously published in NEJM.

Researchers assigned 289 patients to receive mavacamten (starting at 5 mg per day and adjusted up to a maximum of 15 mg per day on the basis of LVEF) and 291 to receive placebo (sham dose adjusted) for 48 weeks. The mean age of patients was 56 years and 46% were women. The primary endpoints were change in peak oxygen from baseline to week 48 and improvements in the Kansas City Cardiomyopathy Questionnaire score (KCCQ-CSS).

Results showed the least-squares mean change in peak oxygen uptake from baseline to 48 weeks was 0.52 ml per kilogram of body weight per minute in the mavacamten group compared with 0.05 ml per kilogram per minute in the placebo group. The least-squares mean change in the KCCQ-CSS was 13.1 points in the mavacamten group compared with 10.4 points in the placebo group.

In other findings, researchers noted that reductions in ejection fraction and interruptions and discontinuations in the trial regimen occurred more frequently among patients assigned to mavacamten than those assigned to placebo. They also highlighted limitations, including the lack of diversity among patients, making the results less generalizable to other populations, as well as the short 48-week trial period.

"There are currently no approved medical therapies for patients with nonobstructive HCM, who experience a high burden of symptoms," said Principal Investigator Milind Y. Desai, MD, MBA, FACC. "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."

In addition to the primary trial results, two separate secondary, exploratory analyses were simultaneously published in JACC. "These analyses are, by design, exploratory. While they offer mechanistic insights, they do not reverse or prompt a reinterpretation of the main result of the trial," writes Harlan M. Krumholz, MD, SM, FACC, and Michelle M. Kittleson, MD, PhD, FACC, in a related editor's note. "Instead, they open important questions about the relationship between changes in cardiac structure or biomarkers and clinical benefit, and they do so in a way that may inform future trial design, endpoint selection, and translational science."

The first analysis assessed the associations between baseline biomarkers (NT-proBNP and high-sensitivity cardiac troponin I) with clinical, exercise, and echocardiographic characteristics. It also compared changes in these biomarkers from baseline to week 48 between the mavacamten and placebo groups. Results suggested that treatment with mavacamten for 48 weeks in nonobstructive HCM patients was associated with marked biomarker improvements compared with placebo.

"Whether these changes translate into longer-term adaptive remodeling and improvements in patient-reported health status, exercise capacity, and outcomes remain to be ascertained," said Desai, et al.

In the second analysis, researchers evaluated echocardiographic changes in nonobstructive HCM patients from baseline to week 48. Overall findings showed symptomatic nonobstructive HCM patients treated with mavacamten demonstrated directional improvements in markers of LV diastolic and LA function and modest regression in LV hypertrophy–related parameters. However, 1 in 5 demonstrated an LVEF <50%, which reversed following therapy interruption.

"The ODYSSEY-HCM trial and its secondary analyses remind us of both the promise and the limitations of biomarkers and imaging parameters as surrogate endpoints," say Krumholz and Kittleson. "These studies invite deeper inquiry into the mechanisms underlying [nonobstructive HCM] and the measurement of therapeutic response."