Study title: ODYSSEY-HCM: Mavacamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy

Presented at Congress: ESC Congress 2025 (Hot Line 2)

Link: https://esc365.escardio.org/presentation/312151

Prepared by: Dr. Mehmet Murat Yiğitbaşı

Introduction
Nonobstructive hypertrophic cardiomyopathy (nHCM) is an HCM phenotype characterized by symptoms and functional limitation in the absence of a significant left ventricular outflow tract gradient. The cardiac myosin inhibitor mavacamten improves symptoms and hemodynamics in obstructive HCM; however, its clinical efficacy in nHCM has remained uncertain.

Objective
To evaluate whether mavacamten, compared with placebo, improves health status—assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ-23) Clinical Summary Score—and exercise capacity—assessed by peak oxygen uptake (pVO²)—at Week 48 in adults with symptomatic nHCM.

Methods
This was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial. A total of 580 patients were randomized 1:1 to mavacamten (starting dose 5 mg/day; blinded titration up to 15 mg/day based on left ventricular ejection fraction [LVEF]) or placebo for 48 weeks. Dual primary endpoints were the changes from baseline to Week 48 in KCCQ-23 Clinical Summary Score and pVO². Secondary endpoints were evaluated under a hierarchical statistical testing plan.

Results
Overall, 580 patients were randomized (mavacamten n=289; placebo n=291; mean age ~56 years; 46% women). At week 48, mavacamten did not demonstrate superiority over placebo for either primary endpoint: the between-group difference in pVO² was approximately 0.47 mL/kg/min (P?0.07), and in KCCQ-23 Clinical Summary Score approximately 2.7 points (P?0.06). Consequently, hierarchical testing of secondary endpoints was not pursued. Exploratory echocardiographic analyses suggested directional improvements in left ventricular diastolic and left atrial function markers, along with modest regression in parameters associated with left ventricular hypertrophy. Regarding safety, about one in five patients experienced a reduction in LVEF to <50%; in most cases, values returned toward baseline after treatment interruption.

Conclusion
In symptomatic nHCM, mavacamten did not significantly improve health status or exercise capacity versus placebo at 48 weeks. While exploratory signals suggested structural and functional benefits, these did not translate into confirmed clinical improvement.

Commentary
The findings underscore potential differences in treatment response between obstructive and nonobstructive HCM phenotypes. Future nHCM research may focus on phenotypic enrichment strategies, biomarker-guided patient selection, and alternative endpoints (e.g., exercise duration, objective daily activity metrics). Given the risk of LVEF decline, close echocardiographic monitoring is advisable during mavacamten therapy.