Highlight
– Mavacamten failed to achieve statistically significant improvements in peak oxygen uptake and symptom scores in symptomatic nonobstructive hypertrophic cardiomyopathy (HCM).
– The ODYSSEY-HCM trial was a large, international, double-blind, placebo-controlled phase 3 study.
– While mavacamten is approved for obstructive HCM, its benefit in nonobstructive HCM remains unconfirmed.
– Safety concerns included greater incidence of reduced ejection fraction and treatment interruptions with mavacamten.
Study Background and Disease Burden
Hypertrophic cardiomyopathy (HCM) is a genetically mediated myocardial disease characterized by unexplained left ventricular hypertrophy, affecting both obstructive and nonobstructive phenotypes. Obstructive HCM, marked by left ventricular outflow tract (LVOT) obstruction, has recognized symptomatic treatment options, including mavacamten, a novel cardiac myosin inhibitor that modulates hypercontractility and improves hemodynamic parameters. In contrast, nonobstructive HCM patients, who lack significant LVOT gradient, experience substantial morbidity from symptoms such as dyspnea and exercise intolerance, yet evidence-based therapies remain limited.
Given mavacamten’s mechanistic targeting of sarcomere hypercontractility, there has been keen interest in its efficacy in nonobstructive HCM; however, clinical effects have been uncertain. This gap in treatment options reflects an unmet need for interventions improving functional capacity and quality of life in this patient group.
Study Design
The ODYSSEY-HCM study was a phase 3, international, double-blind, placebo-controlled clinical trial designed to evaluate the impact of mavacamten on functional capacity and patient-reported outcomes in adults with symptomatic nonobstructive HCM. The trial enrolled 580 participants, randomly allocated in a 1:1 ratio to mavacamten or placebo.
Participants initially received mavacamten at 5 mg daily, with dose titration up to 15 mg based on left ventricular ejection fraction (LVEF) assessments to mitigate potential systolic dysfunction. The placebo group underwent sham dose adjustments to maintain blinding. The treatment period lasted 48 weeks.
Primary endpoints comprised change from baseline to week 48 in peak oxygen uptake (pVO2), an objective measure of functional capacity, and the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), a validated patient-reported outcome scale assessing health status and symptom burden.
Key Findings
A total of 289 patients received mavacamten, and 291 received placebo. The cohort had a mean age of 56±15 years, with women comprising 46% of participants.
Regarding primary outcomes, mavacamten treatment yielded a least-squares mean increase in peak oxygen uptake of 0.52 ml/kg/min (95% CI, 0.09 to 0.95), compared to 0.05 ml/kg/min (95% CI, -0.38 to 0.47) with placebo. The between-group difference of 0.47 ml/kg/min did not reach statistical significance (95% CI, -0.03 to 0.98; P=0.07).
In patient-reported health status, the mavacamten group improved by 13.1 points (95% CI, 10.7 to 15.5) in the KCCQ-CSS versus 10.4 points (95% CI, 8.0 to 12.8) in placebo, with a between-group difference of 2.7 points that fell short of significance (95% CI, -0.1 to 5.6; P=0.06).
Safety data revealed that reductions in LVEF were more frequent among mavacamten recipients and resulted in higher rates of temporary treatment interruption. The overall adverse event profile was consistent with previous data but necessitates careful monitoring of systolic function during therapy.
Expert Commentary
The ODYSSEY-HCM trial represents a milestone in evaluating targeted therapy in nonobstructive hypertrophic cardiomyopathy, though the neutral primary endpoint results suggest that mavacamten’s benefit may not extend to this phenotype. The approximately 0.5 ml/kg/min increase in peak oxygen uptake is below commonly accepted clinical improvement thresholds and did not achieve statistical significance, indicating limited functional enhancement.
Interestingly, both groups experienced improvements in symptom scores, which may reflect placebo effects or background therapy optimization. The numerical superiority in KCCQ-CSS with mavacamten, though not statistically conclusive, suggests some symptomatic relief warranting further exploration.
Mechanistically, mavacamten’s mode of action on actin-myosin interaction primarily mitigates hypercontractility-induced obstruction rather than diastolic dysfunction or microvascular ischemia, which dominate nonobstructive HCM pathophysiology. This biological plausibility supports the inconclusive efficacy observed.
Limitations include the single-blinded nature of dose adjustments, the reliance on peak oxygen uptake as a primary measure in a heterogeneous population, and the 48-week timeframe that may be insufficient to capture long-term outcomes. Further studies may explore alternate biomarkers or combination therapies.
Conclusion
Mavacamten, despite its established role in obstructive HCM, did not demonstrate statistically significant improvement in exercise capacity or symptom burden compared to placebo in adults with symptomatic nonobstructive hypertrophic cardiomyopathy in the ODYSSEY-HCM trial. Safety signals related to systolic function warrant ongoing vigilance. These findings underscore the complexity and unmet therapeutic challenges in nonobstructive HCM and emphasize the need for continued research to develop effective treatments tailored to this distinct phenotype.
References
Desai MY, Owens AT, Abraham T, Olivotto I, Garcia-Pavia P, Lopes RD, Elliott P, Fernandes F, Verheyen N, Maier L, Meder B, Azevedo O, Kitaoka H, Wolski K, Wang Q, Jaber W, Mitchell L, Myers J, Rano T, Gong Z, Zhong Y, Carter-Bonanza S, Florea V, Aronson R, Nissen SE; ODYSSEY-HCM Investigators. Mavacamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy. N Engl J Med. 2025 Sep 11;393(10):961-972. doi: 10.1056/NEJMoa2505927. Epub 2025 Aug 30. PMID: 40888717.
