The cardiac myosin inhibitor mavacamten failed to demonstrate significant clinical benefits in patients with symptomatic non-obstructive hypertrophic cardiomyopathy, according to results from the phase III ODYSSEY-HCM trial presented at the European Society of Cardiology meeting and simultaneously published in the New England Journal of Medicine.
The randomized, double-blind trial enrolled 580 patients across 201 sites in 22 countries, comparing mavacamten with placebo over 48 weeks. Despite the drug's established efficacy in obstructive hypertrophic cardiomyopathy, it showed no statistically significant improvement in the dual primary endpoints of patient-reported health status and peak oxygen consumption in the non-obstructive form of the disease.
Trial Design and Patient Population
The ODYSSEY-HCM study recruited symptomatic adult patients with non-obstructive hypertrophic cardiomyopathy, defined by specific hemodynamic criteria including peak left ventricular outflow tract gradient less than 30 mmHg at rest and less than 50 mmHg with provocation. Participants had New York Heart Association functional class II or III symptoms, Kansas City Cardiomyopathy Questionnaire scores of 85 or less, and left ventricular ejection fraction of 60% or greater.
The enrolled population had a mean age of 56 years, with 46% being women. Patients had lived with their diagnosis for an average of 10.3 years, and 43.3% had a family history of hypertrophic cardiomyopathy. Participants were randomized 1:1 to receive either mavacamten 5 mg with blinded dose titration based on left ventricular ejection fraction or placebo once daily.
Primary Endpoint Results
At 48 weeks, mavacamten failed to meet statistical significance for both primary endpoints. The Kansas City Cardiomyopathy Questionnaire Clinical Summary Score increased by 13.1 points in the mavacamten group compared to 10.4 points in the placebo group, yielding a between-group difference of 2.7 points (95% CI -0.08 to 5.6; p=0.056).
Peak oxygen consumption showed a least-squares mean increase of 0.52 ml/kg/min in the mavacamten group versus 0.05 ml/kg/min in the placebo group, resulting in a between-group difference of 0.47 ml/kg/min (95% CI -0.03 to 0.98; p=0.066). Both groups demonstrated some symptom improvement, which investigators attributed to enhanced background care during the study period.
Safety Profile and Adverse Events
Safety analysis revealed notable differences between treatment groups. Treatment-emergent adverse events leading to study drug interruption occurred in 14.6% of mavacamten patients compared to 5.2% of placebo patients. Permanent treatment discontinuation rates were 5.2% and 2.8%, respectively.
A significant safety signal emerged regarding left ventricular ejection fraction reduction below 50%, occurring in 21.5% of mavacamten patients versus only 1.7% of placebo patients. However, all but three patients recovered to ejection fractions of 50% or greater after study drug interruption.
Clinical Implications and Disease Understanding
"While this drug was not associated with significant improvements in quality of life or peak oxygen consumption, these results help make it clear that obstructive hypertrophic cardiomyopathy and non-obstructive cardiomyopathy are two unique diseases," said principal investigator Dr. Milind Desai from Cleveland Clinic.
The findings underscore fundamental differences between the two forms of hypertrophic cardiomyopathy. In obstructive disease, thickened septal wall blocks blood flow from the left ventricle to the aorta. Non-obstructive disease involves thickening in other cardiac regions without significant outflow obstruction, affecting approximately one-third of hypertrophic cardiomyopathy patients in the United States.
Dr. Desai noted that non-obstructive patients typically experience more severe symptoms due to different patterns of wall thickening. "Therefore it is not surprising that treatments may not work uniformly. These findings should push researchers to explore new targeted strategies for this patient group."
Current Treatment Landscape
Currently, no approved medical therapies exist specifically for non-obstructive hypertrophic cardiomyopathy patients, who experience significant symptom burden including chest pain, palpitations, shortness of breath, fatigue, and syncope. The condition represents the most common cause of sudden cardiac death in individuals under age 30, though most patients have low risk for this complication.
Mavacamten gained worldwide approval for symptomatic obstructive hypertrophic cardiomyopathy following the successful Cleveland Clinic-led VALOR-HCM trial, which demonstrated reduced need for surgical intervention. The drug works by reducing excessive heart muscle contraction and decreasing cardiac stiffness.
Future Research Directions
Investigators are conducting additional analyses to better understand mavacamten's effects in non-obstructive disease and identify potential patient subgroups that might benefit from treatment. Dr. Desai indicated that further subgroup analyses are in progress and will be presented at the ESC Congress.
The trial was funded by MyoKardia, Inc., a wholly owned subsidiary of Bristol Myers Squibb, and coordinated by Cleveland Clinic Coordinating Center for Clinical Research. The results highlight the need for continued research into targeted therapeutic strategies for this distinct patient population with significant unmet medical needs.
