A Study of Mavacamten in Nonobstructive Hypertrophic Cardiomyopathy - ODYSSEY-HCM

Sep 24, 2025
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Author/Summarized by Author:
Kevin G. Tayon, MD
Summary Reviewer:
Fred M. Kusumoto, MD, FACC; Mays Ali, MD
Original Posted Date:
09/24/2025
References

Contribution To Literature:

Among patients with nonobstructive HCM in the ODYSSEY-HCM trial, mavacamten failed to significantly improve peak oxygen uptake or improve health status compared with placebo.

Study Design

ODYSSEY-HCM was a phase 3, multicenter (201 international centers), double-blind, clinical trial in which patients with nonobstructive hypertrophic cardiomyopathy (HCM) were randomized in a 1:1 fashion to receive mavacamten or placebo with sham dose adjustment, for 48 weeks. The starting dose of mavacamten was 5 mg with the possibility of decreasing the dose at weeks 5 and 9 or increasing the dose at weeks 12, 24, and 36 based on left ventricular ejection fraction (LVEF) (possible doses 1 mg, 2.5 mg, 5 mg, 10 mg or 15 mg). There was a sham dose adjustment in the placebo group.

  • Total number of enrollees: 580 (289 mavacamten, 291 placebo)
  • Duration of follow-up: 48 weeks
  • Mean patient age: 56 ± 15 years
  • Demographics: 46% female; mean BMI 28 ± 5 kg/m²; racial/ethnic distribution included White (~69%), Asian (~15%), Black (~4%), and Hispanic ethnicity (~14%).

Inclusion criteria:

  • Adults ≥18 years with a diagnosis of nonobstructive HCM (resting left ventricular outflow tract [LVOT] gradient <30 mm Hg and <50 mm Hg with provocation).
  • New York Heart Association (NYHA) class II–III symptoms.
  • LVEF ≥60% (core lab assessed).
  • Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) ≤85 (scale 0–100; higher scores indicate better health status).
  • Peak VO₂ testing feasible with respiratory exchange ratio ≥1.0.
  • NT-proBNP above the upper limit of normal, adjusted for race, BMI, and atrial arrhythmias.
  • Stable background HCM therapy (e.g., beta-blockers, calcium-channel blockers) with no medication changes within 2 weeks of randomization.

Exclusion criteria:

  • Resting or latent LVOT obstruction ≥30 mm Hg at rest or ≥50 mm Hg with provocation.
  • LVEF <60%.
  • Unstable cardiac disease or recent changes in therapy.
  • Initiation/discontinuation of new cardiac medications within 2 weeks of randomization.
  • Patients with heart failure with preserved ejection fraction mimicking HCM or significant comorbidities that would limit participation.
  • Mid-cavitary obstruction was not an exclusion criterion.

Principal Findings:

Primary outcomes: At 48 weeks, mavacamten did not significantly improve functional capacity or health status compared with placebo.

  • Change in peak oxygen uptake: 0.52 mL/kg/min (95% CI, 0.09 to 0.95) with mavacamten vs. 0.05 mL/kg/min (95% CI, –0.38 to 0.47) with placebo (between-group difference: p=0.07).
  • Change in KCCQ-CSS: 13.1 (95% CI, 10.7 to 15.5) with mavacamten vs. 10.4 (95% CI, 8.0 to 12.8) with placebo (between-group difference: p=0.06)

Secondary outcomes: While mavacamten lowered biomarkers and improved symptom scores modestly, these benefits were offset by a higher incidence of LV dysfunction and heart failure events, underscoring limited clinical benefit in nonobstructive HCM.

  • No significant benefit in ventilatory efficiency, with a change in VE/VCO₂ slope of 0.64 (95% CI, –1.84 to 0.55) for mavacamten vs. 0.16 (95% CI, –1.02 to 1.34) for placebo (between-group difference –0.81, 95% CI, –2.21 to 0.60).
  • NT-proBNP decreased more with mavacamten (geometric mean ratio 0.42 vs. 1.02 for placebo; between-group ratio 0.41, 95% CI 0.36-0.47).
  • Hypertrophic Cardiomyopathy Symptom Questionnaire shortness-of-breath domain score (0-18, with higher scores indicating more frequent shortness of breath) improved slightly more with mavacamten (–1.8 [95% CI, –2.2 to –1.4] vs. –1.1 [95% CI, –1.5 to –0.7]; between-group difference –0.7, [95% CI –1.2 to –0.2]).
  • 36.3% of patients improved by ≥1 NYHA class with mavacamten vs. 31.6% with placebo (difference 5.0%, 95% CI –2.3 to 12.2).
  • Serious adverse events occurred in 19.1% of patients with mavacamten vs. 15.2% with placebo.
  • LVEF <50% occurred in 21.5% with mavacamten vs. 1.7% with placebo. LVEF ≤30% occurred in 2.4% with mavacamten vs. 0% with placebo.
  • Permanent discontinuation occurred in 10.7% of mavacamten patients vs. 5.8% placebo.


Interpretation:

In this large, international trial of patients with symptomatic nonobstructive HCM, mavacamten did not achieve statistically significant improvements in peak oxygen uptake or health status compared with placebo. There was a trend towards improvement in both peak oxygen uptake (p=0.07) and KCCQ-CSS (p=0.06), though these did not reach statistical significance. While biomarkers such as NT-proBNP improved, treatment was also associated with a higher risk of reduced LVEF and heart failure events.

These findings suggest that unlike obstructive HCM, where myosin inhibition has clear benefits, the therapeutic role in nonobstructive HCM is less clear. Future studies may help identify subgroups who could benefit or explore alternative treatment strategies.

References:

Desai MY, Owens AT, Abraham T, et al. Mavacamten in symptomatic nonobstructive hypertrophic cardiomyopathy. N Engl J Med. Published online Aug. 30, 2025. doi:10.1056/NEJMoa2505927.

Editorial: Ambardekar AV. Expanding the role of myosin inhibition in hypertrophic cardiomyopathy — a tale of two conditions. N Engl J Med. Published online Aug. 30, 2025. doi:10.1056/NEJMe2512100.

Presented by Dr. Milind Y. Desai at the European Society of Cardiology Congress, Madrid, Spain, Aug. 30, 2025.


Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure

Keywords: ESC Congress, ESC25, Cardiomyopathy, Hypertrophic, Heart Failure


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