Mavacamten Falls Short in Phase 3 Trial for Non-Obstructive HCM

Mavacamten (Camzyos) missed dual primary endpoints in the Phase 3 ODYSSEY-HCM trial assessing the cardiac myosin inhibitor against placebo for the treatment of adult patients with symptomatic New York Heart Association (NYHA) class II-III non-obstructive hypertrophic cardiomyopathy (HCM).1

Announced by Bristol Myers Squibb on April 14, 2025, mavacamten did not achieve statistical significance in changes from baseline to Week 48 in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-23 CSS) and peak oxygen consumption (pVO2), while reporting no new safety signals.

“The ODYSSEY-HCM trial, the largest and longest-duration study completed to date in patients with non-obstructive HCM, tested the hypothesis of whether a cardiac myosin inhibitor would improve measures of feel and function for these patients, showing clinical benefits similar to what we have seen in obstructive HCM,” said Milind Desai, MD, MBA, vice chair in the Heart, Vascular & Thoracic Institute and director of the HCM center at Cleveland Clinic. “The findings of this trial help us understand that obstructive HCM and non-obstructive HCM are two unique diseases.”1

Granted the green light by the US Food and Drug Administration (FDA) in April 2022, mavacamten marked the first and only approved cardiac myosin inhibitor targeted to boost functional capacity and symptoms in adults with symptomatic NYHA class II-III obstructive HCM. In the pivotal EXLORER-HCM trial, 37% of patients receiving mavacamten achieved pVO2 improvement by ≥1.5 mL/kg/min plus improvement in NYHA class by ≥1 or improvement of pVO2 by ≥3.0 mL/kg/min plus no worsening in NYHA class, compared with 17% on placebo (P =.0005).2

A further label update in June 2023 showed mavacamten significantly reduced the composite endpoint of guideline-based eligibility for septal reduction therapy (SRT) at Week 16 or the decision to proceed with SRT before or at Week 16 in patients with obstructive HCM in the Phase 3 VALOR-HCM trial.3

ODYSSEY-HCM, a Phase 3, randomized, double-blind, placebo-controlled trial, enrolled 580 adults with symptomatic non-obstructive HCM. With dual primary endpoints of change in KCCQ-23 CSS and pVO2 at Week 48, secondary endpoints also included change from baseline in ventilatory efficiency (VE/VCO2), NYHA functional class, N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, and the Hypertrophic Cardiomyopathy Symptom Questionnaire-Shortness of Breath (HCMSQ-SoB).

“These findings represent the first Phase 3 clinical trial data for a cardiac myosin inhibitor in non-obstructive HCM,” said Roland Chen, MD, senior vice president of drug development in immunology and cardiovascular medicines at Bristol Myers Squibb. “Importantly, these results do not change the favorable benefit-risk profile that has been consistently demonstrated across our [mavacamten] clinical trials in obstructive HCM and the robust body of real-world effectiveness and safety evidence showing its benefit for people living with obstructive HCM around the world.”

With an FDA review decision expected by September 2025, aficamten, a competitor cardiac myosin inhibitor developed by Cytokinetics, recently reported positive data for the treatment of non-obstructive HCM. Results from the open-label Phase 2 REDWOOD-HCM Trial, Cohort 4 found aficamten administration generally safe for non-obstructive HCM, with improvement in both NT-proBNP (56%; P <.001) and high-sensitivity cardiac troponin I (22%; P <.005) levels.4

Further analysis of FOREST-HCM presented at the American College of Cardiology (ACC) 2025 Annual Scientific Sessions found aficamten associated with favorable cardiac remodeling in obstructive HCM, including reductions in left ventricular mass, left atrial volume, and mitral regurgitation, while maintaining myocardial integrity.5

References

1. Bristol Myers Squibb Provides Update on Phase 3 ODYSSEY-HCM Trial. Bristol Myers Squibb. April 14, 2025. Accessed April 14, 2025. https://news.bms.com/news/corporate-financial/2025/Bristol-Myers-Squibb-Provides-Update-on-Phase-3-ODYSSEY-HCM-Trial/default.aspx.

2. Campbell P. FDA approves Mavacamten (Camzyos) for obstructive hypertrophic cardiomyopathy. HCP Live. April 28, 2022. Accessed April 14, 2025. https://www.hcplive.com/view/fda-approves-mavacamten-for-obstructive-hypertrophic-cardiomyopathy.

3. Campbell P. FDA approves updated label for Mavacamten in obstructive hypertrophic cardiomyopathy. HCP Live. June 16, 2023. Accessed April 14, 2025. https://www.hcplive.com/view/fda-approves-updated-label-for-mavacamten-in-obstructive-hypertrophic-cardiomyopathy.

4. Masri A, Sherrid MV, Abraham TP, et al. Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4. J Card Fail. 2024;30(11):1439-1448. doi:10.1016/j.cardfail.2024.02.020

5. Ahmad Masri M. Aficamten and cardiac remodeling in forest-HCM, with Ahmad Masri, MD, MS. HCP Live. April 1, 2025. Accessed April 14, 2025. https://www.hcplive.com/view/aficamten-and-cardiac-remodeling-in-forest-hcm-with-ahmad-masri-md-ms.