Mavacamten may Improve Cardiac Biomarkers in HFpEF Patients, Early trial Results Show Promise

The open-label trial focused on individuals with a left ventricular ejection fraction (LVEF) of 60% or higher, aiming to assess the drug's impact on cardiac function and related biomarkers. The findings published in JAMA Cardiology revealed that in such patients, mavacamten was linked to enhancements in biomarkers indicating cardiac wall stress and injury, while no sustained reductions in LVEF were noted.

Heart failure with preserved ejection fraction is a complex condition characterized by the heart's inability to pump effectively despite a seemingly normal ejection fraction. It affects a significant number of patients, often leading to symptoms of heart failure, such as shortness of breath and fatigue. Patients with HFpEF and an LVEF of 60% or higher face a scarcity of effective treatment options. Considering this, Sanjiv J. Shah, Northwestern University Feinberg School of Medicine, Chicago, Illinois, and colleagues aimed to investigate the impact of cardiac myosin inhibition using mavacamten in patients with heart failure with preserved ejection fraction and a left ventricular ejection fraction of 60% or higher.

For this purpose, the researchers conducted the EMBARK-HFpEF trial, a phase 2a, open-label, single-arm study across 20 sites in the US and Canada from November 6, 2020, to February 26, 2024. Eligible participants included patients with symptomatic HFpEF, defined as New York Heart Association functional class II or III, with an LVEF of 60% or greater, elevated N-terminal pro-B-type natriuretic peptide (NTproBNP), and left ventricular hypertrophy.

Participants received mavacamten for 26 weeks, starting at 2.5 mg, with the option to titrate up to 5 mg at week 14 based on specific LVEF and NTproBNP criteria. The primary efficacy endpoints were changes in NTproBNP and high-sensitivity troponin T (hsTnT) from baseline to week 26. Additional endpoints included changes in high-sensitivity troponin I (hsTnI), NYHA functional class, and echocardiographic parameters during rest and peak exercise. Safety endpoints focused on treatment-emergent adverse events and reductions in LVEF to below 30%.

Based on the study, the researchers reported the following findings:

• Thirty patients were enrolled and treated with mavacamten. The median patient age was 76 years, and 53.3% were female.
• From baseline to week 26, mavacamten was associated with reductions in NTproBNP (mean reduction, −26%), hsTnT (mean reduction, −13%), and hsTnI (mean reduction, −20%).
• Cardiac biomarker values returned toward baseline levels eight weeks after drug discontinuation.
• NYHA class improved in 41.7% of patients who had evaluable NYHA class data at the end of treatment, and improvements in echocardiographic markers of LV diastolic function were observed.
• Mean LVEF decreased by 3.2 absolute percentage points during treatment.
• Mavacamten was interrupted in 3 patients (10% of the study population) due to protocol prespecified criteria of LVEF less than 50% (n = 2) or a more than 20% relative decrease from baseline (n = 1; nadir LVEF, 58%), with LVEF recovery observed in all three patients.
• There were no deaths or instances of LVEF less than 30%; 1 patient had worsening heart failure deemed unrelated to the study drug.

"Early findings on cardiac myosin inhibition using mavacamten in patients with HFpEF and normal to supranormal ejection fraction are encouraging, but additional research through randomized clinical trials is needed," the researchers concluded.

Reference:

Shah SJ, Rigolli M, Javidialsaadi A, et al. Cardiac Myosin Inhibition in Heart Failure With Normal and Supranormal Ejection Fraction: Primary Results of the EMBARK-HFpEF Trial. JAMA Cardiol. Published online September 30, 2024. doi:10.1001/jamacardio.2024.3810