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There may be a future for cardiac myosin inhibitors in heart failure with preserved ejection fraction (HFpEF), according to the proof-of-concept EMBARK-HFpEF trial.

An established cardiac myosin inhibitor for hypertrophic cardiomyopathy (HCM), mavacamten (Camzyos) showed potential for reducing myocardial wall stress and cardiomyocyte injury in 30 HFpEF patients with a left ventricular ejection fraction (LVEF) in the upper range of normal or higher (60% and up), theoretically by improving diastolic function and myocardial energetics, said Sanjiv Shah, MD, of Northwestern University Feinberg School of Medicine in Chicago.

Suggesting some treatment effect with mavacamten, relevant cardiac biomarkers improved significantly in these patients 8 weeks after a 26-week course of the study drug:

• N-terminal pro-B-type natriuretic peptide (NTproBNP) by 26% (P=0.04)
• High-sensitivity troponin T by 13% (P=0.02)
• High-sensitivity troponin I by 20% (P=0.01)

Cardiac biomarker values arguably returned to baseline 8 weeks after mavacamten discontinuation, Shah reported during a late-breaking trial session held virtually by the Heart Failure Society of America (HFSA) and in .

The main safety concern with cardiac myosin inhibitors is their reduction of LVEF. Such a warning features prominently in the labeling of mavacamten, which was approved for obstructive HCM in 2022 but currently requires patients to participate in a risk evaluation and mitigation strategy that involves close monitoring of LVEF.

Among EMBARK-HFpEF participants, there was a significant 3.2-percentage point absolute LVEF reduction.

Although there were no deaths or drops in LVEF below 30%, six of the 30 patients discontinued mavacamten prematurely during the study. Another three had to interrupt mavacamten due to their LVEF dropping below 50% or more than 20% relative to baseline; LVEF recovered in all three patients, one of whom had opted to restart mavacamten.

The study authors acknowledged the small sample in their study. It was also possible that the study's open-label design affected the main results via changes in concomitant medications or placebo effects, they said.

Changes in diuretics and SGLT2 inhibitor use would be particularly relevant, according to HFSA's past president Biykem Bozkurt, MD, PhD, of Baylor College of Medicine in Houston, who was the designated study discussant for the virtual session.

"These results are promising but further definitive randomized studies are warranted," she said, pointing to key questions that remain to be answered, including how HFpEF patients should be selected for cardiac myosin inhibitor therapy, whether some subgroups benefit more than others, and how LVEF would be monitored in the high range.

Mavacamten had been FDA approved on the basis of the EXPLORER-HCM trial's finding that the drug resulted in better functional capacity and reduced left ventricular (LV) outflow tract gradients among patients with symptomatic obstructive HCM and LVEFs of at least 55% at baseline.

The choice to narrow EMBARK-HFpEF to patients with LVEFs over 60% occurred because it was believed that these patients "benefit less from neurohormonal therapies compared to patients with HFpEF with an LVEF between 50% and 59%, and these patients often have small LV volumes, increased passive LV stiffness, coronary microvascular dysfunction, and heightened LV end-systolic and arterial elastances, all of which may contribute to the pathogenesis of [heart failure]," Shah's group wrote.

The phase IIa open-label study was conducted in the U.S. and Canada. The study design included a screening period, a 26-week treatment period, and an 8-week washout post-treatment follow-up period. Patients received mavacamten starting at a dose of 2.5 mg, which was titrated up depending on LVEF and biomarker criteria.

Of 96 people screened, the investigators selected 30 patients with HFpEF and LVEFs of 60% or greater who had to meet criteria such as New York Heart Association (NYHA) class II or III symptoms and elevated NTproBNP. The cohort had a median age of 76 years, and 53.3% were women.

Ultimately, 40% of patients made it to the higher dose of 5.0 mg at week 14.

NYHA functional class improved in nearly 42% of patients, with accompanying favorable changes in echocardiographic parameters.

"Mavacamten treatment-induced reductions in E/e' ratio and LA [left atrial] volume at rest and peak exercise suggest that in HFpEF, [cardiac myosin inhibitors] have a lusitropic effect that reduces diastolic stress on cardiomyocytes, thus resulting in less stimulus for natriuretic peptide secretion by cardiomyocytes and less troponin release due to cardiomyocyte injury," the authors noted.

Notably, there were four patients who discontinued treatment prematurely due to adverse events such as new atrial flutter or new atrial fibrillation, acute heart failure and hypertensive crisis, and dizziness, all deemed unrelated to the study drug. Another two patients were lost to follow-up or withdrew from the study.

Bristol Myers Squibb is currently testing a next-generation cardiac myosin inhibitor for HFpEF in the .

Aficamten, another cardiac myosin inhibitor with a different pharmacological profile, is expected to be FDA approved for obstructive HCM following positive results in SEQUOIA-HCM.

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