Mavacamten mends cardiac biomarkers in patients with HFpEF

Treatment with mavacamten results in improvements in cardiac biomarkers of wall stress and injury, as shown by reduced NT-proBNP and troponin, without sustained left ventricular ejection fraction (LVEF) reductions, according to the preliminary findings of the EMBARK-HFpEF trial.

“This is the first experience with cardiac myosin inhibition with HFpEF,” said lead author Dr Sanjiv Shah from Northwestern University Feinberg School of Medicine, Chicago, Illinois, US.

“Twenty-six-week treatment with mavacamten improved cardiac biomarkers of wall stress (NTproBNP) and injury (troponin),” he said. In addition, “[t]here was a good safety profile with no sustained LVEF reductions and no LVEF <30 percent.”

Shah and his team conducted EMBARK-HFpEF, a phase IIa, open-label, single-arm, multicentre trial, to examine the effects of myosin inhibition with mavacamten in patients with heart failure with preserved ejection fraction (HFpEF).

Those aged ≥50 years, LVEF ≥60 percent, and objective evidence of HF (ie, hospitalization for HF, elevated LV filling pressure, elevated historical NT-proBNP or BNP, elevated E/e’ ratio, or left atrial enlargement with chronic loop diuretic use) were eligible for inclusion.

“At screening, elevated NT-proBNP, LVEF ≥60 percent, and LV wall thickness ≥12 mm or elevated LV mass index were required,” Shah said. “Key exclusions were prior hypertrophic cardiomyopathy (HCM) or infiltrative cardiomyopathy, significant valve disease, and prior LVEF <45 percent.”

Eligible patients received mavacamten for 26 weeks, beginning at a dose of 2.5 mg and titrated up to 5 mg at week 14 based on LVEF and NT-proBNP. The investigators did week 34 “end-of-study labs” 8 weeks after treatment cessation. Changes in NT-proBNP and troponin were the primary efficacy endpoints, while safety outcomes included LVEF and adverse events.

Cardiac biomarkers

Thirty patients (mean age 75 years, 53 percent female, 10 percent Black) met the inclusion criteria and were enrolled across 14 sites in US and Canada. Their geometric mean NT-proBNP was 520 pg/mL and mean LVEF was 67 percent, with high-sensitivity troponin T (hsTnT) of 0.017 ng/ml and high-sensitivity troponin I (hsTnI) of 8.35 pg/ml. Many patients also had comorbidities.

Use of mavacamten resulted in a reduction in NT-proBNP by 26 percent (95 percent confidence interval [CI], ‒44 to ‒4), hsTnT by 13 percent (95 percent CI, ‒23 to ‒3), and hsTnI by 20 percent (95 percent CI, ‒32 to ‒6). [Shah S, et al, HFSA 2024]

After discontinuation of mavacamten, biomarker values returned to baseline levels. NYHA class improved in 42 percent of patients and remained unchanged in the rest. Diastolic function parameters also improved, while mean LVEF decreased by 3.2 percent during treatment.

Three patients (10 percent) had treatment interruption due to LVEF <50 percent (n=2) or >20 percent relative decrease from baseline (n=1; LVEF=58 percent). The lowest LVEF at interruption was 40 percent. All three patients had LVEF recovery, and one restarted and completed treatment.

No deaths occurred during the treatment-emergent period, and one patient had worsening HF, which was deemed unrelated to mavacamten treatment.

“These results support further investigation into myosin inhibition for HFpEF,” Shah said.

“And AURORA HFpEF phase II [randomized controlled trial] of a next-generation myosin cardiac inhibitor (ie, BMS-98645/MYK-224) is currently well underway to further validate and expand upon the EMBARK-HFpEF findings,” he added.