Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil

Abstract

Heart failure continues to be a major global health problem with a pronounced impact on morbidity and mortality and very limited drug treatment options especially with regard to inotropic therapy. Omecamtiv mecarbil is a first-in-class cardiac myosin activator, which increases the proportion of myosin heads that are tightly bound to actin and creates a force-producing state that is not associated with cytosolic calcium accumulation. Phase I and phase II studies have shown that it is safe and well tolerated. It produces dose-dependent increases in systolic ejection time (SET), stroke volume (SV), left ventricular ejection fraction (LVEF), and fractional shortening. In the ATOMIC-AHF trial, intravenous (IV) omecamtiv mecarbil did not improve dyspnoea overall but may have improved it in a high-dose group of acute heart failure patients. It did, however, increase SET, decrease left ventricular end-systolic diameter, and was well tolerated. The COSMIC-HF trial showed that a pharmacokinetic-based dose-titration strategy of oral omecamtiv mecarbil improved cardiac function and reduced ventricular diameters compared to placebo and had a similar safety profile. It also significantly reduced plasma N-terminal-pro B-type natriuretic peptide compared with placebo. The GALACTIC-HF trial is now underway and will compare omecamtiv mecarbil with placebo when added to current heart failure standard treatment in patients with chronic heart failure and reduced LVEF. It is expected to be completed in January 2021. The ongoing range of preclinical and clinical research on omecamtiv mecarbil will further elucidate its full range of pharmacological effects and its clinical usefulness in heart failure.

Orthophosphate increases the efficiency of slow muscle-myosin isoform in the presence of omecamtiv mecarbil

“…A promising approach for systolic dysfunction treatment is the development of small molecules that, acting as cardiac myosin activators, are able to increase the contractility during the systole. Among them, omecamtiv mecarbil (OM) has been found to increase the systolic ejection fraction [2][3][4][5][6] and is currently in phase-three clinical trial 7 . OM acts on both α and β cardiac myosin heavy chain (MHC) isoforms and on the slow-skeletal MHC isoform 8 .…”

Update on heart failure management and future directions

“…However, patients with chronic HF showed positive results after OM treatment with increased cardiac function, decreased ventricular dimension, and decreased serum NT-proBNP level (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure [COSMIC-HF]) [112]. The Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF; NCT02929329) trial is currently underway to determine the clinical role of OM in comparison with placebo when added to current HF standard medication in patients with chronic HF [113].…”

Modeling Hypertrophic Cardiomyopathy: Mechanistic Insights and Pharmacological Intervention

“…Interestingly, the effects of OM are dependent on intracellular Ca 2+ levels (increasing contractility at low Ca 2+ concentrations, and decreasing it at higher concentrations [110]). Despite displaying limited effectiveness in R453C-β-MHC hPSC-CMs [81] (possibly due to the inherent immaturity of these cells), OM has shown encouraging clinical results, progressing to Phase III trials (ClinicalTrials.gov NCT02929329) that are due for completion in January 2021 [111].…”