Omecamtiv mecarbil: a new cardiac myosin activator for the treatment of heart failure.

INTRODUCTION: Current available inotropic agents increase cardiac contractility, but are associated with myocardial ischemia, arrhythmias, and mortality. A novel selective cardiac myosin activator, omecamtiv mecarbil (CK-1827452/ AMG-423) is a small molecule that activates the sarcomere proteins directly, resulting in prolonged systolic ejection time and increased cardiac contractility. AREAS COVERED: This paper discusses the chemistry, pharmacokinetics, clinical efficacy and safety of omecamtiv mecarbil. Omecamtiv mecarbil represents a novel therapeutic approach to directly improve cardiac function and is therefore proposed as a potential new treatment of patients with systolic heart failure. The authors review results of previous studies investigating the effect of omecamtiv mecarbil in heart failure animal models, healthy volunteers, and patients with acute and chronic systolic heart failure. EXPERT OPINION: Results of phase I and phase II studies demonstrate that omecamtiv mecarbil is safe and well tolerated both as an intravenous and oral formulation. In healthy volunteers and chronic systolic heart failure patients, administration of omecamtiv mecarbil resulted in a concentration-dependent increase of left ventricular ejection time, ejection fraction, fractional shortening, and stroke volume. The first results of a double-blind, randomized, placebo-controlled phase IIb dose-finding study with the oral formulation of omecamtiv mecarbil demonstrated beneficial effects on cardiac function and N-terminal pro-brain natriuretic peptide levels. This study will provide essential dosing information for the requisite phase III trials which will investigate whether the beneficial effects of omecamtiv mecarbil translate into improved clinical outcomes.