In phase I and II trials, a cardiac myosin activator safely improved systolic function without increasing myocardial oxygen consumption.

It seems intuitive that agents that improve cardiac contractility would help patients with systolic dysfunction. Unfortunately, existing agents — including dobutamine (an adrenergic stimulant), milrinone (a phosphodiesterase inhibitor), and levosimendan (a calcium sensitizer unavailable in the U.S.) — are associated with morbidity and mortality that outweigh their benefits. Two manufacturer-sponsored studies now provide early insights into the possible use of omecamtiv mecarbil, a novel selective cardiac myosin activator that, in animal models, increases cardiac contractility without increasing intracellular calcium.


In a phase I study, 34 healthy volunteers received a 6-hour, double-blind, intravenous infusion of omecamtiv or placebo once weekly in escalating doses for 4 weeks. The maximum dose tolerated by ?8 participants was 0.5 mg/kg/hour. At this dose, omecamtiv produced significant increases in systolic ejection time (85 msec), left ventricular (LV) ejection fraction (7%), and LV fractional shortening (8%) that correlated strongly with plasma concentrations of omecamtiv. Five patients withdrew because of adverse events, three of whom had signs or symptoms suggesting myocardial ischemia at high omecamtiv concentrations. One of these had an elevation in troponin level, ST-segment depression, and chest pain without subsequent magnetic resonance imaging evidence of infarction.

In a phase II, double-blind, placebo-controlled, crossover study, investigators randomized 45 patients (87% men) with clinical heart failure and systolic dysfunction (64% with an ischemic etiology) to varying doses and durations of omecamtiv infusion. Omecamtiv resulted in concentration-dependent increases in systolic ejection time (?80 msec) and LV stroke volume (?9.7 mL) and slight reductions in heart rate (?2.7 bpm). Two patients experienced signs and symptoms of myocardial ischemia at relatively high plasma omecamtiv concentrations. One of these, who had inadvertently received an overdose, experienced a non-fatal non-ST-segment elevation myocardial infarction.


Citation(s):

Teerlink JR et al. Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: A first-in-man study. Lancet 2011 Aug 20; 378:667.

Cleland JGF et al. The effects on the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: A double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial. Lancet 2011 Aug 20; 378:676.