Omecamtiv Mecarbil: A Promising New Drug in Systolic Heart Failure

Over 20 million people in the USA and Europe have chronic heart failure, leading to 4 million hospitalizations for heart failure per year.1,2 Heart failure accounts for 34% of all cardiovascular mortality.1 With a 5-year heart failure mortality rate as grim as 50% under current optimal therapy, additional medical strategies are clearly warranted.1,2 Current medical treatment of chronic heart failure centres around fluid and sodium restriction and blocking the neurohormonal pathways by beta-blockade, angiotensin-converting enzyme (ACE) (receptor) inhibition, and aldosterone antagonism.3 The acute management of decompensated heart failure includes intravenous diuretics, morphine, nitroglycerin, and oxygen. In addition, positive inotropes such as sympathomimetics and phosphodiesterase inhibitors may be required for the treatment of acute heart failure. Sympathomimetics raise intracellular calcium levels and phosphodiesterase inhibitors raise cAMP in order to enhance myocardial contractility. These drugs increase the velocity of contraction development (dP/dt). However, they also increase heart rate and myocardial oxygen consumption, and may induce ventricular and atrial arrhythmias. In addition, desensitization to inotropes occurs, requiring increasing doses. In clinical trials, inotropes failed to demonstrate survival benefit in exacerbation of chronic heart failure.4–6 More recently, levosimendan, a calcium sensitizer with inodilator properties, was developed.7 Unfortunately, levosimendan also failed to show survival benefit in recent phase III studies due to an increased number of adverse events, most notably hypotension and ventricular and atrial arrhythmias.8 The myosin activator omecamtiv mecarbil was developed to circumvent some of the major drawbacks of previous inotropic drugs.9 Rather than sensitizing the regulatory proteins to calcium, as levosimendan does, it directly activates cardiac myosin. Omecamtiv mecarbil was developed from a molecule that was identified by a high-throughput screening of the cardiac myosin adenosine triphosphatase (ATPase). It does not affect non-cardiac muscle myosin. In the cardiac myosin ATPase cycle, myosin hydrolyses ATP to ADP and phosphate (Pi).9 After the release of Pi, myosin-ADP binds strongly to actin accompanied by a force-producing power stroke. Myosin remains in this strongly bound and force-generating state as long as ADP remains bound to myosin. By accelerating the rate-limiting step in the cardiac myosin ATPase cycle, which is the release of Pi from myosin, omecamtiv mecarbil accelerates the transition rate from the weakly to the strongly bound state. Omecamtiv mecarbil does not affect the rate of ADP release. As a result, the number of myosin heads which exert force on actin increase (‘more hands on the rope’) and the systolic ejection time increases. Thus, the myocardial force output and energy efficiency increase. As the systolic ejection time increases, the diastolic period shortens. Potentially, this may compromise coronary perfusion and myocardial perfusion. In vitro, omecamtiv mecarbil was found to enhance myocyte contractility without affecting the calcium transient.9 Treatment of the myocytes with the beta-blocker carvedilol did not alter the effect of omecamtiv mecarbil.9 Subsequently, omecamtiv mecarbil was tested in two different dog models of systolic heart failure.10 In the first model, systolic heart failure was induced by chronic rapid ventricular pacing after the creation of a myocardial infarction by ligation of the left anterior descending artery. In the second model, systolic heart failure was induced by chronic rapid ventricular pacing after the induction of left ventricular hypertrophy by transaortic banding. Omecamtiv mecarbil was infused for 24 h, during which time invasive pressure measurements and echocardiography were performed, and blood samples were collected to calculate myocardial oxygen consumption. The findings were compared with those of dobutamine, which was studied in a similar model previously.11 Omecamtiv mecarbil increased stroke volume by 44% and increased cardiac output by 22%. Presumably in response to the increased stroke volume, heart rate decreased by 15%. In contrast to dobutamine, omecamtiv mecarbil did not affect dP/dt, but it increased systolic ejection time by 26%. Myocardial oxygen consumption, which increased under dobutamine, was not affected. Also, in contrast to dobutamine, no desensitization was observed. As pre-clinical data demonstrated that omecamtiv mecarbil augments left ventricular function without some of the major limitations of catecholamines, a phase I study was undertaken in order to establish the maximum tolerated dose and plasma concentration of the drug.12 In addition, echocardiography was performed. In four successive cohorts, each consisting of 8–10 subjects from a total group of 34 healthy male volunteers, omecamtiv mecarbil was given intravenously in three ascending doses, with placebo treatment randomized into the sequence. At doses >0.5 mg/kg/h (plasma concentration ~900 ng/mL) ischaemia-related side effects were noted in three (of eight) subjects: ST-segment depression, chest pain, and—in one subject—a minor troponin rise (without a rise in creatine kinase). Echocardiography demonstrated a dose-dependent increase in stroke volume, related to a marked increase in systolic ejection time. Additionally, atrial contractile function was found to be improved. Diastolic function and heart rate were not affected. Thus, the dose-limiting ischaemic effects seem to be caused by a dose-related shortening of the diastolic period, which is essential for myocardial perfusion. Subsequently, a phase II study was undertaken in patients with systolic heart failure New York Heart Association (NYHA) class I or II, with left ventricular dysfunction (the baseline left ventricular ejection fraction was 32%).13 Patients had to be in sinus rhythm and had to be on beta-blockers (98%) or ACE inhibitors (98%). Forty-five patients received a total of 151 infusions of omecamtiv mecarbil (and placebo) in ascending doses. The findings were similar to those in healthy volunteers. A dose-dependent increase in systolic ejection time was observed. At an omecamtiv mecarbil plasma concentration of 500 ng/mL, an increase in left ventricular ejection fraction of 10 units and cardiac output of 330 mL/min was observed. Heart rate decreased slightly. In two patients, who unintentionally reached a very high plasma concentration of omecamtiv mecarbil, myocardial ischaemia occurred. The first patient unintentionally received an overdose due to a miscalculation. At a plasma concentration of 1750 ng/mlL, chest pain, ST depression, and a minor troponin rise occurred. In the second patient, a similar event occurred at a plasma concentration of 1350 ng/mL, which was probably due to slow drug clearance due to obesity and renal insufficiency. No long-term negative effects were found at follow-up. As omecamtiv mecarbil was otherwise well tolerated at lower plasma concentrations in the other patients, the positive effects on cardiac output seem highly promising. A phase II study in patients with left ventricular dysfunction hospitalized for acute heart failure is underway [Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure (ATOMIC-AHF) ClinicalTrials.gov NCT01300013]. Depending on the results of this study, phase III trials with intravenous and oral omecamtiv mecarbil will need to determine the place of this promising new drug in the treatment of systolic heart failure. Conflict of interest: none declared.