Omecamtiv mecarbil (INN), is a cardiac-specific myosin activator, being studied for a potential role in the treatment of left ventricular systolic heart failure.
Routes of administration-Intravenous infusion or oral tablet.
Systolic heart failure involves a loss of effective actin-myosin cross bridges in the myocytes of the left ventricle, which leads to a decreased ability of the heart to move blood through the body.
Systolic heart failure causes peripheral edema, which the sympathetic nervous system tries to correct by overstimulating the cardiac myocytes, leading to left ventricular hypertrophy, another characteristic of chronic heart failure.
Current inotropic therapies work by increasing the force of cardiac contraction: calcium conduction or modulating adrenoreceptors.
Inotropic therapies are limited by adverse events, including arrhythmias related to increased myocardial oxygen consumption, desensitization of adrenergic receptors, and altering intracellular calcium levels.
Inotropes are also thought to be associated with worse prognosis.
Cardiac myocytes contract through a cross-bridge cycle between the myofilaments, actin and myosin.
Chemical energy in the form of ATP is converted into mechanical energy which allows myosin binds to actin and produce a power stroke resulting in sarcomere shortening/contraction.
Omecamtiv mecarbil targets and activates myocardial ATPase and improves energy utilization, enhancing effective myosin cross-bridge formation and duration, while the velocity of contraction remains the same.
Omecamtiv mecarbil increases the rate of phosphate release from myosin by stabilizing the pre-powerstroke and the phosphate release states.
It accelerates the rate-determining step of the cross-bridge cycle, which is the transition of the actin-myosin complex from the weakly bound to the strongly bound state.
When myosin is bound to actin, it stays bound longer in the presence of omecamtiv mecarbil.
The overall clinical result of omecamtiv mecarbil is an increase in left ventricular systolic ejection time and ejection fraction, a slight decrease in heart rate while myocardial oxygen consumption is unaffected.
The increased cardiac output is independent of intracellular calcium and cAMP levels.
It improves systolic function by increasing the systolic ejection duration and stroke volume, without consuming more ATP energy, oxygen or altering intracellular calcium levels causing an overall improvement in cardiac efficiency.
There is a direct linear relationship between dose and systolic ejection time.
Maximum tolerated dose is an infusion of 0.5 mg/kg/h.
Adverse effects, such as ischemia are seen at doses beyond this level, due to extreme lengthening of systolic ejection time.
It effectively relieves symptoms and enhances the quality of life of systolic heart failure patients.
While the drug reduces the risk of hospitalization or other urgent care for heart failure by 8% in high-risk patients in the Phase III clinical trial GALACTIC-HF, patients receiving the drug did not live any longer, nor did they improve exercise intolerance in heart failure patients as seen in the Phase III METEORIC trial.
Omecamtiv mecarbil actually inhibits myosin by enhancing the duty ratio, increasing calcium sensitivity and slowing force development.