Omecamtiv mecarbil

Mechanism of action

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 to strongly bind to actin and produce a power stroke resulting in sarcomere shortening/contraction. Omecamtiv mecarbil specifically targets and activates myocardial ATPase and improves energy utilization. This enhances effective myosin cross-bridge formation and duration, while the velocity of contraction remains the same. Specifically, it increases the rate of phosphate release from myosin by stabilizing the pre-powerstroke and the phosphate release states, thereby accelerating 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. The combination of increased and prolonged cross-bridge formation prolongs myocardial contraction. Thus, the overall clinical result of omecamtiv mecarbil is an increase in left ventricular systolic ejection time and ejection fraction.

There is a slight decrease in heart rate while myocardial oxygen consumption is unaffected. The increased cardiac output is independent of intracellular calcium and cAMP levels. Thus omecamtiv mecarbil 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.

Clinical trials

Experimental studies on rats and dogs, proved the efficacy and mechanism of action of omecamtiv mecarbil. The dose-dependent effects persisted throughout the entire trial, suggesting that desensitization does not occur. The maximum tolerated dose was observed to be an infusion of 0.5 mg/kg/h. Adverse effects, such as ischemia, were only seen at doses beyond this level, due to extreme lengthening of systolic ejection time.

Omecamtiv mecarbil effectively relieves symptoms and enhances the quality of life of systolic heart failure patients. It improved cardiac performance in short-term studies; The drug also did not improve exercise intolerance in heart failure patients in the Phase III METEORIC trial. The METEORIC-HF randomized clinical trial found that omecamtiv mecarbil does not significantly improve exercise capacity.

Myosin inhibition

Research groups found that omecamtiv mecarbil actually inhibits myosin by enhancing the duty ratio, increasing calcium sensitivity and slowing force development. It may still activate muscle as a whole however despite suppressing the working stroke of myosin.

History

The US Food and Drug Administration (FDA) granted, in May 2020, a fast-track designation for omecamtiv mecarbil.

References

References

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8. (August 2017). "Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil". Nature Communications.
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10. (June 2018). "Controlling load-dependent kinetics of β-cardiac myosin at the single-molecule level". Nature Structural & Molecular Biology.
11. (September 2018). "Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke". Nature Communications.
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13. (August 2011). "The effects of 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.
14. (15 February 2022). "Cytokinetics' latest PhIII study of omecamtiv flops — kicking out another leg from under the market case it was building". Endpoints News.
15. (July 2022). "Effect of Omecamtiv Mecarbil on Exercise Capacity in Chronic Heart Failure With Reduced Ejection Fraction: The METEORIC-HF Randomized Clinical Trial". JAMA.
16. (March 2017). "Omecamtiv Mecarbil Enhances the Duty Ratio of Human β-Cardiac Myosin Resulting in Increased Calcium Sensitivity and Slowed Force Development in Cardiac Muscle". The Journal of Biological Chemistry.
17. (September 2018). "Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke". Nature Communications.
18. (8 May 2020). "FDA Grants Fast Track Designation For Omecamtiv Mecarbil In Heart Failure". [[Amgen]].