How is Omecamtiv Mecarbil Metabolised?
The metabolism of Omecamtiv Mecarbil (OM) was extensively studied in early clinical trials, establishing key pharmacokinetic parameters. OM is effective at plasma concentrations of 200–1,000 ng/ml, but levels above 1,200 ng/ml may cause myocardial ischemic symptoms. As an oral drug, OM has a high bioavailability of about 93%, largely unaffected by the first-pass effect. OM’s pharmacokinetics remain stable despite renal function variations, hemodialysis, or mild to moderate liver impairment.
Omecamtiv Mecarbil (OM) is a novel small-molecule cardiac myosin activator developed to enhance cardiac contractility without disturbing calcium homeostasis. Unlike traditional inotropic agents that typically increase intracellular calcium levels, OM directly targets the sarcomeric myosin, the motor protein responsible for force generation in cardiac muscle cells. By selectively prolonging the duration of myosin-actin cross-bridge formation, OM enhances systolic function, increasing the force of cardiac muscle contraction without increasing myocardial oxygen consumption or intracellular calcium.
Early studies demonstrated its potential therapeutic effects in heart failure, distinguishing it from conventional therapies that often pose risks of arrhythmias and adverse calcium dynamics. Through unique mechanisms that do not involve altering calcium signaling pathways, OM offers a promising alternative for the treatment of systolic heart failure, potentially improving cardiac output with a reduced side effect profile.
What is the Mechanism of Action?
Recent research challenges the original theory that Omecamtiv Mecarbil (OM) solely acts as a myosin activator. Many possible mechanisms have been proposed:
- Studies suggest OM might activate actin instead of myosin, stabilizing the pre-powerstroke state and increasing force production (SEPTA model).
- OM may reduce ATP hydrolysis, influencing cardiac contraction by altering steps beyond phosphaterelease.
- OM could act as a Ca2+ sensitizer, enhancing cardiac performance by increasing cellular sensitivity to calcium.
Despite differing theories, OM remains a promising therapeutic target for heart failure.
What Evidences Support Omecamtiv Mecarbil Use?
The clinical trials of Omecamtiv Mecarbil (OM) span multiple phases and target different endpoints, providing insights into its efficacy and safety profile for heart failure management.
- ATOMIC-HF: This Phase IIb trial was double-blind, placebo-controlled, and randomized, assessing the effects of intravenous OM over 48 hours on dyspnea as the primary endpoint. The trial demonstrated positive results in secondary endpoints, including the safety and tolerability of three OM dose levels.
- COSMIC-HF: A Phase II, double-blind, placebo-controlled, randomized trial primarily evaluated the safety, tolerability, and pharmacokinetics of oral OM. The study showed improvements in changes in systolic ejection time, stroke volume, left ventricular dimensions, heart rate, and NT-proBNP levels, indicating positive effects on cardiac function.
- GALACTIC-HF: This large-scale Phase III trial followed a similar design, focusing on time to cardiovascular death or the first heart failure event as the primary endpoint. The results established OM’s potential to impact heart failure outcomes significantly.
- METEORIC-HF: Another Phase III trial, it primarily investigated changes in peak oxygen uptake during cardiopulmonary exercise testing. The trial missed both its primary and secondary endpoints, which included alterations in exercise workload, ventilatory efficiency, and daily activity units, suggesting limited effects of OM on exercise capacity
Are There Any Concerns with Omecamtiv Mecarbil Use?
- Insufficient diastolic time: OM prolongs systolic ejection time, reducing diastolic duration, potentially impairing heart reperfusion. Studies in rats revealed that OM did not increase cardiac output but decreased diastolic volume, suggesting adverse effects on diastolic function.
- Arrhythmia risk: OM may cause electromechanical alternans, shown as T wave alternans on ECGs, which are associated with arrhythmias. As OM acts as a Ca2+ sensitizer, it could increase the likelihood of tachyarrhythmias in heart failure patients.
- Skeletal muscle contraction: OM’s myosin activation may impact skeletal muscle functionality due to shared myosin isoforms. However, it appears to target cardiac muscle more specifically than skeletal muscle, mitigating some concerns.
- Off-target effects: OM might interact with unintended biological targets, causing toxicity or adverse effects. 5. Drug-drug interactions: OM’s interaction with heart failure medications like CYP3A4 substrates, digoxin, and amiodarone has been studied, showing slight increases in systemic exposure for drugs like rosuvastatin but overall good tolerance.
These concerns highlight the need for continued research to balance OM’s potential benefits with its risks in heart failure therapy.
