Cytokinetics has announced the initiation of COMET-HF (Confirmation of Omecamtiv Mecarbil Efficacy Trial in Heart Failure), a Phase 3 clinical trial evaluating omecamtiv mecarbil in patients with symptomatic heart failure (HF) with severely reduced ejection fraction. This multinational, multi-center, double-blind, randomized, placebo-controlled trial is designed to assess the efficacy and safety of the drug in this high-risk population with limited treatment options.
Trial Design and Endpoints
The COMET-HF trial aims to enroll approximately 1,800 patients who will be randomized 1:1 to receive either omecamtiv mecarbil or placebo. Patients must have symptomatic heart failure with a left ventricular ejection fraction (LVEF) of less than 30%, an NT-proBNP level of ≥1,000 pg/mL, and a heart failure event within the preceding six months. The primary endpoint is the time to the first event in a composite of cardiovascular death, first heart failure event, left ventricular assist device (LVAD) implantation or cardiac transplantation, or stroke. Secondary endpoints include the individual components of the primary endpoint, as well as a composite of cardiovascular death, LVAD implantation/cardiac transplantation, or stroke.
Eligible patients undergo a two-week run-in period to assess tolerance and adherence to omecamtiv mecarbil. Following the run-in, patients enter a two-week washout period before randomization to omecamtiv mecarbil (up to 50 mg twice daily, adjusted based on plasma concentration during the run-in period) or placebo. Treatment continues until at least 850 primary composite endpoint events have occurred.
Rationale for Omecamtiv Mecarbil
Omecamtiv mecarbil is an investigational, selective cardiac myosin activator designed to directly target the contractile mechanisms of the heart. It binds to cardiac myosin, increasing the number of myosin heads interacting with actin during systole, thereby augmenting contractility without increasing intracellular myocyte calcium concentrations or myocardial oxygen consumption.
Previous Phase 3 data from the GALACTIC-HF trial demonstrated a statistically significant reduction in the risk of cardiovascular death or heart failure events with omecamtiv mecarbil compared to placebo. A pre-specified subgroup analysis of over 4,500 patients with severely reduced ejection fraction (<30%) showed a greater treatment effect. However, no reduction in the secondary endpoint of time to cardiovascular death was observed. The rates of myocardial ischemia, ventricular arrhythmias, and death were similar between treatment and placebo groups.
Unmet Need in Heart Failure
Heart failure affects over 64 million people worldwide, with approximately half experiencing reduced left ventricular function. It is a leading cause of hospitalization and readmission, particularly among older adults. By 2029, an estimated 2.8 million people in the U.S. will have heart failure with severely reduced ejection fraction, highlighting the urgent need for new and effective treatments. Patients with high-risk heart failure and severely reduced ejection fraction account for approximately 60% of all heart failure hospitalizations, with a high rate of re-hospitalization within a year.
Expert Commentary
"We are pleased to be starting COMET-HF to evaluate omecamtiv mecarbil in patients with severe heart failure who have limited treatment options and remain at high risk after failing guideline-directed medical therapy," said Stuart Kupfer, M.D., Senior Vice President, Chief Medical Officer at Cytokinetics. Michael Felker, M.D., M.H.S, Professor of Medicine and Cardiovascular Research Therapeutic Area Lead at DCRI, added, "These patients are at high risk of heart failure hospitalization and death despite existing therapies, highlighting the critical need for new treatments."
