ORLANDO, Fla. — Omecamtiv mecarbil, a novel selective cardiac myosin inhibitor, may improve cardiac function in patients with heart failure and reduced ejection fraction (HFrEF), according to a phase 2 study presented at the American Heart Association Scientific Sessions.

“The ability to find an agent that improves cardiac performances is one of the ‘holy grails’ of heart failure management, and has been elusive to date,” said study investigator John R. Teerlink, MD, of the San Francisco Veterans Affairs Medical Center and the University of California, San Francisco,  at a press conference.

Previous studies have showed promise with intravenous formulations of selective cardiac myosin activators in patients with HF. To select an oral modified-release formulation and dose of omecamtiv mecarbil (Cytokinetics, San Francisco, CA), Dr Teerlink and colleagues conducted COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure).


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The primary objectives were to identify a dose and formulation and characterize the pharmacokinetics over 20 weeks of treatment.

During the study’s dose escalation phase, the researchers randomly assigned 1 cohort of patients with chronic HF and LVEF to 1 of 3 formulations of omecamtiv mecarbil 25 mg twice a day or placebo. In a second cohort, patients were randomly assigned to 1 of 3 formulations of omecamtiv mecarbil 50 mg twice a day or placebo. Each cohort had 40 patients, and treatment lasted for 7 days.

One formulation was selected based on pharmacokinetics, safety, and tolerability to be studied in the expansion phase in which patients were randomly assigned to receive the formulation at a dose of 25 mg; a dose of 25 mg escalatedto 50 mg based on pharmacokinetics; or placebo.

After 20 weeks of treatment, the researchers observed statistically significant improvements in prespecified secondary end point measures of cardiac function in the omecamtiv mecarbil group vs placebo.

Specifically, systolic ejection time (SET) increased (P<.001), stroke volume increased (P=.022), and heart rate decreased (P=.007). The researchers also noted decreases in left ventricular end-systolic (P=.003) and end-diastolic dimensions (P=.013), as well as reductions in left ventricular end-systolic (P=.005) and end-diastolic volumes (P=.021).

Additionally, N-terminal pro-brain natriuretic peptide (NT-proBNP) decreased (P=.007) in patients receiving the study drug, according to the data.

Results also showed that adverse events, including dyspnea, fatigue, and dizziness, were similar between patients who received omecamtiv mecarbil and those who received placebo. A similar observation was made for serious adverse events, as well as cardiac-specific adverse events.

However, a small but apparent increase in cardiac troponin I was found in the omecamtiv mecarbil group, which triggered 278 events, but it was determined that none of those events were ischemic or related to myocardial infarction, noted Dr Teerlink.

“These improvements in function and size were then also associated with a reduction in heart rate, which is unique among these types of agents. [Patients on the study drug] also had a significant reduction in NT-proBNP, so [results] did show across the board beneficial effects in multiple domains,” said Dr Teerlink.

“In conclusion, the pharmacokinetic-based dose titration reliably controlled patient exposure to omecamtiv mecarbil in the titration group,” Dr Teerlink said at a press conference.

Moreover, he underscored the improvements in SET, stroke volume, and LVEF, as well as decreases in cardiac dimensions and volumes and physiological parameters with omecamtiv mecarbil.

“The magnitude of cardiac effects observed in this trial may potentially translate into improvements in clinical outcomes,” he concluded.

Reference

  1. Teerlink JR, Felker M, McMurray JJ, et al; for the COSMIC-HF Investigators. LBCT.01 – Failure is Not an Option: New Drugs and Systems of Care. Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): Final Results from a Double-Blind, Randomized, Placebo-Controlled, Multicenter Study. Presented at the American Heart Association Scientific Sessions; November 7-11, 2015; Orlando, FL.