Oral heart failure medication proves safe, effective in phase 2 trial

Patients with chronic heart failure who received omecantiv mecarbil achieved plasma concentrations associated with improved cardiac function and decreased ventricular function, according to a randomized trial.

Lead researcher John R. Teerlink, MD, of the University of California San Francisco and the San Francisco Veterans Affairs Medical Center, and colleagues published their results online Nov. 30 in The Lancet.

Amgen, which manufactures omecantiv mecarbil along with Cytokinetics, funded the study. The FDA has not approved omecantiv mecarbil, which is an oral, novel cardiac myosin activator.

In this phase 2 study, known as COSMIC-HF, the researchers enrolled 448 patients at 87 sites in 13 countries from March 17, 2014 to March 5, 2015.  They randomized the patients to receive 25 mg of omecamtiv mecarbil twice daily (the fixed-dose group), 25 mg of the drug twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group) or placebo for 20 weeks.

The patients were between 18 and 85 years old and had stable, symptomatic chronic heart failure and left ventricular ejection fraction of 40 percent or lower.

After 12 weeks of treatment, the mean omecamtiv mecarbil concentration was 165 ng/mL in the fixed-dose group and 263 ng/mL in the pharmacokinetic-titration group. Meanwhile, the mean maximum concentrations were 200 ng/mL and 318 ng/mL, respectively.

At 20 weeks, the pharmacokinetic-titration group had a 25.0 msec increase in systolic ejection time, a 3.6 mL increase in stroke volume, a 3.0 beats per minute decrease in heart rate, a 1.8 mm decrease in left ventricular end-systolic dimensions, a 1.3 mm decrease in end-diastolic dimension and a 970 pg/mL decrease in N-terminal pro-brain natriuretic peptide compared with the placebo group.

The incidence of adjudicated deaths, MIs, unstable angina and other adverse events were similar between the groups, according to the researchers.

The researchers also mentioned that the echocardiographic findings in the study were hypothesis generating. In addition, although there were significant differences between the pharmacokinetic-titration omecamtiv mecarbil group and the placebo group in all of the prespecified secondary efficacy endpoints, the researchers did not adjust for multiple comparisons.

“With these caveats, our findings support the hypothesis that directly and specifically improving cardiac systolic function with a cardiac myosin activator results in favourable ventricular remodeling,” they wrote. “The effects on long-term morbidity and mortality remain untested, and the risks and benefits of omecamtiv mecarbil will only be possible to assess in a large outcomes trial.”