This article is more than 5 years old. Information may no longer be current.
COSMIC-HF: Omecamtiv mecarbil safe, effective for patients with chronic HF
Click Here to Manage Email Alerts
ORLANDO, Fla. — Omecamtiv mecarbil was associated with a number of cardiac structural and functional improvements in a phase 2 study of the drug in patients with chronic HF, according to findings presented at the American Heart Association Scientific Sessions.
Researchers conducted the COSMIC-HF study to assess the safety, tolerability and efficacy of omecamtiv mecarbil (Amgen/Cytokinetics), a novel selective cardiac myosin activator, to determine an optimal dose and to better understand its pharmacokinetics.
John R. Teerlink
The drug works “by increasing the entry rate of myosin into the tightly bound, force-producing state with actin,” John R. Teerlink, MD, from the San Francisco Veterans Affairs Medical Center and the University of California, San Francisco, said at a press conference. “In effect it results in `more hands pulling on the rope,’ where the myosin heads are the hands and the actin is the rope. In animal models and in vitro studies, this agent has been shown to increase duration of systole and increase stroke volume, with none of the adverse effects that are associated with other agents that increase cardiac function, such as increases in myocardial calcium, dP/dt [LV contractility] or myocardial oxygen demand.”
Methods of study
Teerlink presented the findings of the expansion phase of the study, in which 448 patients (mean age, 63 years) with chronic HF were randomized to receive omecamtiv mecarbil 25 mg twice daily; omecamtiv mecarbil 25 mg twice daily for 8 weeks, then uptitrated to 50 mg twice daily (PK-titration group); or placebo. Patients were treated for a total of 20 weeks.
All patients were NYHA Class II or III and had left ventricular ejection fraction ≤ 40%. Outcomes of interest included systolic ejection time, stroke volume, LV fractional shortening and LVEF, as well as various structural parameters.
Teerlink said that compared with the placebo group, at 24 weeks both omecamtiv mecarbil groups had improved systolic ejection time (P for 25-mg group < .001; P for PK-titration group < .001) stroke volume (P for 25-mg group = .004; P for PK-titration group = .022) and LV fractional shortening (P for 25-mg group = .017; P for PK-titration group = .013), while the 25-mg group had improved LVEF (P = .025) and the PK-titration group had a trend toward improved LVEF (P = .063).
Compared with controls, the PK-titration group had reduced LV end systolic diameter (P = .003), LV end diastolic diameter (P = .013), LV end systolic volume (P = .005) and LV end diastolic volume (P = .021), Teerlink said. The 25-mg group had lower LV end systolic volume than the placebo group (P = .019) but the other structural parameters did not significantly differ, he said.
The PK-titration group compared with controls had lower heart rate (P = .007) and N-terminal pro B-Type natriuretic peptide levels (P = .007), while the 25-mg group had lower NT-proBNP levels (P = .021) but not lower heart rate (P = .218), he said, noting that the heart-rate lowering property “is unique among agents” that increase cardiac function.
“COSMIC-HF demonstrated that omecamtiv mecarbil produced across-the-board beneficial effect in multiple domains,” he said.
Adverse events, conclusions
Adverse events occurred in 61% of those assigned placebo (8% led to discontinuation) and 63% of those assigned to either omecamtiv mecarbil group (7% led to discontinuation), while serious cardiac events occurred in 13% of those assigned placebo and 12% of those assigned to an intervention, according to the researchers.
While omecamtiv mecarbil was associated with an increase in troponin I levels, no cases were determined by the study’s clinical events committee to be MI or myocardial ischemia, Teerlink said.
“Pharmacokinetics dose titration was able to reliably control exposure of patients to omecamtiv mecarbil, and this was associated with improvements in systolic ejection time, stroke volume and LVEF,” Teerlink said. “These came along with decreases in ventricular sizes and volumes and reduced physiological parameters such as heart rate and NT-proBNP. Safety and tolerability profiles were similar to placebo. … We believe the magnitude of cardiac events observed in this trial may translate into improvement in clinical outcomes.” – by Erik Swain
Reference:
Teerlink J, et al. LBCT 1: Failure Is Not an Option: New Drugs and Systems of Care. Presented at: American Heart Association Scientific Sessions; Nov. 7-11, 2015; Orlando, Fla.
Disclosure: The study was funded by Amgen and Cytokinetics. Teerlink reports receiving research grants from and consulting or serving on an advisory board for Amgen, Bayer, Cytokinetics, Novartis and Trevena.
Perspective
Back to Top
Mariell L. Jessup, MD
We’ve moved on to new molecular signaling pathways for the treatment of HF. Thus far, a lot of these have been tested in mouse models, but we’re now at the point of testing them in human beings. COSMIC-HF is a testament to translational cardiology at its very best. We’ve taken things clinically derived from science into preclinical and now clinical testing, and it looks promising. It represents everything we are all trying to do.
Click Here to Manage Email Alerts