Hot Line IV: Late-breaking trials on heart failure and acute coronary syndrome
Omecamtiv mecarbil, a cardiac myosin-activator, did not achieve its primary efficacy endpoint in reducing dyspnoea (shortness of breath) in patients with acute heart failure, according to the results of the phase II ATOMIC-AHF (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) study.
However, a cohort which received the highest dose of the drug showed greater dyspnoea relief compared with placebo, and there were also other favourable dose and concentration-related trends, noted lead investigator John R. Teerlink, MD, Professor of Clinical Medicine at the University of California San Francisco and Director of Heart Failure at the San Francisco Veterans Affairs Medical Center, USA.
"The study was a real success for its purpose, as a dose-finding, safety and tolerability study," he said. "The main objective of ATOMIC-AHF was to investigate the pharmacokinetics and tolerability of intravenous omecamtiv mecarbil in the acute heart failure (AHF) population, and like most Phase II studies, it was not powered or designed around the efficacy endpoint," he explained.
"We are pleased to see as much efficacy signal as was apparent, and the study provides essential data to inform the dosing regimen for future Phase 3 trials of the intravenous formulation."
ATOMIC-AHF enrolled 613 patients with left ventricular systolic dysfunction who were acutely hospitalised with dyspnoea at rest or minimal exertion.
The subjects, from 106 sites in North America, Europe and Australia, were randomly assigned to receive 48 hours of intravenous placebo or omecamtiv mecarbil (OM) in 3 ascending dose cohorts designed to achieve plasma concentrations of 115, 230, and 310 ng/mL.
The primary efficacy endpoint was the effect on dyspnoea at 6, 24 and 48 hours, with secondary endpoints of safety, tolerability, pharmacokinetics, and echocardiographic indices of cardiac function.
Compared to the pooled placebo groups the OM groups showed no statistically significant difference in dyspnoea symptoms (P = 0.33) - therefore, the primary endpoint was not met, said Prof. Teerlink,
However, in the cohort with the highest OM dose there was a trend towards greater response compared to its paired placebo group (51% vs 37%, P = 0.03), along with significant dose-related and plasma concentration-related trends in response (P = 0.025 and P = 0.007, respectively).
Additionally, there were significant (P < 0.001) concentration-related increases in systolic ejection time, which is the echocardiographic signature of OM, said Prof. Teerlink.
"Unlike prior agents that increased intracellular cAMP and calcium and decrease ejection time, omecamtiv mecarbil's unique mechanism of action prolongs ejection time, allowing for increased stroke volume without significantly increased myocardial oxygen consumption," he said. "This effect has been remarkably reproducible from healthy dogs, dogs with heart failure, healthy human volunteers, and patients with both chronic, and now in ATOMIC-AHF, acute heart failure."