Despite missing primary efficacy endpoint, ATOMIC-AHF identifies positive trends

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 (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 .

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."

As seen in previous studies, OM produced significant reductions in heart rate (P < 0.001) without decreasing systolic blood pressure, said Prof. Teerlink.

There were also trends toward reductions in worsening , reduced incidence of supraventricular arrhythmias, and no increase in ventricular arrhythmias.

"None of these outcomes should be considered confirmed, since that was not the intent of the study, but the trends are very encouraging, especially for a trial of its size and scope," he said, adding that adverse events, including adjudicated deaths and rehospitalisations were "indistinguishable" from placebo.

There were 7 post-randomization myocardial infarctions in the omecamtiv mecarbil treated groups compared with 3 in placebo treated groups (2.3% vs 1.0% respectively). There was a modest increase in cardiac troponin I in OM-treated patients, but no evidence to suggest this was linked to increasing OM concentrations, "however, we will be vigilant about studying the ATOMIC-AHF data for possible explanations."

"One of the greatest challenges of the ATOMIC-AHF trial has been managing expectations, explained Prof. Teerlink. "Omecamtiv mecarbil is probably one of the most interesting new chemical entities in cardiovascular medicine now and consequently, expectations are very high in the scientific and lay communities. Physicians have struggled for decades to develop agents that improve cardiac function without increasing arrhythmias or mortality; omecamtiv mecarbil has the potential to be such an agent."

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