Amgen and Cytokinetics Incorporated, a clinical-stage biopharmaceutical company, have presented data from the ATOMIC-AHF (Acute Treatment with Omecamtiv Mecarbil to Increase Contractility in Acute Heart Failure) study at the ESC Congress 2013, organized by the European Society of Cardiology, in Amsterdam. ATOMIC-AHF was a randomized, double-blind, placebo-controlled phase II study that enrolled 613 patients hospitalized with acute heart failure (AHF) treated for 48 hours with omecamtiv mecarbil or placebo and designed to evaluate the safety, pharmacokinetics, pharmacodynamics, and potential efficacy of an intravenous formulation of omecamtiv mecarbil in patients with AHF.

The study did not meet its primary endpoint of dyspnea (shortness of breath) response as measured by the 7-point Likert scale through 48 hours (p=0.33) but showed favourable dose and concentration-related trends on dyspnea response.

ATOMIC-AHF enrolled three, sequential, dose escalation cohorts of patients treated for 48 hours with omecamtiv mecarbil or placebo. The primary efficacy endpoint in ATOMIC-AHF was dyspnea symptom response. Secondary endpoints included other clinical and pharmacodynamic (echocardiographic) effects including death or worsening heart failure within seven days. The omecamtiv mecarbil treatment groups were not statistically different in their 7-point Likert scale dyspnea symptom response rates compared to the pooled placebo group (p=0.33); therefore, the primary endpoint was not met.

Omecamtiv mecarbil demonstrated favourable dose- and concentration-related trends (nominal p=0.025 and nominal p=0.007, respectively) on dyspnea response. Improvement in dyspnea was observed in the highest omecamtiv mecarbil dose group when compared against its paired placebo group in the third cohort (dyspnea symptom response in 51 per cent of subjects on omecamtiv mecarbil versus 37 per cent on placebo, nominal p=0.03). The incidence of worsening heart failure within seven days of initiating treatment was 17 per cent in the pooled placebo group and was 13 per cent, eight per cent and nine per cent on omecamtiv mecarbil in the first, second and third cohorts, respectively. Systolic ejection time, the echocardiographic signature of omecamtiv mecarbil, increased in a concentration-dependent manner.

Rates of adverse events (AEs), serious AEs, adjudicated deaths and hospitalizations were similar between omecamtiv mecarbil and placebo groups. There were seven post-randomization myocardial infarctions in the omecamtiv mecarbil treated groups compared with three in the placebo groups (2.3 per cent vs. 1.0 per cent, respectively). However, there was no relationship between the maximum increase from the baseline troponin (a biomarker specific for cardiac muscle damage) and increasing plasma concentrations of omecamtiv mecarbil. Omecamtiv mecarbil was not associated with an increased incidence of tachyarrhythmias nor were heart rate or blood pressure adversely affected.

"Although ATOMIC-AHF did not achieve its primary efficacy endpoint, we are encouraged by the data from this study," said Sean E Harper, MD, executive vice president of Research and Development at Amgen. "Omecamtiv mecarbil is a unique investigational therapy for patients with acute and chronic heart failure. We look forward to the data from the COSMIC-HF study, which together with the data from ATOMIC-AHF will inform our decision on whether to progress omecamtiv mecarbil into phase III clinical trials."

"We are pleased with the results from ATOMIC-AHF," stated Robert I Blum, president and CEO at Cytokinetics. "This novel mechanism drug candidate has consistently been associated with dose-related and plasma concentration-related pharmacodynamic and other effects in a robust programme of phase I and phase II clinical trials. We look forward to results from COSMIC-HF and the potential  progression of omecamtiv mecarbil in development."

Oral formulations of omecamtiv mecarbil are currently being evaluated in a phase II trial known as COSMIC-HF (Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure). COSMIC-HF is a double-blind, randomized, placebo-controlled, multicenter, dose escalation study designed to evaluate the safety and efficacy of omecamtiv mecarbil in approximately 420 patients with chronic heart failure and left ventricular systolic dysfunction.

ATOMIC-AHF and COSMIC-HF are clinical trials of omecamtiv mecarbil conducted by Amgen in collaboration with Cytokinetics. Amgen holds an exclusive, worldwide license to develop and commercialize omecamtiv mecarbil and related compounds, subject to Cytokinetics' specified development and commercialization participation rights.

Omecamtiv mecarbil is a novel cardiac myosin activator and is the subject of a collaboration between Cytokinetics and Amgen. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction. Cardiac myosin activators are thought to accelerate the rate-limiting step of the myosin enzymatic cycle and shift the enzymatic cycle in favor of the force-producing state. Preclinical research has shown that cardiac myosin activators increase contractility in the absence of changes in intracellular calcium in cardiac myocytes.

Amgen is committed to unlocking the potential of biology for patients suffering from serious illnesses by discovering, developing, manufacturing and delivering innovative human therapeutics.

Cytokinetics is a clinical-stage biopharmaceutical company focused on the discovery and development of novel small molecule therapeutics that modulate muscle function for the potential treatment of serious diseases and medical conditions.