COSMIC-HF ( Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure ) is a double-blind, randomized, placebo-controlled, multicenter, phase 2 trial designed to evaluate an oral formulation of Omecamtiv mecarbil in chronic heart failure patients with reduced ejection fraction.
The trial consisted of two parts, a dose escalation phase and a larger and longer expansion phase. The dose escalation phase, which completed in 2013, assessed the pharmacokinetics and tolerability of three oral modified-release formulations of Omecamtiv mecarbil and was used to select one formulation for further evaluation in the expansion phase.
In the dose escalation phase, 96 patients were randomized 1:1:1:1 to placebo or one of three Omecamtiv mecarbil oral modified-release formulations in two cohorts ( 25 mg twice daily or 50 mg twice daily ). Each patient cohort was followed for 35 days.

The expansion phase evaluated 448 chronic heart failure patients with reduced ejection fraction who were dosed with the selected oral formulation of Omecamtiv mecarbil for 20 weeks and followed for a total of 24 weeks. Patients were randomized 1:1:1 to receive either placebo or treatment with Omecamtiv mecarbil 25 mg twice daily or 25 mg with dose escalation to 50 mg twice daily depending on plasma concentrations of Omecamtiv mecarbil after two weeks of treatment.
The primary endpoints for the expansion phase were to assess the maximum and pre-dose plasma concentration of Omecamtiv mecarbil. The secondary endpoints were to assess changes from baseline in systolic ejection time, stroke volume, left ventricular end-systolic diameter, left ventricular end-diastolic diameter, heart rate and N-terminal pro-brain natriuretic peptide ( a biomarker associated with the severity of heart failure ) at week 20, as well as the safety and tolerability of Omecamtiv mecarbil including incidence of adverse events from baseline to week 24.

COSMIC-HF was not designed to assess the impact of Omecamtiv mecarbil on cardiovascular outcomes in heart failure patients.

Omecamtiv mecarbil is a novel cardiac myosin activator. 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. ( Xagena )

Source: Amgen & Cytokinetics, 2015

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