Omecamtiv mecarbil has been the subject of a clinical trials program comprised of multiple Phase I and Phase II trials, including an ongoing Phase IIb clinical trial evaluating an intravenous formulation of omecamtiv mecarbil. This program was designed to evaluate the safety, tolerability, pharmacodynamics and pharmacokinetic profile of both intravenous and oral formulations of Omecamtiv mecarbil for the potential treatment of heart failure across the continuum of care, in both hospital and outpatient settings. Two Phase IIa clinical trials of omecamtiv mecarbil from this program have been completed.

The first Phase IIa clinical trial evaluated omecamtiv mecarbil in patients with stable heart failure. Data from that trial were presented at the 2009 Heart Failure Society of America (HFSA) Conference in September 2009. The second Phase IIa clinical trial was designed to evaluate an intravenous formulation together with an oral formulation of omecamtiv mecarbil in patients with ischemic cardiomyopathy and angina. Data from this trial was also presented at the 2009 HFSA Conference in September 2009.

In Q2 2011, the company and its partner, Amgen opened to enrollment a Phase IIb clinical trial of an intravenous formulation of omecamtiv mecarbil to evaluate its safety and efficacy in patients with left ventricular systolic dysfunction hospitalized for acute heart failure. This Phase IIb clinical trial is planned to be an international, multicenter, randomized, double-blind, placebo-controlled study in approximately 600 patients, enrolled sequentially in 3 ascending-dose cohorts. In each cohort, patients will be randomized to receive omecamtiv mecarbil or placebo. The primary objective of the Phase IIb clinical trial will be to evaluate the effect of 48 hours of intravenous (IV) omecamtiv mecarbil compared to placebo on dyspnea (or shortness of breath) in patients with left ventricular systolic dysfunction hospitalized for acute heart failure. The secondary objectives are to assess the safety and tolerability of 3 dose levels of IV omecamtiv mecarbil compared with placebo and to evaluate the effects of 48 hours of treatment with IV omecamtiv mecarbil on additional measures of dyspnea, patients’ global assessments, change in N-terminal pro brain-type natriuretic peptide (a biomarker associated with the severity of heart failure) and short-term clinical outcomes in these patients. In addition, the trial will evaluate the relationship between omecamtiv mecarbil plasma concentrations and echocardiographic parameters in patients with acute heart failure.

Data from the first-in-human Phase I clinical trial of omecamtiv mecarbil administered intravenously were previously announced at the Heart Failure Society of America annual meeting in September 2006 and the American Heart Association Scientific Sessions in November 2006. This clinical trial demonstrated that the maximum tolerated dose (MTD) was 0.5 mg/kg/hr for the six-hour infusion in healthy volunteers. At this dose, the six-hour infusion of Omecamtiv mecarbil produced a statistically significant increase in left ventricular ejection fraction as compared to placebo (p<0.0001). At the same dose, omecamtiv mecarbil also produced a statistically significant increase in fractional shortening versus placebo (p<0.0001). Underlying these increases in indices of left ventricular function was a lengthening of the systolic ejection time (p<0.0001). These mean changes in ejection fraction, fractional shortening and systolic ejection time were dose-proportional across the range of doses evaluated in this clinical trial. In addition, omecamtiv mecarbil exhibited generally linear, dose-proportional pharmacokinetics across the range of doses studied. At the MTD of 0.5 mg/kg/hr for six hours and below, omecamtiv mecarbil was well-tolerated when compared to placebo.

The adverse effects at intolerable doses in humans appeared similar to the adverse findings observed in the preclinical safety studies which occurred at similar plasma concentrations. These effects are believed to be related to an excess of the intended pharmacologic effect, resulting in excessive prolongation of the systolic ejection time, and resolved promptly with discontinuation of the infusions of omecamtiv mecarbil. Pharmacokinetic data from this completed Phase I clinical trial suggested that the half-life of omecamtiv mecarbil was sufficient to support development of an oral dosing formulation.

In December 2006, Cytokinetics announced the results of a Phase I oral bioavailability study which were further described during a poster session at the 2007 Heart Failure Society of America Annual Meeting as detailed above. Analysis of the combined pharmacokinetic data from this oral bioavailability study and from the first-in-human study (in which healthy volunteers received intravenous Omecamtiv mecarbil) supports dosing Omecamtiv mecarbil both intravenously and orally without requiring adjustment for patient weight. Cytokinetics is also currently conducting three Phase I clinical trials of omecamtiv mecarbil:

• Cytokinetics has conducted an additional Phase I clinical trial with omecamtiv mecarbil. This trial was a single-center, two-part, open-label trial of up to twelve healthy male volunteers. The primary objective of this trial was to assess the pharmacokinetics and relative bioavailability of three different oral modified release prototypes of Omecamtiv mecarbil. The secondary objective of the trial was to determine whether there is an effect of food on the pharmacokinetics of these prototypes.Read Press Release
  
  
• Cytokinetics has also completed a Phase I clinical trial of omecamtiv mecarbil designed to evaluate the pharmacokinetics of an oral formulation of omecamtiv mecarbil in healthy volunteers. This trial progressed from a single-blind, single-dose phase to a randomized, double-blind, placebo-controlled, multi-dose phase.Read Press Release
  
  
• In addition, Cytokinetics’ Phase I clinical trial designed to evaluate the potential for certain drug-drug interactions with Omecamtiv mecarbil is completed. This trial was a single-center, open-label, sequential, parallel group study designed to evaluate the effects of ketoconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of omecamtiv mecarbil in healthy male volunteers. A second stage of this clinical trial was designed to evaluate the effects of diltiazem, a moderate CYP3A4 inhibitor, on the pharmacokinetics of omecamtiv mecarbil in an additional cohort of healthy male volunteers. In addition, the pharmacokinetics of Omecamtiv mecarbil are being evaluated in a group of healthy subjects who are poor metabolizers with respect to 2D6 phenotype, plus or minus ketoconazole. Read June 2008 Press Release | Read Press December 2008 Release