CK-1827452 is currently the subject of an ongoing Phase IIa clinical trials program. In April 2007, the company announced the initiation of the first Phase IIa clinical trial for CK-1827452, a multi-center, double-blinded, randomized, placebo-controlled, dose-escalation trial which is designed to evaluate the safety, tolerability, pharmacodynamic and pharmacokinetic profile of an intravenous formulation of CK-1827452 in patients with stable heart failure. The primary objective of this trial is to evaluate the safety and tolerability of CK-1827452 administered as an intravenous infusion to stable heart failure patients. The secondary objectives of this trial are to establish a relationship between plasma concentration and pharmacodynamic effect for CK-1827452 and to determine the pharmacokinetics of CK-1827452 in stable heart failure patients. In addition to routine assessments of vital signs, blood samples and ECG monitoring, echocardiograms will be performed to evaluate cardiac function at various pre-defined time points.

In this trial, CK-1827452 is administered as an intravenous infusion to cohorts of eight patients each. The first two of these cohorts were designed to study the full range of plasma concentrations of CK-1827452 intended for evaluation in this trial. In each of these two cohorts, patients underwent four treatment periods, receiving three escalating active doses of CK-1827452 and one placebo treatment which was randomized into the dose escalation sequence. Patients received a loading infusion to rapidly achieve a target plasma concentration of CK-1827452 during the first hour, followed by a slower infusion intended to maintain that plasma concentration during the second hour.

In March 2008, we announced interim analysis results from this ongoing trial. The safety data from this interim analysis suggest that the drug was well-tolerated with no serious adverse events reported in heart failure patients exposed to the intended range of plasma concentrations. In addition, data from the first two cohorts demonstrated that, when compared to placebo, CK-1827452 produced statistically significant and clinically relevant increases in Doppler-derived stroke volume and fractional shortening in association with statistically significant prolongations of systolic ejection time. Statistically significant correlations were observed between the increases in each of these three indices of cardiac ventricular function and increases in the plasma concentration of CK-1827452. Left ventricular ejection fraction, a measurement with high variability in patients with ventricular disease, also increased with increasing plasma concentrations; however, this increase in left ventricular systolic function did not reach statistical significance in these initial cohorts. Across the plasma concentration levels evaluated, the pharmacokinetics of CK-1827452 were generally linear with respect to dose and similar to those observed in the healthy volunteers in the first-time-in-humans Phase I trial of CK-1827452. Heart rate and blood pressure remained unchanged in the first two cohorts of the Phase IIa trial.

Data from the first-in-human Phase I clinical trial of CK-1827452 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 CK-1827452 produced a statistically significant increase in left ventricular ejection fraction as compared to placebo (p<0.0001). At the same dose, CK-1827452 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, CK-1827452 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, CK-1827452 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 CK-1827452. Pharmacokinetic data from this completed Phase I clinical trial suggested that the half-life of CK-1827452 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 CK-1827452) supports dosing CK-1827452 both intravenously and orally without requiring adjustment for patient weight. Cytokinetics is also currently conducting three Phase I clinical trials of CK-1827452:

• In December 2007, Cytokinetics initiated an additional Phase I clinical trial with CK-1827452. This trial is a single-center, two-part, open-label trial of up to twelve healthy male volunteers. The primary objective of this trial is to assess the pharmacokinetics and relative bioavailability of three different oral modified release prototypes of CK-1827452. The secondary objective of the trial is to determine whether there is an effect of food on the pharmacokinetics of these prototypes.
  
  
• Cytokinetics has also completed enrollment in a Phase I clinical trial of CK-1827452 designed to evaluate the pharmacokinetics of an oral formulation of CK-1827452 in healthy volunteers. This trial progressed from a single-blind, single-dose phase to a randomized, double-blind, placebo-controlled, multi-dose phase.
  
  
• In addition, Cytokinetics’ Phase I clinical trial designed to evaluate the potential for certain drug-drug interactions with CK-1827452 is continuing. This trial is a single-center, open-label, sequential, parallel group study designed to evaluate the effects of ketoconazole, a strong CYP3A4 inhibitor, on the pharmacokinetics of CK-1827452 in healthy male volunteers. A second stage of this clinical trial is designed to evaluate the effects of diltiazem, a moderate CYP3A4 inhibitor, on the pharmacokinetics of CK-1827452 in an additional cohort of healthy male volunteers. In addition, the pharmacokinetics of CK-1827452 are being evaluated in a group of healthy subjects who are poor metabolizers with respect to 2D6 phenotype, plus or minus ketoconazole.