CK-1827452 is a novel, small-molecule, direct activator of cardiac myosin, the motor protein that causes cardiac contraction. It is being evaluated as a potential treatment of heart failure in both intravenous and oral formulations with the goal of establishing a new continuum of care for patients in both the in-hospital and outpatient settings. CK-1827452 is now in a broad clinical trials program designed to evaluate this novel drug candidate in a variety of patients with heart failure. For more information regarding the current and completed clinical trials, please visit the links below: Development Status of CK-1827452Ongoing Phase II Clinical Trials Program Details 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. Phase I Clinical Trials Details 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:
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