Results From Three Trials Support Ongoing Clinical Development Program
Cytokinetics, Incorporated (NASDAQ: CYTK) announced results from three Phase I clinical trials evaluatingCK-1827452, a novel cardiac myosin activator, in healthy subjects. Onestudy was designed to investigate the potential for drug-drug interactionswith CK-1827452, the second, to evaluate the safety, tolerability and doseproportionality of single and multiple doses of two different strengths ofan oral formulation of CK-1827452, and the third, to study the relativebioavailabilities of multiple modified release forms of orally administeredCK-1827452.
The first clinical trial is a single-center, open-label, sequential,parallel group study in healthy male subjects to evaluate the potential forcertain drug-drug interactions. The primary objective of this study is toevaluate the effect of ketoconazole (a potent inhibitor of thedrug-metabolizing enzyme, cytochrome P450 (CYP3A4) at steady-state on thepharmacokinetics of a single oral dose of CK-1827452 in subjects who areeither extensive metabolizers (EM) or poor metabolizers (PM) with respectto their defined genotype for CYP2D6, another drug-metabolizing enzyme.The secondary objectives are to evaluate the pharmacokinetic parameters ofCK-1827452 administered alone in subjects with PM genotype for CYP2D6 ascompared to subjects with EM genotype for CYP2D6 and to evaluate the effectof diltiazem at steady-state in subjects with the EM genotype for CYP450 ifthere is evidence of any significant pharmacokinetic interaction betweenketoconazole and CK-1827452. In EM subjects, ketoconazole caused a modestreduction in the clearance of CK-1827452 and consequently, a modest butstatistically significant increase in the elimination half-life ofCK-1827452, from 22 to 27 hours (p < 0.01). This modest increase in thehalf-life of CK-1827452 with ketoconazole resulted in an approximate 50%increase in the area under the CK-1827452 plasma concentration versus timecurve (AUC), which reflects the overall exposure to the study drug, andwhich was also statistically significant (p < 0.01). Importantly,however, the maximum CK-1827452 plasma concentration (Cmax) was unaffectedby ketoconazole (65 versus 67 ng/mL). Diltiazem had no effect on eitherthe Cmax or AUC of CK-1827452 when the two were co-administered to EMsubjects, although the half-life increased slightly, from 18 to 20 hours (p< 0.01).
"The results with ketoconazole are encouraging, as they suggest minimalpotential for significant drug-drug interactions with CK-1827452," saidAndrew A. Wolff, M.D., F.A.C.C., Cytokinetics' Senior Vice President ofClinical Research and Development and Chief Medical Officer. "First, wesaw no effect of ketoconazole on the Cmax of CK-1827452, and we believe itis the Cmax, rather than the AUC, which determines the potential forintolerable effects of CK-1827452. Second, the approximately 50% increasein the CK-1827452 AUC due to ketoconazole observed in this study is modestby comparison to the increase in AUC observed with many other drugs as aresult of interaction with inhibitors of ketoconazole; for example, somedrugs' AUCs increase by as much as 25- to 30-fold with ketoconazole.Importantly, there was no detectable interaction between CK-1827452 anddiltiazem, a moderate CYP3A4 inhibitor that reflects the potential of manycommonly-used drugs to inhibit CYP3A4 and cause drug-drug interactions."
This clinical trial continues to enroll PM subjects in order to examine thepharmacokinetics of CK-1827452 in this group. Additional data from thistrial comparing the pharmacokinetics of CK-1827452 in subjects with the EMversus the PM genotype for CYP2D6 are expected to be available later in2008.
The second Phase I clinical trial was a single-center study designed toevaluate the safety, tolerability, and pharmacokinetics of an oralformulation of CK-1827452 administered both as a single oral dose and asmultiple oral doses of 10 mg and 30 mg strength capsules of CK-1827452.The primary objective of this study was to evaluate the safety andtolerability of CK-1827452 after a single oral dose and after multiple oraldoses to steady-state in healthy men and women. The secondary objective ofthis study was to evaluate the pharmacokinetics of CK-1827452 after asingle oral dose and after multiple oral doses tosteady-state and to compare the pharmacokinetic parameters between healthymen and women.CK-1827452 was well-tolerated in the trial, with no drug-related seriousadverse events. Dose-proportionality between the 10 mg and 30 mg doselevels was observed in both men and women, both after a single dose andafter multiple doses tosteady-state, with no differences observed between men and women.
The third Phase I clinical trial was a single-center, two-part, open-labelstudy to evaluate modified release forms of CK-1827452 in healthysubjects. Since an immediate release formulation of CK-1827452 was foundto be rapidly absorbed in a previous study in healthy subjects, the purposeof developing these modified release forms is to reduce the rate of drugabsorption without significantly affecting the overall bioavailability.The primary objective of this study was to assess the pharmacokinetics andrelative bioavailability of three different oral modified releaseprototypes of CK-1827452 as compared to the immediate release formulationin up to twelve healthy male subjects. The secondary objective of the trialwas to determine whether there is an effect of food on the pharmacokineticsof one of these oral modified release prototypes of CK-1827452. The singledose pharmacokinetics of one formulation in both the fasted and fed statesdemonstrated that it reduced Cmax as compared to the immediate releaseformulation without a substantial effect on overall bioavailability. Thisprototype modified release oral formulation of CK-1827452 has been selectedto proceed forward into further clinical testing.
"We are pleased with these data, which support our ongoing Phase IIclinical trials program evaluating CK-1827452 for the potential treatmentof heart failure," stated Andrew A. Wolff, M.D., F.A.C.C., Cytokinetics'Senior Vice President of Clinical Research and Development and ChiefMedical Officer. "Our program continues to characterize thepharmacokinetics and pharmacodynamic effects of both oral and intravenousformulations of CK-1827452 in order to enable further study of this noveldrug candidate in both the inpatient and outpatient settings."
Development Status of CK-1827452
CK-1827452 is currently the subject of a clinical trials program comprisedof multiple Phase I and Phase IIa trials. This program is designed toevaluate the safety, tolerability, pharmacodynamics and pharmacokineticprofile of CK-1827452 in a diversity of patients with heart failure. Theseongoing and planned trials are designed to evaluate both intravenous andoral formulations of CK-1827452 for the potential treatment of heartfailure across the continuum of care, in both hospital and outpatientsettings.
In March 2008, Cytokinetics announced positive results from an interimanalysis of its first and ongoing Phase IIa clinical trial of CK-1827452 inpatients with stable heart failure. The safety data from this interimanalysis suggest that the drug was well-tolerated with no serious adverseevents reported in heart failure patients exposed to the intended range ofdoses and plasma concentrations. In addition, data from the first twocohorts demonstrated that, when compared to placebo, CK-1827452 producedstatistically significant and clinically relevant increases inDoppler-derived stroke volume and fractional shortening in association withstatistically significant prolongations of systolic ejection time.Statistically significant correlations were observed between the increasesin each of these three indices of cardiac ventricular function andincreases in the plasma concentration of CK-1827452.
