Cytokinetics Announces Start of Redwood-HCM, a Phase 2 Clinical Trial of CK-3773274 - Seite 2

The trial will enroll two sequential cohorts of patients, with an option for a third cohort.  Within each cohort, 18 patients will be randomized 2:1 to active or placebo treatment and receive up to three escalating doses of CK-274 or placebo based on echocardiographic guidance.  Patients will receive an echocardiogram after two weeks of treatment at each dose to determine whether they will be up‑titrated to the next higher dose. Cohort 1 will employ doses of 5, 10 and 15 mg, once daily.  The doses in Cohort 2 will be determined following a review of the data from Cohort 1. Overall, the treatment duration will be 10 weeks with an echocardiogram to confirm reversibility of effect two weeks after the last dose.  REDWOOD-HCM is expected to enroll patients in approximately 20 investigative sites in North America and Europe. All patients will be eligible to participate in an open label extension study of CK-274. Additional information can be found on www.clinicaltrials.gov.

About CK-274

CK-274 is a novel, oral, small molecule cardiac myosin inhibitor that company scientists discovered independent of its collaborations. CK-274 arose from an extensive chemical optimization program conducted with careful attention to therapeutic index and pharmacokinetic properties that may translate into next-in-class potential in clinical development. CK-274 was designed to reduce the hypercontractility that is associated with hypertrophic cardiomyopathy (HCM). In preclinical models, CK-274 reduces myocardial contractility by binding directly to cardiac myosin at a distinct and selective allosteric binding site, thereby preventing myosin from entering a force producing state. CK-274 reduces the number of active actin-myosin cross bridges during each cardiac cycle and consequently reduces myocardial contractility. This mechanism of action may be therapeutically effective in conditions characterized by excessive hypercontractility, such as HCM.

In preclinical models of cardiac function, both in normal models of cardiac function and mouse models of HCM, CK-274 reduced cardiac contractility in a predictable dose and exposure dependent fashion. The preclinical pharmacokinetics of CK-274 were characterized, evaluated and optimized for potential ease-of-use in the clinical setting. A Phase 1 study demonstrated that CK-274 was safe and well tolerated in healthy participants. The pharmacokinetics of CK-274 were generally dose linear, and steady-state appeared evident within 14 days of dosing. Left ventricular ejection fraction decreased in an exposure dependent manner and the PK/PD relationship for CK-274 observed in humans was similar to that observed preclinically when adjusted for differences in protein binding. Specifically, the shallow exposure-response relationship observed preclinically appears to translate to humans and thereby may enable flexible dose optimization in humans.