CK-3773274, or CK-274, is an investigational, novel, oral, small molecule cardiac myosin inhibitor discovered by company scientists independent of its collaborations, for the potential treatment of hypertrophic cardiomyopathies (HCM).
CK-274 was designed to reduce the hypercontractility associated with HCM. HCM causes the heart to thicken and stiffen, eventually limiting its ability to pump blood. This happens when myosin, a protein in the muscle responsible for converting chemical energy into the mechanical force that causes muscle contraction, is working too hard to grab or pull on actin, another protein within the sarcomere, resulting in hypercontractility, or too many hands pulling on the rope. CK-274 addresses this hypercontractility by blocking some myosins from pulling, resulting in less contraction, or fewer hands on the rope. In preclinical models, CK-274 reversed and reduced thickening and stiffening of the heart.
A phase 1 double-blind, randomized, placebo-controlled, multi-part, single and multiple ascending dose study of CK-274 demonstrated that CK-274 was safe and well tolerated in healthy participants. Decreases in ejection fraction below 50% were readily reversible within six hours following single doses and within 24-48 hours following 14 days of dosing. The pharmacokinetics of CK-274 were generally dose linear, and steady-state appeared evident within 14 days of dosing. Additionally, the shallow exposure-response relationship observed preclinically appears to translate to humans and thereby may enable flexible dose optimization in humans.
CK-274 is currently the subject of REDWOOD-HCM (Randomized Evaluation of Dosing With CK-274 in Obstructive Outflow Disease in HCM), a multi-center, randomized, placebo-controlled, double-blind, dose-finding clinical trial in patients with symptomatic, obstructive HCM. The primary objective of the trial is to determine the safety and tolerability of CK-274. The secondary objectives are to describe the concentration-response relationship of CK-274 on the resting and post-Valsalva left ventricular outflow tract gradient as measured by echocardiography during 10 weeks of treatment, to describe the dose response relationship of CK-274, and to evaluate the plasma concentrations of CK-274 in patients with oHCM. REDWOOD-HCM has completed enrollment in Cohort 1 and Cohort 2, two sequential cohorts in which approximately 20 patients were randomized 2:1 in each cohort to active or placebo treatment and received up to three escalating doses of CK-274 or placebo based on echocardiographic guidance. Cohort 3 is enrolling patients whose background therapy includes disopyramide.