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.
Cytokinetics expects to begin a randomized, placebo-controlled Phase 2 trial of CK-274 in patients with symptomatic obstructive HCM in Q4 2019.