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DIRECTLY TARGETINGHYPER
CONTRACTILITY

CK-274

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.

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 of CK-274 in patients with symptomatic obstructive HCM (oHCM) on background medical therapy. Results from Cohorts 1 and 2 of REDWOOD-HCM demonstrated that treatment with CK-274 for 10 weeks resulted in statistically significant reductions from baseline compared to placebo in the average resting left ventricular outflow tract pressure gradient (LVOT-G) (p=0.0003, p=0.0004, Cohort 1 and Cohort 2, respectively) and the average post-Valsalva LVOT-G (p=0.001, p<0.0001, Cohort 1 and Cohort 2, respectively). The majority of patients treated with CK-274 (78.6% in Cohort 1 and 92.9% in Cohort 2) achieved the target goal of treatment, defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg at Week 10 compared to placebo (7.7%). Reductions in LVOT-G occurred within two weeks of initiating treatment with CK-274, were maximized within two to six weeks of the start of dose titration, and were sustained until the end of treatment at 10 weeks. The observed reductions in LVOT-G were dose dependent, with patients achieving greater reductions of LVOT-G with increasing doses of CK-274. Treatment with CK-274 in REDWOOD-HCM was generally well tolerated. The incidence of adverse events was similar between treatment arms. No serious adverse events were attributed to CK-274 and no treatment interruptions occurred on CK-274. Cohort 3 is currently enrolling patients whose background therapy includes disopyramide.