Rare Daily Staff

Cytokinetics reported positive topline results from Cohorts 1 and 2 of its phase 2 study of its experimental therapy CK-274 in obstructive outflow disease in hypertrophic cardiomyopathy, a genetic heart disease that affects the heart’s ability to pump blood.

Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle becomes abnormally thick. The thickening of cardiac muscle leads to the inside of the left ventricle becoming smaller and stiffer, and thus the ventricle becomes less able to relax and fill with blood. This ultimately limits the heart’s pumping function, resulting in symptoms including chest pain, dizziness, shortness of breath, or fainting during physical activity.

A subset of patients with HCM are at high risk of progressive disease which can lead to atrial fibrillation, stroke and death due to arrhythmias. There are no FDA approved medical treatments that directly address the hypercontractility that underlies HCM.

CK-274 is a novel, oral, small molecule cardiac myosin inhibitor that company scientists discovered independent of its collaborations. CK-274 was designed to reduce the hypercontractility that is associated with HCM. In preclinical models, CK-274 reduced 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 is designed to reduce the number of active actin-myosin cross bridges during each cardiac cycle and consequently reduce myocardial contractility.

The phase 2 clinical trial known as REDWOOD-HCM is 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. The primary objective of the trial is to determine the safety and tolerability of CK-274. The results of REDWOOD-HCM inform dose selection and support progression of CK-274 to a planned Phase 3 registrational clinical trial which is expected to start before year end.

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 and the average post-Valsalva LVOT-G. The majority of patients treated with CK-274 (78.6 percent in Cohort 1 and 92.9 percent in Cohort 2) achieved the target goal of treatment.

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. No new cases of atrial fibrillation in patients treated with CK-274 were reported.

In this dose-range finding trial, one patient experienced a transient decrease in left ventricular ejection fraction (LVEF) that required dose adjustment but not dose interruption. LVEF returned to baseline within two weeks after the end of treatment in both cohorts, which was consistent with the reversibility of LVEF decreases that were similarly observed in healthy participants in the phase 1 study of CK-274.

“The combined data from Cohorts 1 and 2 in REDWOOD-HCM met our high expectations for this trial of CK-274 in patients with obstructive HCM, given the observed onset of response to initiation of treatment, magnitude and breadth of response, reversibility of LVEF decreases and favorable tolerability profile,” said Fady Malik, Cytokinetics’ executive vice president of research and development. “These findings inform the design of our Phase 3 trial, in which we expect to titrate patients with a flexible dosing scheme of 5, 10, 15, and 20 mg to personalize and maximize the potential treatment effect for patients.”

Photo: Fady Malik, Cytokinetics’ executive vice president of research and development