Cytokinetics Announces Cohort 3 of REDWOOD-HCM is Open to Enrollment
“After completing enrollment in the first two cohorts in REDWOOD-HCM, we are pleased to now begin Cohort 3, which is enrolling patients who are being treated with disopyramide,” said
REDWOOD-HCM: Clinical Trial Design
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). 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.
The trial previously completed enrollment in Cohort 1 and Cohort 2, two sequential cohorts. Within each cohort, approximately 20 patients were randomized 2:1 to active or placebo treatment and received up to three escalating doses of CK-274 or placebo based on echocardiographic guidance. Patients received an echocardiogram after two weeks of treatment at each dose to determine whether they would be up-titrated. Overall, the treatment duration is 10 weeks with an echocardiogram to confirm reversibility of effect 2 weeks after the last dose. In Cohorts 1 and 2, patients continued taking background medications exclusive of disopyramide.
Cohort 3 will enroll, in an open label fashion, 8-12 patients whose background therapy includes disopyramide to assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of CK-274 in patients taking disopyramide. All patients will receive up to three escalating doses of CK-274, titrated based on echocardiographic guidance. Overall treatment duration will be 10 weeks with a 4-week follow up period after the last dose.
Interim analysis of data from Cohort 1 of REDWOOD-HCM showed patients experienced substantial reductions in the average resting left ventricular outflow tract gradient (LVOT-G) as well as the post-Valsalva LVOT-G (defined as resting gradient <30 mmHg and post-Valsalva gradient <50 mmHg). These clinically relevant decreases in pressure gradients were achieved with only modest decreases in average left ventricular ejection fraction (LVEF); there were no dose interruptions due to LVEF falling below 50%, the prespecified safety threshold. Pharmacokinetic data were similar to those observed in Phase 1 in healthy subjects. In addition, the safety and tolerability data were supportive of continued dose escalation with no serious adverse events attributed to study treatment reported by the investigators.
Results from REDWOOD-HCM, across both Cohort 1 and Cohort 2, are expected in mid-2021. Additional information about REDWOOD-HCM can be found on clinicaltrials.gov/.
CK-274 is a novel, oral, small molecule cardiac myosin inhibitor arising 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, CK-274 reduced cardiac contractility in a predictable dose and exposure dependent fashion. In preclinical models of disease, CK-274 reduced compensatory cardiac hypertrophy and cardiac fibrosis. The preclinical pharmacokinetics of CK-274 were characterized, evaluated and optimized for potential ease of titration in the clinical setting.
About Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is a disease in which the heart muscle (myocardium) becomes abnormally thick (hypertrophied). 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.
This press release contains forward-looking statements for purposes of the Private Securities Litigation Reform Act of 1995 (the “Act”).
Senior Vice President, Corporate Communications, Investor Relations
Source: Cytokinetics, Incorporated