Cytokinetics Announces Progression of REDWOOD-HCM to Cohort 2
The 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 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.
Based on these results from Cohort 1, the Steering Committee and the
“We are encouraged that clinically relevant reductions in the LVOT gradient were achieved within four to six weeks in the majority of patients of Cohort 1 in this interim analysis,” said
REDWOOD-HCM: Interim Analysis
In Cohort 1, 21 patients were randomized 2:1 in double-blind fashion to escalating doses of CK-274 (5, 10, and 15 mg. once daily) or placebo. Two weeks after initiation of treatment in each patient at the starting dose of 5 mg (or placebo), an echocardiogram was performed and, if escalation criteria were met (LVEF >50% and resting LVOT-G >30 mmHg or post-Valsalva LVOT-G >50 mmHg), the patient was up-titrated to receive 10 mg (or placebo) for two weeks; similarly, if escalation criteria were met at four weeks, the patient up-titrated again to receive 15 mg (or placebo) and continued study drug until 10 weeks. If escalation criteria were not met at Week 2 or 4, the patient continued at the same dose for the rest of the trial.
At the cut-off date for this interim analysis, echocardiographic core lab data were available from 11 patients through Week 6 for review while all 21 patients contributed safety data. Following a review of the aggregate, unblinded dataset, the
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 will enroll two sequential cohorts, with an option for a third cohort. Within each cohort, approximately 18 patients will be randomized 2:1 to active or placebo treatment and receive up to three escalating doses of CK-274 or placebo based on echocardiographic guidance. Patients receive an echocardiogram after two weeks of treatment at each dose to determine whether they will be up-titrated. Overall, the treatment duration will be 10 weeks with an echocardiogram to confirm reversibility of effect 2-weeks after the last dose. REDWOOD-HCM is expected to enroll patients in approximately 20 investigative sites in
About CK-274
CK-274 is a novel, oral, small molecule cardiac myosin inhibitor that company scientists discovered independent of its collaborations. CK-274 arose from an extensive chemical optimization program conducted with careful attention to therapeutic index and pharmacokinetic properties that may translate into best-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-use in the clinical setting.
A Phase 1 study demonstrated that CK-274 was safe and well tolerated in healthy participants. The pharmacokinetics of CK-274 were generally dose linear, and steady-state appeared evident within 14 days of dosing. Left ventricular ejection fraction decreased in an exposure dependent manner and the PK/PD relationship for CK-274 observed in humans was similar to that observed preclinically when adjusted for differences in protein binding. Specifically, the shallow exposure-response relationship observed preclinically appears to translate to humans and thereby may enable flexible dose optimization in humans.
The overall development program will assess the potential of CK‑274 to improve exercise capacity and relieve symptoms in patients with hyperdynamic ventricular contraction due to HCM.
About Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder, affecting approximately 1 in 500 individuals worldwide. 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 current medical treatments that directly address the hypercontractility that underlies HCM.
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Source: Cytokinetics, Incorporated