SOUTH SAN FRANCISCO, Calif.—Cytokinetics Inc. debuted preclinical data for CK-3773274 (CK-274) earlier this summer that supports the compound's development as a potential treatment for hypertrophic cardiomyopathy (HCM).
Hypertrophic cardiomyopathy is an inherited cardiovascular disorder characterized by the thickening of the cardiac muscle, which causes the interior of the left ventricle to become smaller and stiffer and ultimately results in a decreased ability of the ventricle to relax and pump blood properly. Some patients with HCM are at increased risk of progressive disease, which can lead to atrial fibrillation, stroke and even death as a result of arrhythmias.
According to Dr. Fady I. Malik, executive vice president of research and development at Cytokinetics, current treatment options for HCM patients include “beta blockers, calcium channel blockers, as well as implantable devices, septal reduction therapy or transplant.” However, none of these options directly address hypercontractility.
“Given the lack of medications that directly address the hypercontractility that underlies HCM, we believe the market opportunity for cardiac myosin inhibitors is substantial,” he reports.
CK-274 is a novel, oral, small-molecule cardiac myosin inhibitor. Malik says the compound is the result of “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.”
Cytokinetics has optimized CK-274's pharmacokinetics to provide rapid onset, easy titration and rapid symptom relief in the clinical setting. The ultimate aim is to determine the compound's ability to relieve symptoms of HCM—such as chest pain, shortness of breath, dizziness or fainting during physical activity—and to improve exercise capacity.
In preclinical models, Cytokinetics explains that “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.”
In in-vitro studies, CK-274 selectively inhibited cardiac myosin activity, reducing cardiac myosin ATPase activity in a concentration-dependent manner with an IC50 of 1.3 µM. In adult rat cardiomyocytes, the compound reduced fractional shortening, a measure of cardiac contractility, with no effect on the calcium transient.
In-vivo results are also promising. When tested in healthy rats, a single dose of CK-274 ranging from 0.5 to 4.0 mg/kg significantly reduced fractional shortening in a dose-related fashion relative to control. In healthy dogs, single doses of CK-274 ranging from 0.75 to 3.0 mg/kg decreased left ventricular ejection fraction in a dose-related fashion relative to control.
Cytokinetics also assessed CK-274 in the genetic R403Q mouse model of HCM, in which single doses—ranging from 0.25 to 1.5 mg/kg—resulted in significant reduction of fractional shortening in a dose-related fashion relative to baseline. Fractional shortening returned to baseline levels within 24 hours at all dose levels. R403Q mice and wild-type mice saw a 10-percent reduction (IC10) in contractility at nanomolar concentrations, with a >7-fold difference between the IC50 and IC10; this could translate into a gradual on-target effect in HCM patients.
“We are pleased to share these important findings demonstrating that CK-274 decreases cardiac contractility in a dose- and concentration-related fashion, without changes to calcium transient. We further confirmed this effect in a mouse model of HCM and observed its effect appears reversible within 24 hours after administration with CK-274,” commented Dr. Brad Morgan, Cytokinetics’ senior vice president of research and non-clinical development. “We are encouraged by the emerging pharmacologic profile for this drug candidate and look forward to presenting data from its first-in-human Phase 1 study and beginning a Phase 2 trial later this year.”
As DDNews prepared to finalize this issue, Cytokinetics reported data from its Phase 1 trial of CK-274 in healthy volunteers, which sought to evaluate the compound's safety and tolerability. Primary and secondary endpoints were met, as CK-274 proved safe and well tolerated with no serious adverse events and no clinically meaningful changes in vital signs, ECGs or laboratory tests. As for the aforementioned Phase 2 trial, the company plans to initiate it before the end of the year, and the trial will evaluate safety and tolerability in patients with symptomatic obstructive HCM, with secondary objectives of determining the pharmacodynamics and pharmacokinetics of CK-274 in such patients. Cytokinetics intends to add the compound to stable background medical therapy.
Malik tells DDNews that while Cytokinetics is primarily focused on advancing CK-274 in cardiomyopathies, the company is considering additional indications such as heart failure with preserved ejection fraction, or HFpEF. According to the Frankel Cardiovascular Center at the University of Michigan, “Ejection fraction is used to assess the pump function of the heart; it represents the percentage of blood pumped from the left ventricle (the main pumping chamber) per beat. A normal ejection fraction is greater than or equal to 50 percent … If the heart pumps normally but is too stiff to fill properly, the condition is known as heart failure with preserved ejection fraction (HFpEF).” Given the similarities with HCM, CK-274 could have similar potential in this indication as well.