Benzinga | Nov 16, 2020 07:40AM EST

Cytokinetics Reports Preclinical Data For CK-274, CK-271 Shared In Poster Presentations At American Heart Association Scientific Sessions

Cytokinetics, Incorporated (NASDAQ:CYTK) today announced that preclinical data for CK-3773274 (CK-274) and CK-3772271 (CK-271) were shared in poster presentations at the American Heart Association (AHA) Scientific Sessions 2020. CK-274 reduced contractility and left ventricular outflow tract (LVOT) peak pressure gradient in cats with naturally occurring hypertrophic cardiomyopathy (HCM) and left ventricular outflow tract obstruction (LVOTO). In the Dahl/Salt sensitive rat model of heart failure with preserved ejection fraction (HFpEF), CK-271 attenuated the development of fibrosis and diastolic dysfunction.

"We're pleased to share preclinical data that builds on the growing body of evidence for our pipeline of cardiac myosin inhibitors," said Brad Morgan, Ph.D., Cytokinetics' Senior Vice President, Research and Non-Clinical Development. "Collectively, these data demonstrate the potential of this mechanism of action to reduce or arrest the development of cardiac hypercontractility in animal models which may support application in patients with diseases of hypercontractility including HCM and HFpEF."

Previous preclinical data has shown that CK-274 produces exposure related effects on cardiac contractility in healthy animals and mouse models of HCM. New preclinical data demonstrated dose-related changes in left ventricular (LV) systolic function and reductions in LVOT peak pressure gradient in cats with naturally occurring HCM and LVOTO due to the A31P mutation in cardiac myosin binding protein C (cMyBP-C). Treatment with CK-274 (1 mg/kg) reduced mean left ventricular (LV) fractional shortening at 6, 24, and 48 hours post-treatment (mean reduction 13.6%, p = 0.03; 15.4%, p = 0.01; 11.6%, p = 0.02, respectively). In addition to lowering the hypercontractility in cats with naturally occurring HCM and LVOTO, CK-274 reduced the left ventricular outflow tract peak pressure gradient in concentration related manner (median pressure gradient at baseline 27.1 mmHg [interquartile range {IQR} 18.3--33.3] vs 24 hours post-drug, 7.3 mmHg [IQR 14.2--19.7], p= 0.01). CK-274 was well tolerated and no changes in heart rate were observed for any treatment group over time.

A preclinical study of CK-271 demonstrated that treatment with this novel small molecule cardiac myosin inhibitor attenuated the development of fibrosis and diastolic dysfunction in an animal model of HFpEF. Previous studies have shown that CK-271 reduces cardiac myosin ATPase activity in vitro and cardiac contractility in vivo in healthy rats and dogs. In this study of the Dahl/Salt Sensitive rat hypertension model of HFpEF, six weeks of treatment with CK-271 reduced fractional shortening (HS: 53.8 ?1.4 vs HS + CK-271: 42.7 ?1.0%, p< 0.0001) and reduced high salt diet-induced diastolic dysfunction, including reductions in isovolumic relaxation time (IVRT) (HS: 22.8 ?0.6 vs HS + CK-271: 19.5 ?0.5 ms, p< 0.0001) and left atrial area (HS: 42.5 ?2.2 vs HS + CK-271: 35.4 ?0.8 mm2, p< 0.0001). CK-271 also reduced the development of cardiac fibrosis induced by a high salt diet (HS: 5.0 ?0.6 vs HS + CK-271: 3.5 ?0.3%, p< 0.05). These results suggest that cardiac myosin inhibition may be a novel approach to mitigate the development of HFpEF.