The Selective Cardiac Myosin Activator, Ck-1827452, A Calcium-Independent Inotrope, Increases Left Ventricular Systolic Function By Increasing Ejection Time Rather Than The Velocity Of Contraction

Introduction: Current inotropes increase contractility by raising intracellular Ca 2+ , which increases heart rate and O 2 consumption, and is arrhythmogenic. Directly activating cardiac myosin may address these liabilities. CK-1827452 (CK-452), a selective, small molecule, cardiac myosin activator, increased contractility in cardiac myocytes without affecting the Ca 2+ transient. In heart failure dogs, CK-452 increased systolic function; however, unlike Ca 2+ -dependent inotropes, CK-452 prolonged LV systolic ejection time (SET) while myocardial O 2 demand and dP/dt were unaffected. Hypothesis: CK-452 prolongs SET in humans to increase LV systolic function without affecting contraction velocity. Methods: Healthy men in 3 ascending dose cohorts (n=20) received a weekly 6 hr double blind infusion x 4: 3 ascending CK-452 doses, and randomized placebo. Low doses in Cohorts 2 and 3 were the same as the high doses in each prior cohort. Transthoracic echocardiograms, obtained at 0 and 6 hr of infusion, were read without knowledge of time or treatment. Results: CK-452 has been dosed at 5, 15, 25, 62.5, 125, 250 and 500 mcg/kg/hr. Dose-related increases in SET, fractional shortening, and ejection fraction (EF) were observed. Unlike Ca 2+ -dependent inotropes, CK-452 did not decrease isovolumic contraction time (IVCT), nor increase systolic tissue velocity. There were no dose-related effects on vital signs, labs, ECGs, or adverse events. Dose escalation continues to the maximum tolerated dose. Conclusions: Adverse effects of Ca 2+ -dependent inotropes establish the need for new therapies to improve cardiac function. The cardiac myosin activator CK-452, a novel calcium-independent inotrope, increases LV systolic function by a unique mechanism, increasing SET but not contraction velocity. These data recapitulate the pharmacodynamics in normal dogs, and support the potential clinical utility of CK-452 in patients with heart failure.