Benzinga | Apr 12, 2021 07:40AM EDT

Cytokinetics Highlights Presentation Of Preclinical Data For CK-3773274 AtAmerican Chemical Society Spring 2021 Virtual Meeting

Cytokinetics, Incorporated (NASDAQ:CYTK) today announced that data related to the optimization of CK-3773274 (CK-274), including the first disclosure of its chemical structure, were presented at the American Chemical Society Spring 2021 Virtual Meeting. The presentation reviewed scientific activities that involved evaluating CK-274 and precursor compounds for their exposure-response relationship, projected human half-life, and potential for meaningful cytochrome P450 (CYP450) interactions. CK-274 is a next-in-class cardiac myosin inhibitor discovered by company scientists, in development for the potential treatment of hypertrophic cardiomyopathy (HCM).



"These preclinical data provide a first look at the structure of our next-in-class cardiac myosin inhibitor, CK-274, and its performance in certain preclinical assays," said Brad Morgan, Ph.D., Cytokinetics' Senior Vice President, Research and Non-Clinical Development. "CK-274 was synthesized from a newly discovered and distinct chemical series following an optimization program that was intentionally focused on key compound physiochemical characteristics, such as a shallow dose-response relationship and a half-life that may enable flexible and timely dosing adjustments. We look forward to results from REDWOOD-HCM, the Phase 2 clinical trial of CK-274, which is designed to elaborate on how these differentiated properties may translate into its potential use in patients with obstructive HCM."

Data presented described the primary optimization objectives, identification of an initial hit compound, and its subsequent chemical optimization, including preclinical characterization in biochemical assays, cardiac myocytes, and in vivo models of cardiac function. In cardiac myofibrils, the biochemical potency of CK-274 was 1.26 ?M and it reduced cardiac myocyte contractility to 33% of baseline at 5 ?M. Echocardiographic data from healthy rats showed that CK-274 reduced fractional shortening, a measure of cardiac function, in a dose- and exposure-dependent fashion. The pharmacodynamic window, characterized by the ratio of plasma concentrations required to achieve a 50% (IC50) and 10% (IC10) reduction in fractional shortening (IC50/IC10) was 9.6 for CK-274. The exposure-response relationship for CK-274 in healthy dogs was similar to that observed in rats.

Preclinical pharmacokinetic characterization of CK-274 suggested its predicted half-life in humans was 2.8 days1. This projection was borne out in the first-in-human Phase 1 study of CK-274 in healthy volunteers in which the single dose administered half-life was observed to be 3.4 days2, and steady-state was reached within 2 weeks following multiple doses. Reaching steady state within two weeks may translate to ease of dose titration and onset of action in patients with obstructive HCM, as well as timely reversibility of effect if discontinuation is necessary. CK-274 was designed to have a low potential to inhibit representative human CYP450s in order to reduce the potential for drug-drug interactions. CK-274 did not exhibit direct or time dependent inhibition of seven human CYP isoforms (IC50 > 30 ?M for 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4).

Comparison of CK-274 to mavacamten, a cardiac myosin inhibitor, whose precursor was discovered by Cytokinetics' scientists and subsequently optimized in collaboration with Myokardia, Inc. and now being developed by Bristol-Myers Squibb Company, was also performed in certain preclinical assays. The presentation from the American Chemical Society Spring 2021 Virtual Meeting can be found at https://cytokinetics.com/publications-and-presentations.

Together, these data suggest that CK-274 may be a next-in-class, cardiac myosin inhibitor with a shallow pharmacokinetic/pharmacodynamic relationship and pharmacokinetics that may provide for flexible dose titration. The efficacy and safety of CK-274 are now being evaluated in patients with obstructive HCM.