Off-target of a novel TYK2 inhibitor is associated with myocardial necrosis mediated by hemodynamic changes in rats

Abstract

After an observation of myocardial necrosis and inflammation in rats administered an experimental TYK2 inhibitor (ABBV-712), investigative studies were performed to identify the potential mechanism. Telemetry instrumented rats were administered ABBV-712 with or without atenolol to assess hemodynamic changes and cardiac pathology. In vitro studies included cytotoxicity evaluation in human induced pluripotent stem cell-derived cardiomyocytes and assessment of relaxation of an isolated rat aorta model. Off-target pharmacology was evaluated by binding and inhibition screening assays. Finally, TYK2 knockout (KO) mice were instrumented with telemetry to determine hemodynamic changes as compared to wildtype animals following administration of ABBV-712. In these studies in rats, ABBV-712 resulted in decreased mean arterial pressure and increased heart rate that was prevented by pre-dosing atenolol. ABBV-712-induced myocardial pathology was also prevented by atenolol, consistent with a mechanistic link between hemodynamic changes and cardiac injury. The myocardial necrosis observed was determined to be unrelated to direct cytotoxicity on cardiomyocytes as demonstrated in vitro. Further, a compound-related effect on vascular relaxation mediated by endothelial cells was found in the aortic ring model. Overall the toxicity was considered an off-target effect, as suggested by similar hemodynamic responses between TYK2 KO and wildtype mice administered ABBV-712, as well as by the lack of hemodynamic changes in the KO mouse at baseline. Inhibition of the off-targets that were identified in the screening effort were considered unlikely to be the cause of the hemodynamic changes based on canonical pharmacology. In this study, a novel TYK2 small molecule inhibitor resulted in decreased mean arterial pressure, increased heart rate, and secondary myocardial necrosis in rats. These cardiovascular effects were unrelated to TYK2 inhibition. This report is an example of a cross-functional mechanistic investigation into the pharmacologic cause of an observation of cardiovascular toxicity.