ABBV-712-induced cardiac pathology in rats is related to off-target-driven acute vasodilation, tachycardia, and increased cardiac contractility

Following an observation of myocardial toxicity in rats with an experimental TYK2 inhibitor (ABBV-712), investigative studies were performed to identify the mechanism. Telemetry-instrumented rats were administered ABBV-712 with or without atenolol to investigate effects of co-dosing on hemodynamic parameters and cardiac pathology. In vitro studies included cytotoxicity assessment in human-induced pluripotent stem cell-derived cardiomyocytes and relaxation of isolated rat aorta. Off-target pharmacology was evaluated by binding and inhibition screening assays. Finally, TYK2 knockout mice were administered ABBV-712 to evaluate hemodynamics as compared with wild-type animals. ABBV-712 resulted in decreased mean arterial pressure and increased heart rate in rats that was prevented by pre-dosing atenolol. ABBV-712-induced myocardial necrosis was also prevented by atenolol, suggesting a mechanistic link between hemodynamic changes and cardiac pathology. The pathology was unrelated to direct cytotoxicity on cardiomyocytes as demonstrated in vitro and was shown to be a compound-related effect on vascular relaxation mediated by the endothelium. The toxicity was considered an off-target effect, as demonstrated by similar hemodynamic responses between TYK2 knockout and wild-type mice administered ABBV-712, as well as by the lack of hemodynamic alterations in the knockout mouse. Inhibition of identified off-targets was unlikely to be the cause of the hemodynamic changes. In conclusion. a novel TYK2 inhibitor was associated with decreased mean arterial pressure, increased heart rate, and secondary myocardial necrosis in rats. These effects were unrelated to TYK2 inhibition. This report is an example of a cross-functional mechanistic investigation into the pharmacologic cause of an identified cardiovascular toxicity.