No Influence of Asundexian on Cardiac Repolarization.

ABSTRACT

Inhibition of activated factor XI reduces thrombogenesis while maintaining physiological hemostasis, with the expectation of reduced bleeding risk compared with standard of care in the clinical setting. Asundexian (BAY 2433334), an activated factor XI inhibitor, is in clinical development for the prevention of thromboembolic events. The effect of asundexian and its plasma metabolite M10 on cardiac repolarization and potential interactions with the hNav1.5 sodium, hCav1.2 calcium, and human ether-à-go-go-related gene (hERG) potassium channels was investigated in vitro. Additionally, asundexian effects on cardiac parameters and electrocardiogram were examined in telemetered beagle dogs. A randomized, placebo-controlled, 4-way crossover, thorough QT study in healthy adults evaluated the influence of 50 and 150 mg of asundexian on the corrected QT interval, including 400 mg of moxifloxacin as positive control. Across all studies, asundexian and M10 were not associated with any effects on cardiac repolarization. The largest in vitro effects of asundexian (approximately 20% inhibition) were seen for hCav1.2 and hERG. Throughout the thorough QT study, the upper limits of the one-sided 95% confidence interval of placebo-corrected mean changes from baseline in Fridericia corrected QT for 50 and 150 mg of asundexian were below Δ = 10 milliseconds. Asundexian demonstrated favorable safety and tolerability profiles.