First-in-human trial of SAR107375E, a novel small molecule anticoagulant with dual inhibition of factor Xa and factor IIa

Abstract

ABSTRACT Background SAR107375E is a direct dual inhibitor of both Factor Xa and Factor IIa and has shown potent anticoagulation activity in vitro and animals. This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single ascending intravenous doses of SAR107375E in healthy Chinese adult subjects. Methods In this randomized, double-blind, placebo-controlled trial, 60 healthy Chinese adult subjects were administered intravenously single ascending doses (0.5, 1.5, 3.0, 5.0, 7.5, 10.0, 15.0, or 20.0 mg) of SAR107375E (N = 44) or placebo (N = 16). Plasma and urine concentrations of SAR107375E were measured and used to calculate pharmacokinetic parameters. Coagulation functions were measured and compared with baseline values. Treatment-emergent adverse events were recorded to evaluate safety. Results In plasma, from the 0.5 to 20.0 mg dose group, t1/2 is 1.51–4.00 h, Cmax is 59.05–1360 ug/L, and AUC0-t is 25.01–528.45 h*ug/L. And it shows dose proportionality in the 5.0–20.0 mg range. Activated partial thromboplastin time and Ecarin clotting time correlated linearly with drug plasma concentration. No serious adverse events were reported during the study. Conclusion SAR107375E exhibits good safety and tolerability, predictable pharmacokinetics and pharmacodynamics. Clinical trial registration www.chinadrugtrials.org.cn, identifier is CTR20211082.