Rapid Clearing CT-001 Restored Hemostasis in Mice with Coagulopathy Induced by Activated Protein C

Background Activated protein C (APC) is one of the mechanisms contributing to coagulopathy, which is associated with high mortality. The counteraction of the APC pathway could help ameliorate bleeding. However, patients also transform frequently from a hemorrhagic state to a prothrombotic state at a later time. Therefore, a pro-hemostatic therapeutic intervention should take this thrombotic risk into consideration. Objectives CT-001 is a novel factor VIIa (FVIIa) with enhanced activity and desialylated N-glycans for rapid clearance. We assessed CT-001 clearance in multiple species and its ability to reverse APC-mediated coagulopathic blood loss. Methods The N-glycans on CT-001 were characterized by liquid chromatography-mass spectrometry. Three species were used to evaluate the pharmacokinetics of the molecule. The potency and efficacy of CT-001 under APC-pathway induced coagulopathic conditions were assessed by coagulation assays and bleeding models. Results The N-glycosylation sites of CT-001 had high occupancy of desialylated N-glycans. CT-001 exhibited 5 to 16 times higher plasma clearance in human tissue factor knockin mice, rats, and cynomolgus monkeys than wildtype (WT) FVIIa. CT-001 corrected the activated partial thromboplastin time (APTT) and thrombin generation of coagulopathic plasma to normal in in vitro studies. In an APC-mediated saphenous vein bleeding model, 3 mg/kg CT-001 reduced bleeding time in comparison to WT FVIIa. The correction of bleeding by CT-001 was also observed in a coagulopathic tail amputation severe hemorrhage mouse model. The efficacy of CT-001 is independent of the presence of tranexamic acid and the combination of CT-001 and tranexamic acid does not lead to increased thrombogenicity. Conclusions CT-001 corrected APC pathway-mediated coagulopathic conditions in preclinical studies and could be a potentially safe and effective pro-coagulant agent for addressing APC-mediated bleeding. Study Type Basic science research Level of Evidence Not applicable