Abstract
Introduction: Factor XI (FXI) is an important component in the intrinsic pathway of the coagulation system. FXI antisense oligonucleotide achieves antithrombotic efficacy with a low risk of bleeding in preclinical and early clinical studies. ONO-8610539 is a potent, injectable small-molecule inhibitor of activated FXI. We previously reported ONO-8610539 attenuated cerebral ischemic injury without increasing cerebral hemorrhage in a rabbit photothrombosis model. In this study, we aimed to compare the efficacy of ONO-8610539 and tissue plasminogen activator (t-PA) in the stroke model. Methods: Animal experiments were performed in accordance with Regulations for Animal Experiments of ONO Pharmaceutical Co., Ltd. Using a rabbit photothrombosis model, t-PA was intravenously infused at 1 mg/kg/h for 1 hour from immediately or 1 hour after thrombosis induction. ONO-8610539 at 0.3 mg/kg/h was intravenously infused for 24 hours from 1 or 2 hours after thrombosis induction. Moreover, ONO-8610539 was intravenously infused at 0.3 mg/kg/h for 24 hours from 3, 4.5 or 6 hours after thrombosis induction to examine the therapeutic time window (TTW) of ONO-8610539. The neurological function, infarct volume and cerebral hemorrhage volume were evaluated at 24 hours after thrombosis induction. Blood was collected to measure activated partial thromboplastin time (APTT) and prothrombin time (PT) before and 24 hours after thrombosis induction. Results: Administration of t-PA immediately after thrombosis induction tended to attenuate neurological deficits and infarct volume without increasing cerebral hemorrhage. Administration of t-PA at 1 hour after thrombosis induction did not attenuate neurological deficits and infarct volume and tended to exacerbate cerebral hemorrhage. ONO-8610539 significantly attenuated neurological deficits and infarct volume without increasing cerebral hemorrhage, with a TTW of 4.5 hours. The APTT ratios of ONO-8610539 increased by 2.0-fold from baseline, while changes in PT were not observed. Conclusion: ONO-8610539 has a potent effect comparable to t-PA with a wide TTW in rabbit photothrombosis model and is expected to be a useful anticoagulant for ischemic stroke without increasing the risk of bleeding.
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