Abstract WP286: ONO-8610539, an Injectable Small-Molecule Inhibitor of Blood Coagulation Factor XIa, Improves Cerebral Ischemic Injuries Associated with Photothrombotic Occlusion of Rabbit Middle Cerebral Artery

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Abstract

Background and Purpose: High levels of blood coagulation factor XI (FXI) are an established risk factor for acute ischemic stroke and thrombosis. Patients with severe FXI deficiency have a low risk of ischemic stroke. In addition, FXI-deficient or anti-FXI antibody-treated mice are protected against cerebral ischemic injury and bleeding is not observed. Therefore, FXI is considered to be a promising drug target for the treatment and secondary prevention of ischemic stroke that would not increase the risk of bleeding. ONO-8610539 is a potent, injectable small-molecule inhibitor of activated FXI. The objective of this study was to elucidate the effects of ONO-8610539 on preventing ischemic brain injury in an experimental stroke model.

Methods: The preventive and hemorrhagic effects of ONO-8610539 were compared with those of argatroban, a direct thrombin inhibitor, in a rabbit middle cerebral artery (MCA) occlusion model. To occlude the MCA photothrombotically, rose bengal was administered, followed by irradiation with green light for 30 minutes. The intravenous administration of ONO-8610539 or argatroban was then initiated and continued for 23.5 hours. The effects of these compounds on neurological function, infarcted brain volume, and cerebral hemorrhage volume were evaluated in a blinded manner. Blood was collected to measure activated partial thromboplastin time (APTT) and prothrombin time (PT) before and at 24 hours after photothrombosis.

Results: ONO-8610539 at doses of 0.3 and 1 mg/kg/h significantly attenuated neurological deficits and infarct volumes in the cortex. Even at a dose of 1 mg/kg/h, ONO-8610539 did not increase cerebral hemorrhage volume. The APTT ratios increased by 1.9-fold from baseline at the 0.3 mg/kg/h dose and increased by 4.4-fold at 1 mg/kg/h, while changes in PT were not observed at either doses. Argatroban also prevented ischemic neuronal injuries at 0.3 mg/kg/h; however, these effects were attenuated at 1 mg/kg/h. Moreover, argatroban significantly exacerbated cerebral hemorrhage at 1 mg/kg/h.

Conclusion: ONO-8610539 is expected to be a novel potent anticoagulant for the treatment and prevention of ischemic stroke that does not increase bleeding risk.

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