PB0384 - Antibodies against factor XI/factor XIa effectively anticoagulate without increasing bleeding risk in cynomolgus monkeys

Background: Venous and arterial thromboses are common causes of morbidity and mortality. Although several classes of anticoagulant agents are approved, an unmet need exists for anticoagulants without an increased bleeding risk. Genetic and pharmacologic evidence from human and animal studies suggests inhibition of coagulation factor XI (FXI) can effectively prevent thrombosis with little-to-no increased bleeding risk.

Aims: To evaluate two monoclonal antibodies (mAbs) to FXI/activated FXI (FXIa), one to the catalytic domain (Cat-mAb) and the other to the apple 2 domain (A2-mAb), in in vitro plasma coagulation activity assays and in vivo thrombosis and hemostasis challenge models using cynomolgus monkeys.

Methods: Functional effects of mAbs on monkey plasma coagulation activities were assessed with activated partial thromboplastin time (aPTT) and prothrombin time (PT), and in thrombin generation assays (TGAs) with activators specific for intrinsic or extrinsic pathway activation. Efficacy of anti-FXI/FXIa mAbs was evaluated in monkeys undergoing hemodialysis, a model of contact-mediated thrombosis, while bleeding risk was evaluated with a gastrointestinal (GI) bleeding model.

Results: Functional dose–response analysis in cynomolgus plasma revealed Cat-mAb more effectively inhibited intrinsic activity than A2-mAb (aPTT ratio 2.5 vs ~1.9, respectively). Similarly, TGA data revealed Cat-mAb exerted a 90% reduction in intrinsic pathway-triggered thrombin generation, whereas A2-mAb exerted a 60% reduction. Neither mAb affected PT ratio; however, Cat-mAb reduced extrinsic pathway-triggered thrombin generation by 50%, whereas A2-mAb had no effect.

Both mAbs, like heparin, enabled completion of hemodialysis, but unlike heparin, did not increase bleeding. Additionally, the mAbs did not augment bleeding beyond that induced by indomethacin in the GI bleeding model.

Conclusion(s): These results demonstrate that Cat-mAb and A2-mAb effectively prevent thrombosis (via intrinsic pathway inhibition) without increasing bleeding risk in monkeys; therefore, anti-FXI/FXIa mAbs may be a safer approach to anticoagulation than standard of care anticoagulants in humans.