Decoding factor XI inhibition

In this issue of Blood, Chalothorn et al 1 report preclinical and first-in-human data on 2 novel monoclonal antibodies targeting factor XI (FXI): REGN9933A2, which blocks the apple 2 domain, and REGN7508Cat, which inhibits the catalytic domain.These agents are designed to provide safer anticoagulation by selectively targeting the intrinsic pathway, potentially reducing bleeding risk compared with current therapies.REGN7508Cat demonstrated greater anticoagulant potency than REGN9933A2, consistent with its catalytic blocking mechanism.First-in-human studies in healthy adults revealed dose-dependent, durable activated partial thromboplastin time prolongation without changes in prothrombin time or major bleeding events; both antibodies were well tolerated.The investigators used a translational approach encompassing structural characterization, in vitro assays, nonhuman primate thrombosis and bleeding models, and first-in-human studies.Together, these findings support continued development and suggest potential for mechanism-tailored therapy.Coagulation is complex, dynamic, and organ specific, and proteins contribute differently across vascular beds and clinical settings.This perspective informs rational drug development strategies aimed at precision modulation of coagulation as the proximate cause of pathological thrombosis. 2