Anticoagulation with the mechanistically distinct FXI/FXIa antibodies amrecibart (REGN9933A2) and cenvacibart (REGN7508Cat)

Thrombosis is a major contributor to global morbidity and mortality. Current standards of care target the extrinsic and/or common pathways of coagulation, effectively inhibiting thrombosis but also increasing bleeding risk, highlighting the unmet need for additional treatment options. Genetic deficiency in factor XI (FXI), a component of the intrinsic pathway, reduces thrombosis risk without spontaneous bleeding. We generated 2 FXI monoclonal antibodies (mAbs) with distinct profiles to provide new approaches to anticoagulation. Cenvacibart (REGN7508Cat) targets the catalytic domain to completely block FXI activity (induced by activated FXII [FXIIa] or activated FXI [FXIa] in the intrinsic pathway or thrombin in the intrinsic/common pathway amplification loop), thereby maximizing anticoagulation. Amrecibart (REGN9933A2) targets the apple 2 domain of FXI/FXIa to specifically prevent FXI activity induced by FXIIa, delivering perhaps less anticoagulation but with potentially lower bleeding risk. We evaluated the anticoagulant effects of both mAbs in vitro in human and nonhuman primate plasma, in vivo in nonhuman primates, and healthy volunteers. Both mAbs inhibited intrinsic pathway-triggered coagulation, assessed by activated partial thromboplastin time (aPTT); cenvacibart exhibited a greater increase in aPTT vs amrecibart or other FXI-targeted inhibitors. Neither amrecibart nor cenvacibart affected the extrinsic pathway, assessed by prothrombin time (PT). In nonhuman primates, both mAbs prevented thrombosis without increasing bleeding. In first-in-human studies, both mAbs were generally well tolerated and dose-dependently inhibited intrinsic pathway-triggered coagulation, with durable aPTT prolongation without affecting PT. Amrecibart and cenvacibart may offer tailored therapies for patients with different bleeding risk profiles. These trials were registered at www.clinicaltrials.gov as NCT05102136 and NCT05603195.