Rationale for the milvexian dosing in the phase 3 LIBREXIA program

BACKGROUND: Milvexian is an oral, small-molecule inhibitor of factor (F)XIa undergoing evaluation in phase 3 clinical trials. OBJECTIVES: This manuscript aimed to explain the rationale underpinning the hypothesis that FXIa may be a safer target for anticoagulants than FXa; describe the pharmacology of milvexian; review the results of the phase 2 trials with milvexian; and detail how the phase 2 program informed the dosing regimens for the phase 3 trials. METHODS: This narrative review addresses the above objectives with the primary focus on addressing how the milvexian dosing regimens were selected for the phase 3 LIBREXIA program, which compares milvexian with apixaban for atrial fibrillation (AF) in the LIBREXIA AF trial (NCT05757869) and with placebo, in addition to background single or dual antiplatelet therapy, in patients with acute coronary syndrome (ACS) in the LIBREXIA ACS trial (NCT05754957), and for noncardioembolic ischemic stroke and high-risk transient ischemic attack in the LIBREXIA Stroke trial (NCT05702034). RESULTS: The milvexian dose regimen selected for the LIBREXIA AF trial is 100 mg twice daily, and for the LIBREXIA ACS and Stroke trials, it is 25 mg twice daily. CONCLUSIONS: The phase 3 LIBREXIA program will determine whether these dose regimens afford safe and effective anticoagulation in approximately 50 000 patients with AF, ACS, or prior stroke.