Reversal of the Anticoagulant Effect of Milvexian By 4-Factor PCC and rFVIIa in Healthy Participants

作者：Victor Dishy, Sue Sha, Madhu Chintala, Anastasiya Koshkina, Fisseha Tesfaye, Peter Zannikos, Hideo Makimura · 发表于：Blood · 年份：2024 · DOI：10.1182/blood-2024-207466 · 研究领域：Systemic Sclerosis and Related Diseases

Introduction/Objective:Milvexian is a novel, selective, oral factor XIa (FXIa) inhibitor, currently being evaluated in the Librexia Phase III program for the prevention of thrombosis in patients with atrial fibrillation, acute coronary syndrome and ischemic stroke and transient ischemic attacks. In patients receiving anticoagulation, treatment of bleeding events or need for urgent interventions may require use of reversal agents. The present study assessed the potential of 4-Factor Prothrombin Complex Concentrate (4F-PCC) and recombinant human factor VIIa (rFVIIa) to reverse the anticoagulant effects of milvexian in healthy participants. Materials/Methods:This was an open-label, randomized, placebo-controlled, crossover, 2-part study. In Part 1, milvexian 100 mg BID was administered for 3 days, followed by 50 IU/kg 4F-PCC IV or placebo, 4 hours after the morning milvexian dose on Day 4. In Part 2, single doses of milvexian (100 or 500 mg) were administered followed by 30 μg/kg rFVIIa IV or placebo 4 hours later. Anticoagulation was assessed by activated partial thromboplastin time (aPTT) and thrombin generation (TG) using 2 different activators: kaolin, to assess anticoagulant effect on the intrinsic pathway, and tissue factor (TF) to assess the effect on the extrinsic pathway. The effect of 4F-PCC or rFVIIa coadministration on the pharmacokinetics (PK) of milvexian was also assessed. Results: Milvexian showed prolongation of aPTT and inhibition of kaolin-initiated TG (ETP de...