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

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 decrease by ~85%), while having mild inhibition (ETP decrease by ~35%) on TF-initiated TG. 4F-PCC, partially reversed the effects of milvexian on aPTT and kaolin induced TG parameters (Endogenous thrombin potential - ETP and Peak Thrombin). The reversal effect was rapid (within 15 minutes after the end of infusion) and lasted for at least 8 hours. 4F-PCC completely reversed the effect of milvexian on TF-initiated peak thrombin and increased ETP from the pre-milvexian baseline by ~68%. rFVIIa partially reversed the effects of milvexian on aPTT, kaolin induced ETP and peak thrombin and TF induced peak thrombin. Changes in lag time and time to peak were also partially reversed by rFVIIa. The reversal effect was acute (maximum effects observed at 15 minutes after infusion start) and transient in agreement with rFVIIa half-life. The PK of milvexian was comparable after BID administration of 200 mg for 4 days with a single IV infusion of 50 IU/kg 4F-PCC or placebo on Day 4. The single-dose PK of milvexian (100 mg or 500 mg) was not affected by coadministration of 30 μg/kg rFVIIa. Single and repeated doses of milvexian and single infusions of 4F-PCC and rFVIIa were generally safe and well tolerated.

Discussion/Conclusion:Anticoagulant effect of milvexian was successfully reversed by two commonly available, non-specific reversal agents - 4F-PCC and a low dose of rFVIIa. This may provide clinicians with additional data to assess treatment options in cases of active bleeding or the need for urgent surgical interventions in patients treated with milvexian.

Dishy:Johnson & Johnson Innovative Medicine: Current Employment, Current equity holder in publicly-traded company. Sha:Johnson & Johnson Innovative Medicine: Ended employment in the past 24 months. Chintala:Johnson & Johnson Innovative Medicine: Current Employment, Current equity holder in publicly-traded company. Koshkina:Johnson & Johnson Innovative Medicine: Ended employment in the past 24 months; MBX Biosciences: Current Employment, Current equity holder in publicly-traded company. Tesfaye:Johnson & Johnson Innovative Medicine: Ended employment in the past 24 months. Zannikos:Johnson & Johnson Innovative Medicine: Current Employment, Current equity holder in publicly-traded company. Makimura:Johnson & Johnson Innovative Medicine: Current Employment, Current equity holder in publicly-traded company.