Discovery of Milvexian, a High-Affinity, Orally Bioavailable Inhibitor of Factor XIa in Clinical Studies for Antithrombotic Therapy

Abstract

Factor XIa (FXIa) is an enzyme in the coagulation cascade thought to amplify thrombin generation but has a limited role in hemostasis. From preclinical models and human genetics, an inhibitor of FXIa has the potential to be an antithrombotic agent with superior efficacy and safety. Reversible and irreversible inhibitors of FXIa have demonstrated excellent antithrombotic efficacy without increased bleeding time in animal models (WeitzJ. I.ChanN. C. Weitz, J. I. Chan, N. C. Arterioscler. Thromb. Vasc. Biol.201939712). Herein, we report the discovery of a novel series of macrocyclic FXIa inhibitors containing a pyrazole P2′ moiety. Optimization of the series for (pharmacokinetic) PK properties, free fraction, and solubility resulted in the identification of milvexian (BMS-986177/JNJ-70033093, 17, FXIa K i = 0.11 nM) as a clinical candidate for the prevention and treatment of thromboembolic disorders, suitable for oral administration.

Milvexian, an orally bioavailable, small‐molecule, reversible, direct inhibitor of factor XIa: In vitro studies and in vivo evaluation in experimental thrombosis in rabbits

“…4 Given the preclinical and early clinical evidence for robust antithrombotic efficacy with limited hemostatic liability upon genetic disruption or pharmacologic inhibition, FXIa is an attractive target for antithrombotic therapy. [4][5][6][7][8][9][10] Milvexian (formerly referred to as BMS-986177/JNJ-70033093; Figure 1A), an orally bioavailable small molecule that inhibits FXIa with high affinity and selectivity, 11 is being developed to prevent thrombotic events in diverse patient populations. In a phase 1 study, milvexian given orally either as a single dose or multiple ascending doses for 14 days was orally bioavailable, and generally safe and well tolerated in healthy volunteers.…”

“…Milvexian (formerly referred to as BMS‐986177/JNJ‐70033093; Figure 1A), an orally bioavailable small molecule that inhibits FXIa with high affinity and selectivity, 11 is being developed to prevent thrombotic events in diverse patient populations. In a phase 1 study, milvexian given orally either as a single dose or multiple ascending doses for 14 days was orally bioavailable, and generally safe and well tolerated in healthy volunteers 12 .…”

Safety, pharmacokinetics, and pharmacodynamics of milvexian in healthy Japanese participants

“…This study investigated the safety, tolerability, PK, and PD of multiple ascending oral doses of milvexian in healthy Japanese participants. Milvexian is one of the first oral, small-molecule FXIa inhibitors being developed to prevent and treat thrombotic events in diverse patient populations 24 and may offer an improvement over the benefit/risk profile of current anticoagulants. Demonstration of the safety and tolerability of milvexian in Japanese participants will allow inclusion of this population in subsequent phase 2 and 3 studies and inform whether dose adjustments will be necessary for future trials and for routine clinical care.…”

“…Milvexian is a potent orally bioavailable small molecule that binds and inhibits FXIa with high affinity and selectivity 24 . Milvexian is being developed to prevent and treat thrombotic events in multiple patient populations.…”

Factor XI as a target for preventing venous thromboembolism

“…This results in a FXI deficiency‐like state, in the sense that the amount of FXI available for activation in plasma is reduced. Milvexian, a macrocyclic small‐molecule inhibitor, engages the FXIa catalytic active site, where it competes for binding with natural substrates such as FIX 33,34 . Information for the TKA trials using these drugs is presented in Table 2.…”