In the search for novel antithrombotic agents that could offer an improved differential between safety and efficacy versus current standard of care, inhibition of factor XIa (fXIa) has emerged as a target for therapeutic intervention. The rationale is based on several points of validation from human genetics and animal models. Human fXI genetic deficiency is tolerated and spontaneous bleeding is rare. Epidemiologic studies show that elevated fXI levels are associated with increased thrombosis risk, whereas fXI deficiency is associated with a reduced incidence of ischemic stroke. In preclinical studies by BMS researchers employing irreversible and reversible direct fXIa inhibitors, robust antithrombotic efficacy with minimal effects on hemostasis was demonstrated. These finding are also supported by fXI gene ablation in mice. More recently, additional clinical validation was provided via knocking down Factor XI with an anti-sense oligonucleotide (ASO) in patients undergoing elective knee arthroplasty surgery.<br/><br/>Despite the promising therapeutic profile of fXIa inhibitors, identifying potent, selective, orally bioavailable agents has been extremely challenging with research spanning over 2 decades. One of the particular challenges for discovering orally bioavailable inhibitors of fXIa is the need to interact with the substrate S’ region binding pocket of the active site through polar interactions. Given the constraints of interactions over a larger region of the active site through polar interactions, there is a dynamic tension in simultaneously optimizing affinity and pharmacokinetics. In contrast, inhibitors of thrombin and factor Xa (fXa) interact with the substrate S binding pocket, spanning a smaller region within the active site.<br/><br/>Our discovery of a macrocyclic chemotype provided a platform with efficient interactions in the active site for affinity while presenting multiple options for improving pharmacokinetics and pharmaceutical properties. Through an extensive optimization effort the macrocyclic platform culminated in the discovery of BMS-986177. In well validated preclinical models, BMS-986177 blocked thrombus formation at doses which preserved hemostasis. In Phase 1 studies, BMS-986177 was well tolerated. Phase 2 studies are underway to explore the safety and efficacy of BMS-986177 for antithrombotic therapy.

Discovery of BMS-986177/JNJ-70033093 an inhibitor of FXIa in phase 2 studies for antithrombotic therapy

ACS Fall 2020 Virtual Meeting

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