The serine protease factor XI (FXI) is a prominent drug target as it holds promise to deliver efficacious anticoagulation without an enhanced risk of major bleeds. Several efforts have been described targeting the active form of the enzyme, FXIa. Herein, we disclose our efforts to identify potent, selective, and orally bioavailable inhibitors of FXIa. Compound 1, identified from a diverse library of internal serine protease inhibitors, was originally designed as a complement factor D inhibitor and exhibited submicromolar FXIa activity and an encouraging absorption, distribution, metabolism, and excretion (ADME) profile while being devoid of a peptidomimetic architecture. Optimization of interactions in the S1, S1β, and S1' pockets of FXIa through a combination of structure-based drug design and traditional medicinal chemistry led to the discovery of compound 23 with subnanomolar potency on FXIa, enhanced selectivity over other coagulation proteases, and a preclinical pharmacokinetics (PK) profile consistent with bid dosing in patients.

A large unmet medical need exists for safer antithrombotic drugs because all currently approved anticoagulant agents interfere with hemostasis, leading to an increased risk of bleeding. Genetic and pharmacologic evidence in humans and animals suggests that reducing factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with a minimal risk of bleeding. We generated a fully human antibody (MAA868) that binds the catalytic domain of both FXI (zymogen) and activated FXI. Our structural studies show that MAA868 traps FXI and activated FXI in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process, revealing a particularly attractive anticoagulant profile of the antibody. MAA868 exhibited favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a ferric chloride-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by activated partial thromboplastin time without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects and showed that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in dose- and time-dependent robust and sustained prolongation of activated partial thromboplastin time and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as a potential once-monthly subcutaneous anticoagulant therapy.

A large unmet medical need exists for safer anti-thrombotic drugs since all currently approved anticoagulants interfere with hemostasis leading to an increased risk of bleeding. Genetic and pharmacological evidence in humans and animals suggest that reducing Factor XI (FXI) levels has the potential to effectively prevent and treat thrombosis with minimal risk of bleeding. We generated a fully human antibody—MAA868—that binds the catalytic domain of both FXI (zymogen) and the activated FXI (FXIa). Our structural studies show that MAA868 traps FXI and FXIa in an inactive, zymogen-like conformation, explaining its equally high binding affinity for both forms of the enzyme. This binding mode allows the enzyme to be neutralized before entering the coagulation process revealing a particularly attractive anticoagulant profile of the antibody. MAA868 showed favorable anticoagulant activity in mice with a dose-dependent protection from carotid occlusion in a FeCl3-induced thrombosis model. MAA868 also caused robust and sustained anticoagulant activity in cynomolgus monkeys as assessed by aPTT without any evidence of bleeding. Based on these preclinical findings, we conducted a first-in-human study in healthy subjects demonstrating that single subcutaneous doses of MAA868 were safe and well tolerated. MAA868 resulted in doseand time-dependent robust and sustained aPTT prolongation and FXI suppression for up to 4 weeks or longer, supporting further clinical investigation as potential once monthly subcutaneous anticoagulant therapy. For personal use only. on January 30, 2019. by guest www.bloodjournal.org From