Abstract TMP117: Preclinical and Early Clinical Characterization of a Parenterally Administered Direct Factor XIa Inhibitor

Introduction: Acute stroke intervention with antithrombotic agents is limited due to an increased risk of bleeding and a frequent inability to swallow existing oral agents. Preclinical and early clinical data with an antisense oligonucleotide suggest inhibition of Factor XI (FXI) as a means to achieve antithrombotic efficacy with a reduced risk of bleeding. Here we report a preclinical characterization and results from first-in-human studies of BMS-962212, a first in class, direct, reversible, and highly selective IV small molecule inhibitor of FXIa (FXIa Ki = 0.7 nM). Methods: BMS-962212 at 0.001+0.0063 to 0.46+3.1 mg/kg+mg/kg/h or its vehicle were administered IV in anesthetized rabbit models of electrically-induced carotid artery thrombosis and cuticle bleeding time. To evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of BMS-962212 in humans, 6 healthy subjects per dose panel received BMS-962212 at 1.5, 4, 10, and 25 mg/h as 2 hour IV infusions and, respectively, 1, 3, 9, and 2...