First randomized evaluation of safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, an antibody targeting coagulation factor XI and factor XIa, in healthy men

Abstract

Background Bleeding is a clinically significant issue with all current anticoagulants. Safer antithrombotic strategies are required. Objectives To investigate the safety, pharmacodynamics, and pharmacokinetics of BAY 1831865, a humanized, factor XI (FXI)‐directed monoclonal antibody, after single intravenous (i.v.) or subcutaneous (s.c.) doses in healthy volunteers. Patients/Methods In a first‐in‐human, phase I study, 70 volunteers were randomly assigned (4:1) to receive single‐dose BAY 1831865 (3.5, 7, 17, 35, 75, or 150 mg i.v. or 150 mg s.c.) or placebo. Adverse events, pharmacodynamics, and pharmacokinetics were evaluated. Results In this study, no hemorrhage, or hypersensitivity or infusion‐/injection‐related reactions were reported. Drug‐related adverse events occurred in 3 (5.4%) of 56 volunteers; all were mild and self‐limited. Dose‐dependent prolongation of activated partial thromboplastin time (aPTT) and inhibition of FXI clotting activity was observed with BAY 1831865 i.v. (geometric mean maximum ratio‐to‐baseline: aPTT, range, 1.09–3.11 vs. 1.05 with placebo; FXI, range, 0.70–0.04 vs. 0.91 with placebo). Onset of effect was rapid after i.v. administration, with duration of effect (up to 55 days) determined by dose. BAY 1831865 s.c. had similar pharmacodynamic effects but a slower onset of action. Terminal half‐life increased continuously with increasing i.v. dose (range, 28–208 h), leading to strong and continuous increases in systemic exposure to BAY 1831865. Absolute bioavailability of BAY 1831865 s.c. was 47.2% (95% confidence interval, 30.2–73.7). Conclusions BAY 1831865 i.v. or s.c. was well tolerated, with no evidence of bleeding in healthy volunteers. BAY 1831865 exhibited pronounced, sustained dose‐dependent prolongation of aPTT and duration of FXI inhibition.

Clinical Pharmacology of Factor XI Inhibitors: New Therapeutic Approaches for Prevention of Venous and Arterial Thrombotic Disorders

“…doses, ranging from 1.0 h to 2.0 h after the start of infusion. As expected, a dose-dependent decrease of clearance (CL) was observed, from 0.0815 L/h at 7 mg until 0.0137 L/h at 150 mg [ 26 ].…”

“…Since abelacimab binds directly to the FXI catalytic domain [ 23 ] and osocimab to a region adjacent to the active site providing an allosteric inhibitory activity [ 24 ], an antibody combining FXI zymogen inhibition with active site-focused inhibition may have distinct properties. BAY 1831865 is a humanized, sequence-optimized, mAb that binds specifically to the apple domain 3 of FXI [ 26 ]. This domain binds several ligands, including FIX and FXIIa.…”

“…Following i.v. administration, there was a dose-dependent increase in plasma concentration of BAY 1831865 (C max ) without a significant deviation from dose-proportionality [ 26 ]. However, the t 1/2 increased with the dose, from 28.4 h at 7 mg until 208 h at 150 mg, suggesting a potential accumulation of the drug.…”

“…For FXIa activity, values returned to baseline after 13 days with the 3.5 mg i.v. dose and were almost, but not fully, restored to baseline during the observation period (55 days) at the dose of 150 mg (0.82 vs. basal) [ 26 ].…”

“…and 150 mg i.v., respectively. The onset of effect after s.c. administration on clotting time was slower compared to i.v., with ratios to baseline value equal to 2.9 [ 26 ].…”