BAY 1213790, a fully human IgG1 antibody targeting coagulation factor XIa: First evaluation of safety, pharmacodynamics, and pharmacokinetics

Abstract

Background Coagulation factor XI ( FXI ) contributes to the development of thrombosis but appears to play only a minor role in hemostasis and is therefore an attractive anticoagulant drug target. Objectives To evaluate the safety, pharmacodynamic, and pharmacokinetic properties of BAY 1213790, a fully human immunoglobulin (Ig) G1 antibody targeting activated coagulation FXI ( FXI a), in healthy men. Methods In this phase 1, single‐blind, parallel‐group, placebo‐controlled, dose‐escalation study, 83 healthy Caucasian men were randomized 4:1 to receive a single 60‐minute intravenous infusion of BAY 1213790 (0.015‐10 mg/kg) or placebo. Adverse events, pharmacodynamic parameters (including activated partial thromboplastin time [ aPTT ]) and pharmacokinetic parameters were determined. Volunteers were followed up for 150 days. Results BAY 1213790 demonstrated favorable safety and tolerability; there were no observed cases of bleeding or clinically relevant antidrug antibody formation. One volunteer (1.2%) experienced an infusion reaction. Following intravenous administration of BAY 1213790, dose‐dependent increases in aPTT (maximal mean increase relative to baseline: 1.85 [conventional method] and 2.17 [kaolin‐triggered method]) and rotational thromboelastometry whole blood clotting time were observed, as well as dose‐dependent reductions in FXI activity. Bleeding times did not increase following administration of BAY 1213790 and were similar for all dose cohorts, including placebo. Measurable and dose‐dependent increases in systemic exposure were detected for all doses of BAY 1213790 of 0.06 mg/kg or higher. Conclusions Based on these safety, pharmacodynamic, and pharmacokinetic results, further evaluation of BAY 1213790 in patients with, or at risk of, thrombosis is warranted.

The contact pathway and sepsis

“…While these data suggest that the CAS contributes to the pathology of sepsis in humans, further study is needed before any major conclusions are drawn to determine if targeting this pathway could offer a meaningful benefit to septic patients. As multiple novel contact pathway inhibitors enter clinical testing, additional clinical investigations may begin to address this question …”

“…Finally, while contact pathway inhibition in general holds promise, it remains to be clarified which specific component(s) of this pathway should be targeted to optimize clinical outcomes. Phase 1 clinical trial data have now been published on 4 different monoclonal antibodies targeting FXI, all with unique mechanisms . Our group has worked extensively with 14E11/3G3, a monoclonal antibody inhibiting FXIIa‐mediated activation of FXI.…”

New anticoagulants: Moving beyond the direct oral anticoagulants

“…A fully human immunoglobulin G (IgG)1 monoclonal antibody generated using phage display, osocimab binds the catalytic domain of FXIa and blocks its activity. When given as a single intravenous bolus to healthy volunteers, osocimab prolonged the aPTT in a concentration‐dependent manner and had no effect on the bleeding time 52 . The half‐life tended to increase with higher doses to around 30 to 44 days.…”

Role of Factor XIa and Plasma Kallikrein in Arterial and Venous Thrombosis

“…Compared with controls, the aPTT was prolonged and FXIa activity was reduced in cohorts receiving the anti-FXIa antibody osocimab (BAY 1213790). 103 Administration of MAA868, an antibody against FXI and FXIa, also diminished FXIa activity and increased aPTT in a phase 1 study 104 and is currently investigated in a phase 2 trial (NCT04213807). Anti-FXI antibodies reduced thrombus formation in a primate model 73 and decreased thrombus size in FXI-deficient mice administered with human FXI.…”