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 (FXIa), 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.

Keywords: anticoagulant; factor XI; hemostasis; phase 1; thrombosis.

Figure 1

Volunteer disposition. *One volunteer in the placebo group and one in the BAY 1213790 0.06 mg/kg group were randomized but did not receive treatment. ^†One volunteer in the BAY 1213790 0.6 mg/kg group who did not complete the study owing to an AE completed follow‐up; one volunteer who completed the study was lost to follow‐up. AE, adverse event; PD, pharmacodynamics; PK, pharmacokinetics

Figure 2

Effects of increasing doses of BAY 1213790 on aPTT in healthy volunteers measured using (A) a conventional method and (B) a kaolin‐triggered method. Data are presented as mean and standard deviation. aPTT, activated partial thromboplastin time

Figure 3

Effects of increasing doses of BAY 1213790 on apparent factor XI activity in healthy volunteers. Data are presented as mean and standard deviation

Figure 4

Effect of increasing doses of BAY 1213790 on bleeding time in healthy volunteers measured using the Surgicutt system. Data are presented as box‐and‐whisker plots and represent pooled values for d 1‐7; upper and lower lines of the box denote the upper and lower quartiles, respectively, midlines denote the medians, and upper and lower lines denote the maximum and minimum values, respectively

Figure 5

Plasma concentration–time profile of total BAY 1213790 (0.06‐10 mg/kg)* in healthy volunteers following a 60‐minute intravenous infusion. *Data for the 0.015 mg/kg dose group are not shown because measurable plasma concentrations were only detected in one volunteer. LLOQ, lower limit of quantification