Abstract Number: PB0243
Meeting: ISTH 2020 Congress
Background: Anticoagulants are the cornerstone of prevention and treatment of thrombotic disorders, even though those currently in clinical use are associated with risk of bleeding, limiting their antithrombotic potential. Coagulation factor XI (FXI) contributes to the development of thrombosis but plays only a minor role in hemostasis and is therefore an attractive target for novel antithrombotic therapy without the risk of relevant bleeding.
Aims: To evaluate the safety, pharmacokinetic (PK) and pharmacodynamic (PD) properties of BAY 2433334, a small molecule targeting FXIa, in healthy male participants.
Methods: This Phase I study was divided into two parts. A single dose escalation with a focus on safety, tolerability, PK, and PD properties of BAY 2433334. Oral doses of 5 mg up to 150 mg were administered orally. Second part investigating the effect of food on the PK of BAY 2433334. Adverse events were closely monitored. Key PK parameters included exposure, maximum plasma concentration and terminal half-life. The coagulation properties were assessed using activated partial thromboplastin time (aPTT), rotational thromboelastometry, bleeding time and FXIa activity. The study was approved by the local ethics committee and all volunteers provided written informed consent.
Results: BAY 2433334 demonstrated a favorable safety profile. BAY 2433334 showed a terminal half-life of approximately 15 hours allowing for a once daily administration. The intake of food decreased the peak concentrations by 31% compared to fasted state with a minor effect on exposure (decrease by 12.4%). Dose- and time dependent inhibition of FXIa activity and increase in aPTT were observed. There was no increase in mean bleeding time assessed by Surgicutt®.
Conclusions: BAY 2433334 was safe and well tolerated and demonstrated a favorable PK/PD profile in healthy volunteers with once-daily dosing potential. It is currently being evaluated in several Phase II dose finding programs.
To cite this abstract in AMA style:Thomas D, Kanefendt FS, Schwers S, Unger S, Yassen A, Boxnick S. First Evaluation of the Safety, Pharmacokinetics and Pharmacodynamics of BAY 2433334 a Small Molecule Targeting Coagulation Factor XIa in Healthy Young Male Participants [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/first-evaluation-of-the-safety-pharmacokinetics-and-pharmacodynamics-of-bay-2433334-a-small-molecule-targeting-coagulation-factor-xia-in-healthy-young-male-participants/. Accessed May 6, 2021.
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