Abstract Number: PB0187
Meeting: ISTH 2020 Congress
Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors
Background: Coagulation factor XIa (FXIa) contributes to the development of thrombosis but seems to play only a minor role in hemostasis. In contrast to current anticoagulants, which are limited in their clinical efficacy by a dose-dependent increase in bleeding risk, inhibition of FXIa may therefore offer the potential to reduce the risk of thrombosis without increasing the risk of bleeding.
Aims: To evaluate the in vitro pharmacology of BAY 2433334 and to assess its in vivo antithrombotic properties and bleeding profile in rabbits.
Methods: The in vitro properties of BAY 2433334 were analyzed by using FXIa assays in buffer and human plasma, standard clotting assays (aPTT and PT) and thrombin generation assays in human and rabbit plasma. Antithrombotic efficacy of BAY 2433334 was assessed in rabbits in an arterial thrombosis model after ferrous chloride-injury of the carotid artery and in an arterio-venous shunt model after i.v. and p.o. administration. The impact of BAY 2433334 on hemostasis was evaluated in the same animals by measuring ear and gum bleeding.
Results: BAY 2433334 inhibited human FXIa activity with an IC50 of 1 nM in buffer and an IC50 of 0.14 µM in human plasma. It prolonged the aPTT 1.5-fold at 0.6 µM while having no significant effect on PT. Thrombin formation induced by low tissue factor concentrations was inhibited with an IC50 (peak) of 0.3 µM. BAY 2433334 reduced thrombus formation in the ferrous chloride model and in the AV-shunt model correlating with aPTT prolongation, and reduction of FXIa activity closely following plasma concentrations. Simultaneously determined ear and gum bleeding times were not prolonged.
Conclusions: BAY 2433334 is a potent, direct and reversible inhibitor of FXIa showing strong antithrombotic efficacy without increasing the bleeding risk. Its potential as anticoagulant with a broad therapeutic window is currently being evaluated in a phase 2 development program.
To cite this abstract in AMA style:
Heitmeier S, Visser M, Gäfke A-, Harwardt M, Griessbach C, Mueller V, Tersteegen A, Strassburger J, Gerdes C, Laux V, Jimenez-Nunez E, Ackerstaff J, Roehrig S. Preclinical Pharmacology of BAY 2433334, a Small Molecule Inhibitor of Coagulation Factor XIa [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/preclinical-pharmacology-of-bay-2433334-a-small-molecule-inhibitor-of-coagulation-factor-xia/. Accessed October 2, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/preclinical-pharmacology-of-bay-2433334-a-small-molecule-inhibitor-of-coagulation-factor-xia/