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. 2022 Jun;20(6):1400-1411.
doi: 10.1111/jth.15700. Epub 2022 Mar 25.

Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa

Stefan Heitmeier  1 , Mayken Visser  1 , Adrian Tersteegen  1 , Julia Dietze-Torres  1 , Julia Glunz  1 , Christoph Gerdes  1 , Volker Laux  1 , Jan Stampfuss  1 , Susanne Roehrig  1
Affiliations

Pharmacological profile of asundexian, a novel, orally bioavailable inhibitor of factor XIa

Stefan Heitmeier et al. J Thromb Haemost. 2022 Jun.

Erratum in

  • Corrigendum.
    [No authors listed] [No authors listed] J Thromb Haemost. 2022 Oct;20(10):2448. doi: 10.1111/jth.15845. J Thromb Haemost. 2022. PMID: 36123577 Free PMC article. No abstract available.

Abstract

Background: Activated coagulation factor XI (FXIa) contributes to the development and propagation of thrombosis but plays only a minor role in hemostasis; therefore, it is an attractive antithrombotic target.

Objectives: To evaluate the pharmacology of asundexian (BAY 2433334), a small molecule inhibitor targeting FXIa, in vitro and in various rabbit models.

Methods: The effects of asundexian on FXIa activity, selectivity versus other proteases, plasma thrombin generation, and clotting assays were evaluated. Antithrombotic effects were determined in FeCl2 - and arterio-venous (AV) shunt models. Asundexian was administered intravenously or orally, before or during thrombus formation, and with or without antiplatelet drugs (aspirin and ticagrelor). Potential effects of asundexian on bleeding were evaluated in ear-, gum-, and liver injury models.

Results: Asundexian inhibited human FXIa with high potency and selectivity. It reduced FXIa activity, thrombin generation triggered by contact activation or low concentrations of tissue factor, and prolonged activated partial thromboplastin time in human, rabbit, and various other species, but not in rodents. In the FeCl2 -injury models, asundexian reduced thrombus weight versus control, and in the arterial model when added to aspirin and ticagrelor. In the AV shunt model, asundexian reduced thrombus weight when administered before or during thrombus formation. Asundexian alone or in combination with antiplatelet drugs did not increase bleeding times or blood loss in any of the models studied.

Conclusions: Asundexian is a potent oral FXIa inhibitor with antithrombotic efficacy in arterial and venous thrombosis models in prevention and intervention settings, without increasing bleeding.

Keywords: BAY 2433334; anticoagulant; asundexian; factor XIa inhibitor; thrombosis.

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Conflict of interest statement

Stefan Heitmeier, Adrian Tersteegen, Julia Glunz, Jan Stampfuss, Christoph Gerdes, Susanne Roehrig, and Julia Dietze‐Torres are all employees of Bayer AG. At the time this work was conducted, Mayken Visser and Volker Laux were both employees of Bayer AG but have subsequently left. Christoph Gerdes, Julia Glunz, Jan Stampfuss, Susanne Roehrig, and Adrian Tersteegen also own shares in Bayer AG.

Figures

FIGURE 1
FIGURE 1
Effect of asundexian on human FXIa activity in buffer (A; n = 6) and human plasma (B; n = 4). Results are presented as mean ±SEM. Representative thrombograms showing the effect of asundexian on thrombin generation initiated by the FXII activating agent ellagic acid (Actin® FS) 2.5% (C), or 0.1 pM or 5 pM tissue factor (D and E). Effect of asundexian on clotting time prolongation in human plasma, with the inset expanding the curve for APTT over the asundexian 0–2 μM range (F). Results are presented as mean ±SEM (n = 2___9). APTT, activated partial thromboplastin time; FXIa, activated coagulation factor XI; PT, prothrombin time; SEM, standard error of the mean
FIGURE 2
FIGURE 2
Effects of asundexian versus rivaroxaban on thrombus weight following FeCl2‐induced damage to the carotid artery (A), ear bleeding time (B), and gum bleeding time (C) in rabbits. Plasma concentrations of asundexian (D), inhibition of FXIa activity (E), and APTT prolongation (F) according to asundexian dose, and correlation of plasma concentrations (G), inhibition of FXIa (H), and APTT prolongation (I) with thrombus weight. Asundexian was administered as an intravenous bolus, whereas rivaroxaban was administered as an intravenous bolus followed by continuous infusion. Results are presented as individual values and median with 25th and 75th percentiles (Parts A–F). * P < .05, *** P < .001. APTT, activated partial thromboplastin time; FXIa, activated coagulation factor XI
FIGURE 3
FIGURE 3
Effects of asundexian in combination with aspirin/ticagrelor versus apixaban in combination with aspirin/ticagrelor on thrombus weight following FeCl2‐induced damage to the carotid artery (A) and ear bleeding time (B) in rabbits. Results are presented as individual values and medians (± interquartile range). Adjusted P‐values versus control: *P < .05, **P < .01, ***P < .001, ****P < .0001. ASA, acetylsalicylic acid (aspirin); Tica, ticagrelor
FIGURE 4
FIGURE 4
Effects of asundexian on thrombus weight (A) and ear bleeding time prolongation (B) following FeCl2‐induced damage to the jugular vein in rabbits. Asundexian was administered as an intravenous bolus. Results are presented as individual values and medians (± interquartile range). **** P < .001
FIGURE 5
FIGURE 5
Effect of intravenously administered asundexian 6 mg/kg and 12 mg/kg on bleeding time (A) and blood loss (B) in the rabbit liver‐injury model. Results are presented as medians with interquartile ranges (n = 6). * P < .05, ** P < .001, *** P < .0001 versus controls
FIGURE 6
FIGURE 6
Effects of asundexian in the AV‐shunt model in rabbits on thrombus weight in the prevention protocol (A) and intervention protocol (B). Asundexian was administered as an intravenous bolus 10 min before or 10 min after the shunt was opened, respectively. Results are presented as individual values (diamonds) and mean values (bars) (± interquartile range). * P < .05, ** P < .01, *** P < .001. AV, arterio‐venous
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