PB0025 - Asundexian in atrial fibrillation: A predictable failure based on pharmacodynamic data

Sunday, June 23, 2024

13:45 – 14:45 ICT

Room: Exhibition Hall

Presenting Author(s)

ND

Nathalie Donis

Project Leader
QUALIblood s.a., QUALI-Research Department, Namur, Belgium
Namur, Namur, Belgium

Co-Author(s)

JV

Julie Vassart

PhD Student
University of Namur, Department of Pharmacy, Clinical Pharmacology and Toxicology Research Unit, Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium
Namur, Namur, Belgium
Marie Didembourg, PhD student

PhD student
University of Namur, Clinical Pharmacology and toxicology Research Unit (URPC),Namur Thrombosis and Hemostasis Center (NTHC), Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium
Namur, Namur, Belgium
LM

Laure Morimont

Research & Project leader
University of Namur, Department of Pharmacy, Clinical Pharmacology and Toxicology Research Unit, Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium
Namur, Namur, Belgium
CB

Clotilde Brisbois

Technician
QUALIblood s.a., QUALI-Research Department, Namur, Belgium
Namur, Namur, Belgium
LJ

Laurent Jamar

MD
Service de cardiologie interventionnelle, Centre Hospitalier Régional Sambre et Meuse (CHRSM), Namur, Belgique
Namur, Namur, Belgium
JF

Julien Favresse

PhD Student
Department of Laboratory Medicine, Clinique St-Luc Bouge, Namur, Belgium
Namur, Namur, Belgium
Aurélien Lebreton, MD,PhD

MD
Service d’hématologie, CHU Clermont-Ferrand, Hôpital Estaing, France
Clermont Ferrand, Auvergne, France
JD

Jean-Michel Dogné

Head of the faculty of medicine
University of Namur, Department of Pharmacy, Clinical Pharmacology and Toxicology Research Unit, Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium
Namur, Namur, Belgium
JD

Jonathan Douxfils

Professor
University of Namur, Department of Pharmacy, Clinical Pharmacology and Toxicology Research Unit, Namur Research Institute for Life Sciences (NARILIS), Namur, Belgium
Namur, Namur, Belgium

Background: The sudden interruption of the phase 3 OCEANIC-AF trial (NCT05643573) has raised concerns regarding the ability of asundexian, as well as FXI inhibitors in general, to prevent stroke and systematic embolism in patients with atrial fibrillation (AF).

Aims: We aimed to investigate the thrombin generation assay profiles of asundexian, milvexian and apixaban to detect possible differences that could explain the results of the OCEANIC-AF trial.

Methods: Thrombin generation assay was performed on a Calibrated Automated Thrombogram. Asundexian, milvexian and apixaban 1 mg/mL solutions in DMSO underwent serial dilution in phosphate buffer saline without calcium or magnesium. These solutions were spiked in normal pooled plasma retrieved from the Namur Biobank Exchange (NAB-X, Namur, Belgium), (dilution factor=20). 80 µL of plasma solutions were added to 20 µL of Platelet Poor Plasma (PPP) reagent low (1 pM tissue factor (TF) [0.16 pM in final concentration]), PPP reagent (5 pM TF [0.80 pM in final concentration]), PPP reagent high (20 pM tissue factor [3.2 pM in final concentration]; 4 μM phospholipids) and thrombin calibrator reagent. For each condition, thrombin generation was triggered adding 20 µL of a reagent containing a fluorogenic substrate, buffer, and calcium chloride. All conditions were tested in triplicate for each analysis.

Results: The concentrations needed to halve the peak and the mVRI in PPP reagent low were above 1500 ng/mL for asundexian and around 400 ng/mL for milvexian. Pharmacokinetic investigations showed that the maximum concentration (Cmax) of asundexian (oral doses from 25 to 100 mg once daily) and milvexian (100 mg once daily) were 358 to 1230 ng/mL and 350 to 1000 ng/mL, respectively. Inhibition with apixaban was more potent in all conditions.

Conclusion(s): These results confirm that asundexian 50 mg daily is unable to prevent thromboembolism in patients with AF while milvexian 100 mg daily (LIBREXIA-AF) may be more adequate in this setting.