Asundexian and milvexian: Pharmacodynamic insights from coagulation assays

Introduction: The sudden interruption of the OCEANIC-AF Phase 3 trial (NCT05643573) comparing asundexian to apixaban in atrial fibrillation has raised concerns regarding the ability of asundexian, but also other FXI(a) inhibitors such as milvexian to prevent thromboembolism in this indication. We aimedto investigate the impact of therapeutically plausible concentrations of asundexian and milvexian on different coagulation assays to compare the pharmacodynamic profiles of these anticoagulants.

Method: Normal pooled plasma (Namur Exchange Biobank, Namur, Belgium) was spiked with different solutions of asundexian and milvexian (dilution factor=20) to yield final concentration ranges of 0-2000 ng/mL (asundexian) and 0-5000 ng/mL (milvexian). Thrombin Generation Assay (TGA) was performed on a Calibrated Automated Thrombogram (CAT). Each plasma solution was tested in the presence of four different reagents: 1 pM Tissue factor (TF), 4 μM phospholipids (PL) (PPP-Reagent Low); 5 pM TF, 4 µM PL (PPP-Reagent); 20 pM TF, 4 µM PL (PPP-Reagent High) and a mixture of ellagic acid 0.42 µM and purified phosphatides (Actin FS®​). Thrombin generation was triggered by adding FluCa Reagent (fluorogenic substrate, buffer, calcium chloride). aPTT (activated partial thromboplastin time) and prothrombin time (PT) assays were performed on an ACL-TOP 700 (HemosIL®​ reagents) and a STA R MAX (other reagents). The aPTT was realized with four different reagents: HemosIL®​ SynthASil (activator=silica), STA®​-C.K. Prest (activator=kaolin), STA®​ PTT Automate 5 (activator=silica) and Actin FS®​ (activator=ellagic acid). Two prothrombin time (PT) assays were measured with the following reagents: HemosIL®​RecombiPlasTin 2G (human recombinant tissue factor) and STA®​-NeoPTimal 5 (rabbit brain tissue factor). Statistical analyses were performed with the GraphPad Prism software version 10.3.1 (Boston, Massachusetts USA). The relations between the concentration of inhibitors and the parameters of the different assays were described by one-phase decay equations and inhibitory concentrations 50 (IC₅₀) or double clotting times were computed.

Results: In the aPTT assay and TGA milvexian globally showed lower IC₅₀ and two-fold times than asundexian. Both molecules had no impact on the PT assays (detailed results in [Fig. 1]).

Fig. 1 Pharmacodynamic parameter from the aPTT, PT and TGA assays performed in normal pooled plasma spiked with asundexian (0-2000 ng/mL) or milvexian (0-5000 ng/mL).

Conclusion: These results indicate that milvexian might be a more potent inhibitor of intrinsic pathway-dependent coagulation and that asundexian would require higher plasma concentrations to exert similar effects on coagulation assays.

Publikationsverlauf

Artikel online veröffentlicht:
13. Februar 2025