PB0558 - Lack of interaction of milvexian, an investigational oral FXIa inhibitor with aspirin and ticagrelor on platelet aggregation, thrombin generation and thromboelastography in vitro

Background: Milvexian, an oral FXIa inhibitor has recently completed Phase II clinical trials including in secondary stroke prevention where it was added on top of dual antiplatelet therapy of aspirin and the P2Y12 inhibitor clopidogrel.

Aims: Assess potential for interaction of milvexian, with antiplatelet drugs on platelet aggregation (PA), thrombin generation (TG) and thromboelastography (TEG) using human donor plasma or whole blood in vitro. Clopidogrel is a pro-drug and not suitable for in-vitro studies, hence ticagrelor a direct acting P2Y12 inhibitor was used.

Methods: Citrated whole blood was collected from consenting, healthy adult volunteers (n=6). Platelet rich plasma was used for PA using light transmission aggregometry and TG with the Thrombinoscope method. TEG was performed in whole blood with TEG 5000 Hemostasis Analyzer. Milvexian (0.1-10 uM), ticagrelor (0.6-6 uM) and aspirin (10-100uM) were spiked into the plasma or whole blood.

Results: PA: Aspirin and ticagrelor inhibited (>70%) arachidonic acid and ADP induced aggregation in a concentration dependent manner respectively. Milvexian alone had no effect on PA and when combined with aspirin and ticagrelor at concentrations that inhibited PA by 50% did not inhibit or potentiate the response to these antiplatelet drugs.
TG: Milvexian resulted in a concentration dependent inhibition (>60%) of TG. Addition of aspirin and ticagrelor did not alter the effect of milvexian.
TEG: Milvexian resulted in concentration dependent prolongation (2.5X) in time to clotting. Addition of aspirin and ticagrelor did not affect the response to milvexian.

Conclusion(s): Milvexian inhibited TG and clotting in TEG in a concentration dependent manner. Milvexian did not affect PA and did not show any potential for interaction with antiplatelet drugs tested in the various in vitro assays described above. This lack of interaction at a wide range of concentrations of milvexian supports further evaluation in patients where antiplatelets are the standard of care.