Background: Milvexian (formerly known as BMS-986177/JNJ-70033093) is a novel small molecule FXIa inhibitor currently in Phase II clinical trials with the potential for reduced bleeding risk compared to currently approved direct oral anticoagulants (DOACs). Since FXIa inhibition represents a new mechanism of antithrombotic therapy, establishing assays sensitive to milvexian to facilitate measuring its anticoagulant activity is desirable. The thrombin generation assay (TGA) has been used clinically with currently approved DOACs, but its use of tissue factor (TF) to generate thrombin via the extrinsic pathway limits sensitivity toward the intrinsic pathway.
Aims: Develop a modified TGA sensitive to FXIa inhibition by milvexian using a specific activator of the intrinsic pathway.
Methods: TGAs were performed in platelet-poor plasma (PPP) using the Thrombinoscope method (Stago). Thrombin generation (TG) was initiated with TF reagent or dilute aPTT reagents. After establishing preliminary assay conditions, a validation study was performed to assess reproducibility of TGA parameters from 0.1 – 10 μM milvexian spiked into plasma from 20 healthy donors.
Results: TGAs initiated with dilute aPTT reagents clearly differentiated normal from FXI-deficient plasmas, versus a modest difference in reactions initiated with TF. Primary TGA endpoints (Lag Time, Peak Thrombin, Time to Peak, and Endogenous Thrombin Potential (ETP)) correlated dose-dependently with FXI plasma concentration or with a small molecule FXIa inhibitor. A validation study with milvexian confirmed reproducible dose response in plasma from 20 healthy donors. Intra-
assay, inter-assay, inter-operator, and aPTT reagent lot-to-lot precision were within acceptable ranges (< 20% CV).
Conclusions: Initiating TGAs with dilute aPTT reagent enables sensitive measurement of changes in FXI(a) activity resulting from differences in FXI antigen or FXIa inhibitors. A validation study confirmed the ability to sensitively measure ≥ 100 nM milvexian in PPP. The modified TGA has consequently been included as an exploratory pharmacodynamic assay in the AXIOMATIC TKR trial (NCT03891524).
To cite this abstract in AMA style:Bunce M, Bonilla F, Cardenas J, Kotha J, Jennings L, Chintala M. Development of a Modified Thrombin Generation Assay with Improved Sensitivity to Factor XIa Inhibition by the Novel Small Molecule Milvexian (BMS-986177/JNJ-70033093) [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 1). https://abstracts.isth.org/abstract/development-of-a-modified-thrombin-generation-assay-with-improved-sensitivity-to-factor-xia-inhibition-by-the-novel-small-molecule-milvexian-bms-986177-jnj-70033093/. Accessed September 23, 2021.
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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/development-of-a-modified-thrombin-generation-assay-with-improved-sensitivity-to-factor-xia-inhibition-by-the-novel-small-molecule-milvexian-bms-986177-jnj-70033093/