Differential impact of milvexian, an investigational oral FXIa inhibitor vs apixaban and dabigatran on thrombin generation in human donor plasma in vitro

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Abstract Introduction All approved anticoagulants including the direct oral anticoagulants have been associated with an increased risk of bleeding in a dose-dependent manner when used either as monotherapy and/or on top of antiplatelet drugs. Literature reports have suggested that the extrinsic pathway of coagulation is important for haemostasis while the intrinsic pathway of coagulation along with thrombin feedback activation of FXI are primarily responsible for pathological thrombus formation and propagation. Recent clinical trials with several FXI/FXIa inhibitors in development including milvexian (BMS-986177/ JNJ-70033093) have demonstrated robust antithrombic efficacy without any increase in bleeding compared with standard of care in the settings of total knee arthroplasty. Milvexian inhibits FXIa upstream in the intrinsic pathway of coagulation while approved anticoagulants including warfarin, heparin, bivalirudin, and DOACs inhibit FXa and/or thrombin, which are components of the final common pathway of coagulation that lies in the interface of the intrinsic and extrinsic pathways. Purpose To evaluate the impact of milvexian, apixaban and dabigatran on thrombin generation (TG) initiated by the intrinsic vs extrinsic pathway activators in human plasma in vitro. Methods Platelet-poor plasma prepared from citrated whole blood collected from consenting, healthy adult volunteers (n=6) was spiked with 0.1–10 μM milvexian, apixaban, or dabigatran. TG via the extrinsic pathway (5 pM tissue factor, PPP Reagent, Stago) and intrinsic pathway (1:100 dilution of STA®-PTT Automate) was measured using using the Thrombinoscope method (Stago) and included peak thrombin, lag time and the endogenous thrombin potential (ETP). Results All compounds tested demonstrated robust (>70%) to complete inhibition of the ETP initiated by the intrinsic pathway activator (STA®-PTT Automate reagent, Fig. 1A). Apixaban and dabigatran also completely inhibited ETP initiated by the extrinsic pathway activator (PPP Reagent, Fig. 1B). In contrast, milvexian only had a modest inhibition (<20%) of ETP when initiated by the extrinsic pathway activator. Conclusions By inhibiting the final common pathway of coagulation, apixaban and dabigatran inhibit TG initiated via both, intrinsic and extrinsic pathways, in a concentration-dependent manner. In contrast, by inhibiting FXIa upstream in the intrinsic pathway, milvexian predominantly inhibits TG initiated by the intrinsic pathway activator but only has a minimal impact on TG initiated by the extrinsic pathway that is deemed critical for haemostasis. These findings with milvexian are consistent with observations of TG in FXI immunodepleted plasma reported previously by our group (ISTH 2021). The potential haemostasis sparing effect of milvexian and perhaps of other FXI/FXIa inhibitors may explain in part the low rate of bleeding observed to date with this new class of experimental anticoagulant drugs in clinical development. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Janssen Research & Development