Engineering and evaluation of FXa bypassing agents that restore hemostasis following Apixaban associated bleeding

Wojciech Jankowski, Stepan S. Surov, Nancy E. Hernandez, Atul Rawal, Marcos Battistel, Daron Freedberg, Mikhail V. Ovanesov and Zuben E. Sauna ()
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Wojciech Jankowski: Center for Biologics Evaluation & Research, US FDA
Stepan S. Surov: Center for Biologics Evaluation & Research, US FDA
Nancy E. Hernandez: Center for Biologics Evaluation & Research, US FDA
Atul Rawal: Center for Biologics Evaluation & Research, US FDA
Marcos Battistel: Center for Biologics Evaluation & Research, US FDA
Daron Freedberg: Center for Biologics Evaluation & Research, US FDA
Mikhail V. Ovanesov: Center for Biologics Evaluation & Research, US FDA
Zuben E. Sauna: Center for Biologics Evaluation & Research, US FDA

Nature Communications, 2024, vol. 15, issue 1, 1-9

Abstract: Abstract Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.

Date: 2024
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DOI: 10.1038/s41467-024-48278-1

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