Title:Specific Antidotes in Development for Reversal of Novel Anticoagulants: A Review
Volume: 9
Issue: 1
Author(s): Antonio Gomez-Outes, Mª L. Suarez-Gea, Ramon Lecumberri, Ana I. Terleira-Fernandez and Emilio Vargas-Castrillon
Affiliation:
Keywords:
Andexanet alfa, anivamersen, anticoagulant, antidote, aripazine, idarucizumab.
Abstract: In the last decade, several direct oral anticoagulants (DOAC; dabigatran, rivaroxaban, apixaban,
edoxaban) have been marketed for prophylaxis and/or treatment of thromboembolism without having specific antidotes
available for their reversal. Current management of bleeding associated to DOAC includes the removal of all antithrombotic
medications and supportive care. Non-specific procoagulant agents (prothrombin complex concentrates and activated
factor VIIa) have been used in case of serious bleeding. Currently, some specific antidotes for the DOAC are under
development. Idarucizumab (BI 655075; Boehringer Ingelheim) is a fragment of an antibody (Fab), which is a specific antidote
to the oral direct thrombin inhibitor dabigatran. Andexanet alfa (r-Antidote, PRT064445; Portola Pharmaceuticals)
is a truncated form of enzymatically inactive factor Xa, which binds and reverses the anticoagulant action of the factor Xa
inhibitors (e.g.: rivaroxaban, apixaban and edoxaban). Aripazine (PER-977, ciraparantag; Perosphere Inc.) is a synthetic
small molecule (~500 Da) that reverses oral dabigatran, apixaban, rivaroxaban, as well as subcutaneous fondaparinux and
LMWH in vivo. These antidotes could provide an alternative for management of life-threatening bleeding events occurring
with the above-mentioned anticoagulants. In addition, the specific antidote anivamersen (RB007; Regado Biosciences
Inc.) is an RNA aptamer in clinical development to reverse the anticoagulant effect of the parenteral factor IXa inhibitor
pegnivacogin, which is also in development. This anticoagulant-antidote pair may provide an alternative in situations in
which a fast onset and offset of anticoagulation is needed, like in patients undergoing cardiac surgery with extracorporeal
circulation, as an alternative to the heparin/protamine pair. This patent review includes a description of the pharmacological
characteristics of the novel specific antidotes, the available results from completed non-clinical and clinical studies and
the description of ongoing clinical trials with the new compounds.
