Abstract 19361: Reversal of Anticoagulant-induced Bleeding in External and Internal Bleeding Models by PER977, a Small Molecule Anticoagulant Antidote
The new oral anticoagulants (NOACs) offer significant advantages over heparins and warfarin therapies. However, concern over serious bleeding and potential over-dosage is heightened with the lack of a specific reversal agent. PER977 is a synthetic small molecule in clinical development as an anticoagulant reversal agent. In the current studies, PER977 reversal was evaluated in two preclinical bleeding models, recapitulating the clinical scenarios of reversal in actively bleeding cutaneous wounds and internal large organ lacerations. Reversal of anticoagulation-induced, active bleeding was demonstrated in a rat tail transection model. Rats were dosed with the direct factor Xa inhibitor, edoxaban, resulting in large increases in blood loss mass. Briefly, the rat was orally dosed with edoxaban. After 75 min, rat tails were fully transected 2 mm from the tip. Immediately after tail transection, PER977 solution or saline was administered through the jugular vein. Blood from the tail was collected for 7.5 minutes and then transferred into a second collection tube for an additional 7.5 minutes. PER977 significantly decreased bleeding in vivo in rats treated with edoxaban (Figure 1a) within the first 7.5 minutes after PER977 administration. Additionally, bleeding was evaluated in a rat liver laceration model of internal bleeding. Following calibrated cuts to the medial lobe of the exposed liver, bleeding time was determined to the nearest 15 seconds. This rat liver laceration internal bleeding model demonstrated that edoxaban can significantly increase the bleeding time after the rat liver is lacerated. Moreover, the i.v. administration of PER977 can fully reverse the anticoagulant effect of edoxaban 10 minutes after PER977 administration (Figure 1b). In conclusion, PER977 is a synthetic small molecule that reverses NOAC anticoagulation in animal models of external and internal bleeding, and is currently in phase 2 clinical studies with edoxaban.
Author Disclosures: S. Bakhru: Employment; Significant; Perosphere Inc. B. Laulicht: Employment; Significant; Perosphere Inc. X. Jiang: Employment; Significant; Perosphere Inc. L. Chen: Employment; Significant; Perosphere Inc. M. Grosso: Employment; Significant; Daiichi Sankyo Inc. Y. Morishima: Employment; Significant; Daiichi Sankyo Co. Ltd. K. Brown: Employment; Significant; Daiichi Sankyo Inc. M. Mercuri: Employment; Significant; Daiichi Sankyo Inc. H. Masumoto: Employment; Significant; Daiichi Sankyo Inc. J. Costin: Employment; Significant; Perosphere Inc. S. Steiner: Employment; Significant; Perosphere Inc..
- © 2014 by American Heart Association, Inc.