Abstract 14657: Andexanet-alfa and PER977 (Arapazine) Correct Blood Loss in a Rabbit Liver Laceration Model - Only Andexanet Reverses Markers of fXa-mediated Anticoagulation

Abstract

As use of oral fXa inhibitors has increased, so has the need for an antidote to treat the major side effect of these drugs - bleeding. Andexanet alfa (AnXa) (PRT064445), a recombinant fXa derivative, reverses fXa inhibitor-mediated anticoagulation in animals and humans by sequestering the fXa inhibitor in a 1:1 molar ratio, reducing both anti-fXa activity and plasma free fraction of fXa inhibitor, and restoring normal thrombin generation, PT, and aPTT. These parameters correlate closely with reduced blood loss in a rivaroxaban-treated rabbit liver laceration model. Aripazine (PER) (PER977; Perosphere, Inc.) is a small molecule that has been reported to reverse the anticoagulant effects of a broad range of anticoagulants (fXa and thrombin inhibitors; heparins) by direct binding. We synthesized PER and compared it to AnXa in this same liver laceration model at PER doses of 0.3, 3 and 30 mg/kg, and observed reductions in blood loss of 27%, 16% and 76%, respectively ( p <0.02 for 30 mg/kg dose only). There was an unexpected dose-responsive, but non-significant, trend toward decreased blood loss in non-anticoagulated rabbits with PER alone, with the 30 mg/kg dose showing a 23% decrease. The reduction in blood loss between the two agents was similar at the highest dose studied (76% decrease for 75 mg AnXa/rabbit [ASH 2012] and 76% decrease for 30 mg/kg PER in this study). PER dose groups, however, did not show reduction in riva-induced increases in PT, aPTT or anti-fXa activity. Moreover, there was no change in total plasma concentration of riva after PER administration compared to the 6-fold increase seen with AnXa due to its high affinity for riva and redistribution of riva from the extravascular to the intravascular compartment. Unlike the ~1:1 molar ratio needed for AnXa to sequester riva, a 30:1 PER:Riva molar ratio was needed to reduce blood loss. While the mechanism of action (MOA) for AnXa has been well characterized in preclinical and clinical studies, the mechanism of prevention of blood loss with PER in this model is unclear. In summary, the MOA of PER differs from that of AnXa, where direct (1:1) binding of AnXa to the fXa inhibitor decreases the free fraction of the anticoagulant, reverses PD markers and restores normal hemostasis. Further investigation of PER is required.