A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Reversal of Edoxaban-Induced Anticoagulation in Healthy Subjects By Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa (fXa) Inhibitors

Background: Direct fXa inhibitors appear to have similar or superior anticoagulant efficacy and safety relative to warfarin (and in some cases low molecular weight heparin) in the management of venous thromboembolism and stroke prevention in atrial fibrillation. However, they are limited by the lack of a specific antidote to reverse anticoagulation in cases of major bleeding episodes or prior to urgent/emergency surgery. Andexanet alfa (AnXa, PRT064445) is a modified, recombinant human fXa molecule that is catalytically inactive but retains high-affinity binding to direct and indirect fXa inhibitors, therefore acting as a decoy to bind and sequester fXa inhibitors. We previously reported Phase 2 data with apixaban, rivaroxaban and enoxaparin in healthy subjects and demonstrated that AnXa was able to rapidly and extensively reverse pharmacodynamic (PD) markers of anticoagulation. Here we report new clinical data demonstrating that AnXa rapidly reverses the PD markers of edoxaban-mediated anticoagulation – anti-fXa activity and inhibition of thrombin generation.

Methods: This ongoing Phase 2, double-blind, placebo-controlled study is examining the reversal by AnXa of the anticoagulant activity of edoxaban (edox, the most recent fXa inhibitor for which an NDA/MAA was submitted) as well as its pharmacokinetics (PK) and safety profile in healthy subjects. Reversal of edox anticoagulation is being studied with up to 3 different dose cohorts/regimens of AnXa or placebo in a 6:3 ratio (i.e., 9 subjects per cohort). Edox is administered at an oral dose of 60 mg qd for 6 days and AnXa administered intravenously on Day 6, 3 hours after the last edox dose. PD and safety data are collected through Day 48 with PK data through Day 10.

Results and Conclusions: We report here available data from the first 2 AnXa dose cohorts (600 mg bolus, n=9; 800 mg bolus followed by 8 mg/min infusion for 1 hr, n=9). Immediately after completion of the 600 mg or 800 mg bolus, anti-fXa activity decreased dose-dependently by 52% and 73%, respectively, from the pre-AnXa level, remained constant during the infusion, and returned to placebo levels by approximately 2 hours after treatment. In addition, edox-induced inhibition of thrombin generation and prolongation of clotting times were also reversed by AnXa in a dose-dependent manner. AnXa was well tolerated and there were no thrombotic events, serious, or severe adverse events. One subject was discontinued on Day 5 prior to AnXa dosing due to a vasovagal reaction. These data are consistent with previously reported results for other fXa inhibitors in that AnXa rapidly reverses PD markers of anticoagulation, restores normal thrombin generation, and is well tolerated.