Abstract 10: Randomized, Double-Blind, Placebo-Controlled Single Ascending Dose Pharmacokinetic and Pharmacodynamic Study of PRT064445, a Universal Antidote for Factor Xa Inhibitors

Background Direct factor Xa inhibitors [fXaI] have superior anticoagulant efficacy and/or safety relative to warfarin and LMWH but are limited by lack of a specific antidote to reverse anticoagulation during episodes of serious bleeding or before surgery. PRT064445 [PRT] is a modified, human recombinant fXa that is catalytically inactive but retains high-affinity binding to direct fXaI and heparin- antithrombin III complexes. It competes with native fXa for fXaI drugs, thus reversing direct and indirect fXaI-mediated anticoagulation. Methods In this phase I, first-in-man double-blind study, 32 healthy volunteers were randomized (6:2) within dosing cohorts to a single IV bolus of PRT (30 mg, 90 mg, 300 mg, or 600 mg) or placebo and followed for 28 days. Anti-fXa activity was assayed in vitro by adding exogenous rivaroxaban (50 ng/mL) to subject plasma samples. Results The terminal t1/2 was ~6 hours. AUC and Cmax increased disproportionately relative to dose. In the presence of PRT, thrombin generation and anti-fXa activity of rivaroxaban ( Figure ) were reversed in a dose-dependent manner. There were no thrombotic AEs or deaths. There was 1 serious AE (pneumonia) and 3 non-serious infusion-related reactions without anaphylaxis [90 mg (2) and placebo (1)]. One unplanned pregnancy occurred ~10 days post-treatment, followed shortly by a spontaneous abortion. Prothrombin fragment 1 + 2, thrombin-antithrombin complex, and D-dimer transiently increased with dose; other coagulation parameters including PT, aPTT, ACT and platelet activity were unchanged. Conclusions PRT is a promising universal antidote for fXaI. A Phase 2 trial evaluating PRT reversal of several fXaI is ongoing.