ALBERT

Description: Introduction: Andexanet alfa (andexanet) is a modified recombinant human factor Xa (FXa), developed to reverse the anticoagulation effects of both direct and indirect FXa inhibitors. For antithrombin III (ATIII)-dependent FXa inhibitors, such as enoxaparin, andexanet binds to the ATIII-enoxaparin complex with high affinity and reverses the inhibition of coagulation factors Xa and IIa. This study evaluated the ability of andexanet to reverse anticoagulation effects and blood loss due to the indirect FXa inhibitor, enoxaparin, in a rabbit liver laceration model. Methods: In a rabbit model of surgically-induced, acute hemorrhage (liver laceration model), rabbits were randomized to receive enoxaparin (8 mg/kg; subcutaneous bolus) or enoxaparin vehicle. This route of administration and dose of enoxaparin was based on the pharmacokinetic profile of enoxaparin and pharmacodynamic activity in the rabbit (2-fold increase in blood loss relative to non-anticoagulated rabbits). Andexanet (15, 35, or 75 mg per rabbit) or andexanet vehicle was administered to anesthetized rabbits as a 5-minute bolus, 120 minutes after enoxaparin injection (from Time 120 to Time 125 minutes), prior to livery injury. The five treatment groups were enoxaparin vehicle + andexanet vehicle, enoxaparin + andexanet vehicle, or enoxaparin + andexanet (3 dose levels). For liver laceration, a standardized injury (10 1-cm-long and 2- to 3-mm-deep incisions) was made into two liver lobes with 5 incisions in each lobe, and bleeding was allowed to progress for 15 minutes (from Time 125 to Time 140 minutes). Study efficacy endpoints included evaluations of blood loss in rabbits anticoagulated with enoxaparin, and anti-FXa activity in plasma. Results: In rabbits anticoagulated with enoxaparin, andexanet significantly decreased blood loss 2-3 fold, relative to vehicle control (assessed at Time 140 minutes) at all doses of andexanet administered (15, 35, 75 mg per animal) (see Table 1). The mean blood loss in anticoagulated rabbits administered andexanet was similar to that in non-anticoagulated rabbits (enoxaparin vehicle + andexanet vehicle). In enoxaparin-anticoagulated rabbits, andexanet rapidly (5 minutes after the start of andexanet administration; Time 125 minutes) reduced mean anti-FXa activity, and the reduction was significant for the 35-mg and 75-mg doses of andexanet (see Table 1). Anti-FXa activity did not return to baseline levels for the duration of the study from Time 120 to Time 140 minutes. These results are consistent with previous studies in enoxaparin-anticoagulated rats where a similar decrease in anti-FXa activity was sufficient to significantly reduce blood loss. These findings with an indirect (ATIII-mediated) FXa inhibitor enoxaparin are distinct from those with a direct FXa inhibitor (e.g., rivaroxaban), which showed that larger reductions in anti-FXa activity were required for significant reductions in blood loss. Conclusions: Administration of andexanet resulted in reversal of the anticoagulant effects of enoxaparin as well as restoration of hemostasis in enoxaparin-anticoagulated rabbits, suggesting it could be clinically valuable for the management of major bleeding associated with indirect FXa inhibitors. This study suggests a potential difference in the extent of reduction in anti-FXa activity required for significant reduction in blood loss associated with indirect vs. direct FXa inhibitors. Further studies are ongoing to better understand correlations between anti-FXa activity and blood loss following andexanet administration in enoxaparin-anticoagulated animals. Disclosures Pine: Portola Pharmaceuticals: Employment. Lu:Portola: Employment, Patents & Royalties. Canivel:Portola Pharmaceuticals: Employment. Pratikhya:Portola Pharmaceuticals: Employment. DeGuzman:Portola Pharmaceuticals: Employment. Karbarz:Portola Pharmaceuticals: Employment. Takeda:Portola Pharmaceuticals: Employment. Malinowski:Portola Pharmaceuticals: Employment. Leeds:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding. Curnutte:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding; 3-V Biosciences: Equity Ownership; Sea Lane Biotechnologies: Consultancy. Conley:Portola Pharmaceuticals: Employment, Equity Ownership, Patents & Royalties, Research Funding.

Description: 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. Disclosures Crowther: CSL Behring: Honoraria; Shire: Honoraria; Celgene: Honoraria; Bayer: Honoraria; AKP America: Consultancy; Leo Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Portola Pharmaceuticals, Inc.: Consultancy; The Heart and Stroke Foundation of Ontario: Career Investigator Award, Career Investigator Award Other. Levy:Portola Pharmaceuticals: Employment; University of Michigan: Patents & Royalties. Lu:Portola Pharmaceuticals Inc: Employment. Leeds:Portola Pharmaceuticals, Inc: Employment. Lin:Portola Pharmaceuticals, Inc.: Employment. Pratikhya:Portola Pharmaceuticals, Inc.: Employment. Conley:Portola Pharmaceuticals Inc: Employment; Portola Pharmaceuticals Inc: Equity Ownership. Connolly:Portola Pharmaceuticals Inc: Consultancy. Curnutte:Portola Pharmaceuticals, Inc.: Employment, Equity Ownership; Sea Lane Biotechnologies: Consultancy; 3-V Biosciences: Equity Ownership.