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The new oral anticoagulants have many advantages over warfarin, but one disadvantage is the inability to rapidly reverse their anticoagulant effects. Andexanet, a small-molecule factor Xa fragment, rapidly lowered levels of rivaroxaban and apixaban in older healthy volunteers. The direct factor Xa inhibitors apixaban, rivaroxaban, and edoxaban are used in the prevention and treatment of thromboembolism. Indications for the use of these agents include the prevention of stroke in patients with nonvalvular atrial fibrillation, the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism, and the prevention of venous thrombosis after orthopedic surgery. In spite of the demonstrated safety and efficacy of factor Xa inhibitors, as well as their practical advantages over vitamin K antagonists such as warfarin, the lack of a specific antidote to reverse their anticoagulant effects is an important limitation. In clinical trials involving . . .

In a single-group trial, 352 patients with acute major bleeding while taking a factor Xa inhibitor were treated with andexanet. Andexanet markedly reduced anti–factor Xa activity, and 82% of the patients had excellent or good hemostatic efficacy at 12 hours.

Coagulation factor Xa is targeted by a new generation of antithrombotic drugs such as rivaroxaban. However, as excessive factor Xa inhibition can cause bleeding, the clinical use of factor Xa inhibitors would be enhanced by the availability of a specific antidote. Uma Sinha and her colleagues devise such an antidote, an inactive form of recombinant factor Xa that can bind to and neutralize factor Xa inhibitors, and demonstrate its efficacy in animal models. Inhibitors of coagulation factor Xa (fXa) have emerged as a new class of antithrombotics but lack effective antidotes for patients experiencing serious bleeding. We designed and expressed a modified form of fXa as an antidote for fXa inhibitors. This recombinant protein (r-Antidote, PRT064445) is catalytically inactive and lacks the membrane-binding γ-carboxyglutamic acid domain of native fXa but retains the ability of native fXa to bind direct fXa inhibitors as well as low molecular weight heparin–activated antithrombin III (ATIII). r-Antidote dose-dependently reversed the inhibition of fXa by direct fXa inhibitors and corrected the prolongation of ex vivo clotting times by such inhibitors. In rabbits treated with the direct fXa inhibitor rivaroxaban, r-Antidote restored hemostasis in a liver laceration model. The effect of r-Antidote was mediated by reducing plasma anti-fXa activity and the non–protein bound fraction of the fXa inhibitor in plasma. In rats, r-Antidote administration dose-dependently and completely corrected increases in blood loss resulting from ATIII-dependent anticoagulation by enoxaparin or fondaparinux. r-Antidote has the potential to be used as a universal antidote for a broad range of fXa inhibitors.

Andexanet alfa, a catalytically inactive decoy of factor Xa, successfully reversed the factor Xa inhibitory effects of rivaroxaban and apixaban in a small study involving patients with acute major bleeding. In randomized clinical trials, factor Xa inhibitors have been shown to be safe and effective for the treatment and prevention of venous thromboembolism and for stroke prevention in patients with atrial fibrillation. 1 – 4 However, factor Xa inhibitors have been associated with major and even fatal bleeding events. 1 – 4 Such episodes of acute major bleeding may be difficult to treat because there is no reversal agent. Andexanet alfa (andexanet) has been designed and developed specifically to reverse the effects of both direct and indirect factor Xa inhibitors. It is a recombinant, modified human factor Xa decoy protein that binds factor Xa . . .

Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. In vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury. Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035). These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Andexanet alfa (andexanet) is a modified human factor Xa (FXa) approved for anticoagulation reversal in patients with life‐threatening bleeding treated with rivaroxaban or apixaban. Four‐factor prothrombin complex concentrates (4F‐PCCs) are approved for reversal of vitamin K antagonist–induced anticoagulation but not FXa inhibitors. The mechanism and effectiveness of 4F‐PCCs for FXa inhibitor reversal are unclear. To investigate the mechanism and impact of 4F‐PCCs on reversal of rivaroxaban and apixaban in vitro compared to andexanet. The effect of 4F‐PCCs (or individual factors) on tissue factor‐initiated thrombin generation (TF‐TG) was evaluated in human plasma, with or without rivaroxaban or apixaban, and compared with andexanet under the same conditions. In the TF‐TG assay, 4F‐PCC completely reversed warfarin anticoagulation. Andexanet normalized TF‐TG over a wide range of apixaban and rivaroxaban concentrations tested (19‐2000 ng/mL). However, 4F‐PCC (or individual factors) was unable to normalize endogenous thrombin potential (ETP) or peak thrombin (Peak) in the presence of apixaban or rivaroxaban (75‐500 ng/mL). TF‐TG was only normalized by 4F‐PCC at inhibitor concentrations <75 ng/mL (ETP) or <37.5 ng/mL (Peak). These data can be explained by the estimated thresholds of FXa activity required to support normal TF‐TG based on the inhibitor:FXa ratios and levels of uninhibited FXa. The data are consistent with healthy volunteer studies where TF‐TG is not normalized until inhibitor levels are substantially decreased. Both the theoretical calculations and experimental data demonstrated that 4F‐PCCs are only able to normalize TG over a low and narrow range of FXa inhibitor concentrations (<75 ng/mL).

Abstract INTRODUCTION Andexanet alfa (andexanet) is a modified, recombinant human factor Xa (FXa) that acts as a decoy to bind and sequester FXa inhibitors, thus reversing their anticoagulation effects. Here, we report the efficacy of andexanet in reversing the anticoagulant activity of betrixaban, a direct FXa inhibitor which has recently completed a large Phase 3 clinical trial in acute medically ill patients (APEX). METHODS In this Phase 2, randomized, double-blind study, healthy subjects were dosed with 80 mg qd po betrixaban to steady state (7 days). In Cohort 1, subjects (n = 6) received 800-mg andexanet bolus 3 hours after the last dose of betrixaban, or matching placebo (n = 3). In Cohort 2, subjects (n = 6) received 800-mg andexanet bolus 4 hours after the last betrixaban dose, followed immediately by a 2-hour andexanet infusion (8 mg/min), or matching placebo (n = 3). Study endpoints included assessments of safety and pharmacodynamic markers of anticoagulation reversal. RESULTS >Following dosing with betrixaban, andexanet rapidly (2 minutes after the bolus) decreased anti-FXa activity by ∼80% in both cohorts (P < 0.001 vs. placebo) and decreased unbound betrixaban plasma concentration by 73% and 83% in Cohorts 1 and 2, respectively (P < 0.001 vs. placebo). The effects were maintained during the 2-hour infusion of andexanet. Thrombin generation was restored in 11/12 (91.7%) subjects administered andexanet vs. 2/6 (33.3%) placebo subjects. Andexanet was well-tolerated; there were no thrombotic events or other serious/severe adverse events. CONCLUSION Andexanet was well-tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. The results of this and previous studies in healthy subjects indicate the potential of andexanet as a universal antidote for FXa inhibitors. An ongoing Phase 3b/4 study (ANNEXA-4) in patients receiving a FXa inhibitor who present with acute major bleeding and require urgent reversal of anticoagulation will provide efficacy and safety information on andexanet in this target patient population.

Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. In vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury. Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035). These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Increasing use of factor Xa (FXa) inhibitors necessitates effective reversal agents to manage bleeding. Andexanet alfa, a novel modified recombinant human FXa, rapidly reverses the anticoagulation effects of direct and indirect FXa inhibitors. To evaluate the ability of andexanet to reverse anticoagulation in vitro and reduce bleeding in rabbits administered edoxaban. In vitro studies characterized the interaction of andexanet with edoxaban and its ability to reverse edoxaban-mediated anti-FXa activity. In a rabbit model of surgically induced, acute hemorrhage, animals received edoxaban vehicle+andexanet vehicle (control), edoxaban (1 mg/kg)+andexanet vehicle, edoxaban+andexanet (75 mg, 5-minute infusion, 20 minutes after edoxaban), or edoxaban vehicle+andexanet prior to injury. Andexanet bound edoxaban with high affinity similar to FXa. Andexanet rapidly and dose-dependently reversed the effects of edoxaban on FXa activity and coagulation pharmacodynamic parameters in vitro. In edoxaban-anticoagulated rabbits, andexanet reduced anti-FXa activity by 82% (from 548±87 to 100±41 ng/ml; P<0.0001), mean unbound edoxaban plasma concentration by ~80% (from 100±10 to 21±6 ng/ml; P<0.0001), and blood loss by 80% vs. vehicle (adjusted for control, 2.6 vs. 12.9 g; P = 0.003). The reduction in blood loss correlated with the decrease in anti-FXa activity (r = 0.6993, P<0.0001) and unbound edoxaban (r = 0.5951, P = 0.0035). These data demonstrate that andexanet rapidly reversed the anticoagulant effects of edoxaban, suggesting it could be clinically valuable for the management of acute and surgery-related bleeding. Correlation of blood loss with anti-FXa activity supports the use of anti-FXa activity as a biomarker for assessing anticoagulation reversal in clinical trials.

Abstract INTRODUCTION: Direct FXa inhibitors have demonstrated convincing anticoagulant efficacy. However, risk of major bleeding is a concern and no specific antidotes are available for reversal. Andexanet alfa (AnXa), a recombinant modified FXa, is an investigational specific antidote for FXa inhibitors. We report data from the ANNEXA”! Phase 3 registration studies in older healthy subjects anticoagulated with apixaban (apix) or rivaroxaban (riva). METHODS: ANNEXA A&R were 2 phase 3, randomized, double-blind, placebo-controlled studies of AnXa in healthy subjects age 50 to 75 administered either apixaban or rivaroxaban. Andexanet dose selection was based on phase 2 data and PK/PD modeling, which will be presented. In ANNEXA”!-A, subjects were treated with apix 5 mg twice daily for 4 days to achieve steady-state concentrations. AnXa (Part 1: 400 mg bolus; Part 2: 400 mg bolus plus 4 mg/min × 2-hour infusion) or placebo was administered on day 4, 3 hours after the last apix dose. In ANNEXA”!-R, subjects were treated with riva 20 mg every day for 4 days to achieve steady-state concentrations. AnXa (part 1: 800 mg bolus; part 2: 800 mg bolus plus 8 mg/min × 2-hour infusion) or placebo was administered on day 4, 4 hours after the last riva dose. Safety data were collected through day 43. RESULTS: ANNEXA-A&R enrolled 63 and 82 subjects, respectively. The primary efficacy end point, percent change from baseline in anti-FXa activity to nadir (part 1: between 2 and 5 minutes postbolus; part 2: between 10 minutes before and 5 minutes after the end of the continuous infusion) was met for each part with high statistical significance (P < .001 vs placebo). Additional efficacy end points, including reduction in plasma free inhibitor concentration and restoration of thrombin generation, were also met. There were no serious adverse events, thrombotic events, or antibodies to FX or FXa. The andexanet PK/PD model accurately predicted the riva and apix anti-FXa activity observed in this study. CONCLUSION: ANNEXA-A&R achieved all primary and secondary end points with high statistical significance. AnXa treatment resulted in rapid and sustained reversal of both apix- and riva-induced anticoagulation. A phase 3b/4 confirmatory study (ANNEXA-4) in patients with acute major bleeds is ongoing.