ALBERT

Description: Introduction Andexanet alfa (AnXa) is a specific antidote under development for direct and indirect factor Xa (fXa) inhibitors. AnXa is a recombinant, engineered version of human fXa that is catalytically inactive but retains high affinity for direct fXa inhibitors. AnXa binds fXa inhibitors, sequestering them in plasma, thereby reducing the free inhibitor concentration, reversing fXa inhibition, and normalizing thrombin generation. The decreased unbound concentrations of the direct fXa inhibitors (apixaban, rivaroxaban and edoxaban) cause a portion of the extravascular fXa inhibitors to move into the vasculature. Reversal of fXa inhibitor-induced anticoagulation requires a molar excess of AnXa relative to the total amount of fXa inhibitor in the blood - i.e., the initial fXa inhibitor plasma concentration plus the redistributed amount. We report a PKPD model that accounts for this extravascular-intravascular redistribution and allows determination of the appropriate AnXa dose to reverse the anti-fXa activity for each approved direct fXa inhibitor. Methods A model for rivaroxaban was constructed first by jointly analyzing AnXa concentrations, total and unbound rivaroxaban concentrations, and anti-fXa activity for 5 different doses of AnXa (each administered at the peak plasma level of 20 mg QD rivaroxaban at steady state). Model parameters were estimated by maximum likelihood using nonlinear regression (NONMEM, v. 7.2.0). The model was used to simulate the potential level of reversal of anti-fXa activity after 2.5-40 mg/day rivaroxaban (QD and BID) for different bolus doses of AnXa and to predict maintenance of reversal by various follow-on infusion rates. A similar model was developed to characterize the interaction between AnXa and apixaban. Learnings from the rivaroxaban and apixaban models were used to develop a universal model to predict the level of reversal of anticoagulation for 60 mg edoxaban after a particular dose of AnXa. The model accurately predicted the degree of reversal of edoxaban anticoagulation. The final model was used to construct a nomogram of AnXa doses that could be used for each fXa inhibitor at each approved dose based on timing of the last dose of the inhibitor. Results The final PKPD model was a three-compartment PK model for the fXa inhibitors, including one central and two tissue compartments. The two tissue compartments included one that rapidly equilibrated with the central compartment and a second that equilibrated slowly. The combined volume of the central and rapidly equilibrating compartments was similar to the volume of central compartment of the fXa inhibitor PK models in the absence of AnXa. The AnXa PK was best described by a two-compartment PK model with an additional saturable binding component. The AnXa-fXa inhibitor complex moved to a "sequestration" compartment. Upon release from AnXa, the fXa inhibitor was able to return to the central compartment. The fXa inhibitor did not clear with AnXa. The binding between AnXa and free fXa inhibitor was characterized by a reversible binding equilibrium. There was a direct PKPD linear relationship between free fXa inhibitor concentrations and anti-fXa activity. Simulations were used to estimate the best dosing regimen to reverse anticoagulation for each direct fXa inhibitor. A bolus dose of 800 mg of AnXa followed by an 8 mg/min infusion was sufficient to fully reverse the peak level of anti-fXa activity after the 20 mg QD dose of rivaroxaban. This represents a 〉90% decrease in anti-fXa activity compared to pre-AnXa administration. Sustained reversal of peak anti-fXa levels for the 5 mg BID dose of apixaban required a 400 mg bolus AnXa dose with a follow-on infusion of 4 mg/min. The peak anticoagulant activity of the 60 mg dose of edoxaban could be reversed by an 800 mg bolus dose of AnXa followed by an 8 mg/min infusion. Conclusions A PKPD model was constructed that accurately predicted the AnXa dose necessary to reverse coagulation inhibition of each direct fXa inhibitor. The model incorporated the PK of AnXa, the anti-fXa activity, unbound and total levels of the fXa inhibitor, and the redistribution of each fXa inhibitor between the extravascular and intravascular compartments. Simulations were used to predict the AnXa dose necessary to reverse each approved dose of each direct fXa inhibitor and for different times after the last dose taken of the fXa inhibitor. Disclosures Janet: Portola Pharmaceuticals, Inc.: Employment. Lu:Portola Pharmaceuticals, Inc.: Employment. Curnutte:3-V Biosciences: Equity Ownership; Sea Lane Biotechnologies: Consultancy; Portola Pharmaceuticals, Inc.: Employment. Conley:Portola Pharmaceuticals, Inc.: Employment. Mandema:Portola Pharmaceuticals, Inc.: Consultancy.

Description: Introduction: A challenge for dose-ranging trials of a new anticoagulant is to minimize subject risk for venous thromboembolism (VTE) and major bleeding while exploring the efficacy and safety of a wide dose range of the study drug. This study utilized an adaptive design to evaluate PD 0348292 across a 100-fold dose range for the prevention of VTE in subjects after total knee replacement (TKR) surgery. Methods: Adult subjects who had undergone unilateral TKR were randomized to 1 of 6 treatments: double-blind oral PD 0348292 (0.1, 0.3, 0.5, 1.0, or 2.5 mg qd) or open-label subcutaneous enoxaparin (30 mg bid) in a 1:1:1:1:1:2 ratio, respectively. PD 0348292 and enoxaparin were initiated 6 to 8 hours and 12 to 24 hours after surgery, respectively; both were continued for 6 to 14 days. The primary efficacy outcome was the incidence of VTE (proximal or distal deep vein thrombosis assessed by bilateral venography, and/or pulmonary embolism) as adjudicated by an independent central imaging laboratory. The primary safety endpoint was the incidence of total bleeding. The adaptive design allowed for the discontinuation of doses of PD 0348292 due to excessive VTE or major bleeding, and the addition of higher doses (4 and 10 mg qd), based on acceptable major bleeding. The decision to discontinue and/or add doses was based upon pre-specified interim assessments of the incidence of VTE and major bleeding by an independent Data Monitoring Committee (DMC) via model-based dose-response analysis (logistic regression). Results: A total of 1411 subjects were randomized at 99 sites in 16 countries; 1389 were treated with at least 1 dose of study drug; and 749 (53.1%) were evaluable for primary efficacy analysis. As a result of DMC assessments, 3 lower dose groups of PD 0348292 (0.1, 0.3, and 0.5 mg qd) were discontinued, and 2 higher dose groups (4 and 10 mg qd) were added during the study. The observed incidence of VTE was 37.1%, 37.1%, 28.8%, 19.2%, 14.3%, 1.4%, and 11.1% for PD 0348292 doses of 0.1, 0.3, 0.5, 1.0, 2.5, 4.0, and 10.0 mg qd, respectively, compared with 18.1% for enoxaparin. The dose response for PD 0348292 was statistically significant (P 〈 0.001). Based on the dose-response model for efficacy, the dose of PD 0348292 equivalent to enoxaparin 30 mg bid for VTE prevention in TKR subjects was estimated to be 1.16 (95% CI, 0.56, 2.41) mg qd. Overall, PD 0348292 and enoxaparin were well tolerated. No deaths and no unexpected adverse events were reported. A dose-related increase in the incidence of total bleeding, driven mainly by minor bleeding, was observed with PD 0348292, but was not statistically significant (P = 0.2464). The PD 0348292 dose-response relationship for major bleeding was relatively flat and was not statistically significant (P = 0.6040). Observed incidence of major bleeding ranged from 0% to 1.5% across the PD 0348292 dose range studied, compared with 0.8% for enoxaparin. Three of the 5 reported major bleeding events in PD 0348292 subjects occurred at the surgical site, compared with 2 out of 3 in enoxaparin subjects. Conclusion: The adaptive design utilized in this study enabled comparison of a wide dose range of PD 0348292 (0.1 to 10.0 mg qd) to enoxaparin 30 mg bid in TKR surgical subjects using a single study. Modeling of the efficacy data provided an estimate of a dose of PD 0348292 that was equivalent to enoxaparin 30 mg bid for VTE prevention. The adaptive design and modeling allowed use of approximately 2.5-fold fewer subjects than would have a traditional parallel-arm, pairwise-comparison study design.