A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers

Abstract

As with any anticoagulant, factor Xa (FXa) inhibitors are associated with a risk of major bleeding. Andexanet alfa is a recombinant modified human FXa lacking enzymatic activity, developed for reversal of FXa inhibitor-induced anticoagulation. In two phase 2, randomized, double-blind, placebo-controlled, single-center studies, different regimens of andexanet alfa were administered to healthy volunteers after therapeutic anticoagulation with rivaroxaban or edoxaban, and multiple anticoagulation reversal and safety end points were evaluated. Andexanet alfa rapidly and effectively reversed anticoagulation with both rivaroxaban and edoxaban. Within 2 minutes after bolus, anti-FXa activity decreased significantly, with maximum decreases of ≈93% (P < .05) and ≈82% (P < .05), respectively, compared with placebo. The stoichiometric ratios of andexanet alfa:total anticoagulant at maximum reversal of anti-FXa activity ranged from 1:1 to 1.3:1 for rivaroxaban and 1.41:1 to 2.58:1 for edoxaban. Sustained normalization of thrombin generation for ≈2 hours and sustained decrease in unbound anticoagulant (maximum ≈80%) for up to ≈4 hours following completion of andexanet alfa administration, compared with placebo, were observed when andexanet was administered as a bolus or as a bolus followed by continuous infusion. Andexanet alfa was well tolerated, and there were no serious adverse events or thrombotic events. Andexanet alfa has been approved in the United States and Europe for reversal of anticoagulation in patients treated with rivaroxaban or apixaban who experience life-threatening or uncontrolled bleeding. These studies were registered with clinicaltrials.gov (#NCT03578146 and #NCT03551743).

Conflict of interest statement

Conflict-of-interest disclosure: J.C., P.B.C., J.T.C., J.M.L., G.L., and M.J.K. are employees and stockholders of Portola Pharmaceuticals. G.G.L. was an employee and stockholder of Portola Pharmaceuticals at time of study. V.S.M. reports personal fees from Portola Pharmaceuticals during the conduct of the study. M.C. has served as a consultant and/or speaker for Shionogi, Alexion, Pfizer, Daiichi, Octapharma, BMS Canada, CSL Behring, Servier Canada, Diagnostica Stago, and Asahi Kasei; his institution has received research grants from Leo Pharma and the Heart and Stroke Foundation; and he owns stock in Alnylam Pharmaceuticals.

© 2020 by The American Society of Hematology.

Figures

Graphical abstract

Figure 1.

Unbound and total rivaroxaban plasma concentrations on day 6 after the last dose of rivaroxaban with different andexanet alfa dosing regimens. (A) Unbound rivaroxaban (cohorts 1-3, upper left panel; cohorts 4-5, upper right panel). (B) Total rivaroxaban (cohorts 1-3, lower left panel; cohorts 4-5, lower right panel). Andexanet alfa was dosed at 3 hours after the last dose of rivaroxaban with a 210-, 420-, and 600-mg bolus (cohorts 1-3), 720-mg bolus plus 4 mg/min × 1-hour infusion (cohort 4), and 800-mg bolus plus 8 mg/min × 2-hour infusion (cohort 5), respectively.

Figure 2.

Unbound and total edoxaban and D21-2393 plasma concentrations on day 6 after the last dose of edoxaban with different andexanet alfa dosing regimens. (A) Unbound edoxaban. (B) Unbound D21-2393. (C) Total edoxaban (lower left panel) and total D21-2393 (lower right panel). Andexanet alfa was dosed at 3 hours (cohorts 1-2) or 5 hours (cohort 3) after the last dose of edoxaban with the 600-mg bolus (cohort 1), 800-mg bolus plus 8 mg/min × 1-hour infusion (cohort 2), and 800-mg bolus (cohort 3), respectively.

Figure 3.

Arithmetic mean anti-FXa activity vs time on day 6 after the last dose of rivaroxaban or edoxaban following andexanet alfa/placebo administration. (A) Rivaroxaban studies (cohorts 1-3, upper left panel; cohorts 4-5, upper right panel). Andexanet alfa was dosed at 3 hours after the last dose of rivaroxaban. (B) Edoxaban studies (cohorts 1-2, lower left panel; cohort 3, lower right panel). Andexanet alfa was administered at 3 hours (cohorts 1-2) or 5 hours (cohort 3) after the last dose of edoxaban.

Figure 4.

Relationship between mean unbound FXa inhibitor plasma concentration and anti-FXa activity on day 6. Group mean of anti-FXa activity is plotted against unbound rivaroxaban (A) and edoxaban (B) for andexanet alfa–treated subjects at each time point on day 6, between pre–andexanet alfa and 21 hours post–andexanet alfa bolus. Day 6 was the last dose of the inhibitor and the day when andexanet alfa was administered. Total inhibitor concentrations were increased after andexanet alfa administration, as shown in Figures 1 and 2. The solid line represents the best linear regression; the dashed lines indicate the 95% confidence intervals.

Figure 5.

Arithmetic mean thrombin generation vs time following andexanet alfa/placebo administration. Rivaroxaban studies (A, cohorts 1-3, upper left panel; cohorts 4-5, upper right panel); edoxaban studies (B, cohorts 1-2, lower left panel; cohort 3, lower right panel). Shaded regions represent day 1 pre-anticoagulant (mean ± 1 standard deviation [light shading]; ± 2 standard deviation [dark shading]) values. rfu, relative fluorescence unit.

Figure 6.

Time courses of median prothrombin fragments 1 and 2 and D-dimer levels before and after the administration of andexanet alfa. Rivaroxaban: F1+2 (A), D-dimer (C). Edoxaban: F1+2 (B), D-dimer (D).