Mechanism Of Action
Coagulation factor Xa (recombinant), inactivated-zhzo exerts its procoagulant effect by binding and sequestering the FXa inhibitors, rivaroxaban and apixaban. Another observed procoagulant effect of the ANDEXXA protein is its ability to bind and inhibit the activity of Tissue Factor Pathway Inhibitor (TFPI). Inhibition of TFPI activity can increase tissue factor-initiated thrombin generation.
The effects of ANDEXXA can be measured using assays for its anti-FXa activity, free fraction of FXa inhibitor and thrombin generation. In addition to its ability to sequester the FXa inhibitors, rivaroxaban and apixaban, ANDEXXA has been shown to inhibit the Tissue Factor Pathway Inhibitor (TFPI) activity.
The dose and dosing regimen of ANDEXXA that are required to reverse anti-FXa activity and to restore thrombin generation were determined in dose-ranging studies on healthy volunteers. Dosing of ANDEXXA, as a bolus followed by a 2-hour continuous infusion, resulted in a rapid decrease in anti-FXa activity (within two minutes after the completion of the bolus administration) followed by reduced anti-FXa activity that was maintained throughout the duration of the continuous infusion [see Clinical Studies]. The anti-FXa activity returned to the placebo levels approximately 2 hours after completion of a bolus or continuous infusion. Whereas, TFPI activity in plasma was sustained for at least 22 hours following ANDEXXA administration.
Elevation of Tissue Factor (TF)-initiated thrombin generation above the baseline range (prior to anticoagulation) occurred within two minutes following a bolus administration of ANDEXXA and was maintained throughout the duration of the continuous infusion. The TF-initiated thrombin generation was elevated above placebo for up to 22 hours. The sustained elevation of thrombin generation over the baseline range, and sustained elevation over placebo were not observed in a contact-activated thrombin generation assay (an assay that is not affected by TF-TFPI interaction).
The volume of distribution (Vd) for ANDEXXA is approximately equivalent to the blood volume of 5 L.
Clearance for ANDEXXA is approximately 4.3 L/hr. The elimination half-life ranges from 5 to 7 hours.
The pharmacokinetics of ANDEXXA was not affected by apixaban (5 mg orally BID for 6 days) or rivaroxaban (20 mg orally once daily for 6 days).
The safety and efficacy of ANDEXXA were evaluated in two prospective, randomized, placebo-controlled studies, conducted in healthy volunteers. Both studies examined the percent change in anti-FXa activity, from baseline to nadir, for the low-dose and high-dose regimens of bolus followed by continuous infusion. Nadir is defined as the smallest value measured within 5 minutes after the end of the continuous infusion.
Study 1(NCT02207725) – Apixaban Reversal
In Study 1, healthy subjects (median age: 57 years; range: 50 to 73 years) received apixaban 5 mg twice daily for 3.5 days to achieve steady-state. At 3 hours after the last apixaban dose (~ Cmax), ANDEXXA or placebo was administered. Eight subjects received placebo and 24 received ANDEXXA, administered as a 400 mg intravenous (IV) bolus followed by a 4 mg per minute continuous infusion for 120 minutes (total 480 mg).
Study 2 (NCT02220725) – Rivaroxaban Reversal
In Study 2, healthy subjects (median age: 57 years, range: 50 to 68 years) received rivaroxaban 20 mg once per day for 4 days to achieve steady-state. At 4 hours after the last rivaroxaban dose (~ Cmax), ANDEXXA or placebo was administered. Thirteen subjects received placebo and 26 received ANDEXXA, administered as an 800 mg IV bolus followed by an 8 mg per minute continuous infusion for 120 minutes (total 960 mg).
Reduction In Anti-FXa Activity
The percent change from baseline in anti-FXa activity at its nadir was statistically significant (p < 0.0001) in favor of the ANDEXXA groups compared to placebo in both Studies 1 and 2. The results of Study 1 and Study 2 are provided in Table 3 (see below).
The time courses of anti-FXa activity before and after ANDEXXA administration are shown in Figure 1.
Table 3: Change in Anti-FXa Activity
| Mean baseline
ng/mL (± SD)
| Mean ng/mL
(± SD) change
at the nadir a
| Mean %
(± SD) change
at the nadir a
| 95% Confidence
|-59.5 (-64.1, -55.2)
||-51.9 (-58.0, -47.0)
||< 0.0001 c
||< 0.0001 c
SD = Standard deviation
Note: Baseline is the last assessment obtained prior to the first dose of ANDEXXA or placebo.
a Nadir is the smallest value for anti-FXa activity at the 110 minute (10 minutes prior to the end of the infusion) time
point, 2-minute time point before completion of the infusion, or the 5 minute time point after the completion of the
infusion for each subject.
b The CI is for the Hodges-Lehman estimate of shift.
c p-value obtained from a 2-sided exact Wilcoxon rank-sum test.
Figure 1: Change in Anti-FXa Activity (ng/mL) in Subjects Anticoagulated with
Apixaban (A – Study 1) and Rivaroxaban (B – Study 2)
Anti-FXa activity was measured prior to and after ANDEXXA or placebo administration.
Dashed lines indicate the end of the bolus or infusion. A break in the x-axis is added to better visualize the
immediate, short-term dynamics of anti-FXa activity following ANDEXXA treatment. The points on the graph
represent the mean anti-FXa activity level; error bars illustrate standard error. There was a statistically significant
difference (p < 0.05) in the percent change of anti-FXa activity normalized to pre-bolus between ANDEXXA and placebo until 2 hours after administration of infusion.
A. Apixaban – with ANDEXXA 400 mg IV bolus plus 4 mg/min infusion for 120 minutes.
B. Rivaroxaban – with ANDEXXA 800 mg IV bolus plus 8 mg/min infusion for 120 minutes.
In an ongoing multinational, prospective, single-arm, open-label study, ANDEXXA was
administered to patients taking FXa inhibitors who presented with acute major bleeding.
Interim results of the study include data for 185 patients. Of the 185 patients, 129 were
considered efficacy-evaluable, defined as patients who: 1) were dosed with ANDEXXA; 2) had a
baseline anti-FXa activity above 75 ng/mL; and 3) were adjudicated as meeting eligibility
criteria for acute major bleeding. [also see ADVERSE REACTIONS].
For anti-FXa activity, the median decrease from baseline to nadir was -93% for apixaban
and -90% for rivaroxaban. ANDEXXA has not been shown to be effective for bleeding related to
any FXa inhibitors other than apixaban and rivaroxaban.