Approval Probability
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Adjusted LOA
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Also known as ALXN2070, Andexanet Alfa, PRT064445, Andexxa
Andexanet · 2 trials · 2 indications
Anti-fXa activity was measured to assess the ability of andexanet to reverse the anticoagulant effect of FXa inhibitors. Baseline was defined as the last value obtained prior to the start of the andexanet bolus. The change from baseline was calculated as the reduction in anti-fXa activity from baseline to the on-treatment nadir (that is, the minimum value between end of bolus and end of infusion). Percent reduction was calculated as the ratio between the maximum change from baseline and the baseline value, multiplied by 100.
Hemostatic efficacy was achieved when the body had time to produce thrombin and a subsequent clot and was rated by the EAC as: excellent; good; poor/none; not evaluable due to non-administrative reasons; not evaluable due to administrative reasons. These ratings were based on pre-specified criteria that were included in the EAC Charter. The EAC was blinded to anti-fXa activity levels. Participant results were classified as either success or failure based on the hemostatic efficacy rating (success = excellent/good, failure = poor/none). Participants rated by the EAC as non-evaluable due to administrative reasons were excluded from the analysis of hemostatic efficacy.
To determine the pharmacodynamic (PD) effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured by chromogenic enzymatic anti-FXa activity assays.
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured by chromogenic enzymatic anti-FXa activity assays.
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as thrombin generation potential (including Endogenous Thrombin Potential \[ETP\]).
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as thrombin generation potential (including ETP).
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as thrombin generation potential (including ETP).
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as time to onset of coagulation.
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as time to onset of coagulation.
To determine the PD effect of andexanet doses by assessing reversal of rivaroxaban or apixaban anticoagulation measured as time to onset of coagulation.
To determine anticoagulation by enoxaparin at different time points after andexanet treatment measured by chromogenic enzymatic anti-FXa activity assays.
To determine anticoagulation by enoxaparin at different time points after andexanet treatment measured as thrombin generation potential (including ETP).
| Arm | Type | Description |
|---|---|---|
| Andexanet | EXPERIMENTAL | Participants received andexanet as an intravenous bolus administered over \~15 to 30 minutes, followed immediately by a continuous infusion administered over \~120 minutes. |
| Module 1: Rivaroxaban + Andexanet (dose A) | EXPERIMENTAL | Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose A) dosing, the participants will receive an additional dose of rivaroxaban. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after the end of andexanet bolus. |
| Module 1: Rivaroxaban + Andexanet (dose B) | EXPERIMENTAL | Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose B) dosing, the participants will receive an additional dose of rivaroxaban. |
| Module 1: Rivaroxaban + Andexanet (dose C) | EXPERIMENTAL | Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose C) dosing, the participants will receive an additional dose of rivaroxaban. |
| Module 1: Rivaroxaban + Placebo | EXPERIMENTAL | Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before placebo (equivalent to dose B of andexanet) dosing, the participants will receive an additional dose of rivaroxaban. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after placebo administration. |
| Module 2: Apixaban + Andexanet (dose B) | EXPERIMENTAL | Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose B) dosing, the participants will receive an additional dose of apixaban. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after the end of andexanet bolus. |
| Module 2: Apixaban + Andexanet (dose C) | EXPERIMENTAL | Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose C) dosing, the participants will receive an additional dose of apixaban. |
| Module 2: Apixaban + Andexanet (dose D) | EXPERIMENTAL | Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose D) dosing, the participants will receive an additional dose of apixaban. |
| Module 2: Apixaban + Placebo | EXPERIMENTAL | Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before placebo (equivalent to dose B of andexanet) dosing, the participants will receive an additional dose of apixaban. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after placebo administration. |
| Module 3: Rivaroxaban + Andexanet (Dose A) | EXPERIMENTAL | Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose A) dosing, the participants will receive an additional dose of rivaroxaban. |
| Module 3: Apixaban + Andexanet (Dose B) | EXPERIMENTAL | Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before andexanet (dose B) dosing, the participants will receive an additional dose of apixaban. |
| Module 3: Rivaroxaban + Placebo | EXPERIMENTAL | Participants will receive once daily dose of 20 mg rivaroxaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before placebo (equivalent to dose A of andexanet) dosing, the participants will receive an additional dose of rivaroxaban. |
| Module 3: Apixaban + Placebo | EXPERIMENTAL | Participants will receive twice daily dose of 5 mg apixaban from Day -3 to Day -1 to achieve steady state plasma levels. On Day 1, approximately 3 hours before placebo (equivalent to dose B of andexanet) dosing, the participants will receive an additional dose of apixaban. |
| Module 4: Placebo + Andexanet (dose C) | EXPERIMENTAL | Participants will receive daily dose of one placebo tablet from Day -3 to Day -1. On Day 1, approximately 3 hours before andexanet (dose C) dosing, the participants will receive an additional placebo tablet. |
| Module 4: Placebo + Andexanet (dose B) | EXPERIMENTAL | Participants will receive daily dose of one placebo tablet from Day -3 to Day -1. On Day 1, approximately 3 hours before andexanet (dose B) dosing, the participants will receive an additional placebo tablet. Participants will be further allocated to groups to receive doses of enoxaparin at different time points after the end of andexanet bolus. |
| Name | Type | Description |
|---|---|---|
| Andexanet | BIOLOGICAL | There were 2 possible dosing regimens: Low dose = 400 milligram (mg) bolus plus 4 mg/minute continuous infusion for 120 minutes; High dose = 800 mg bolus plus 8 mg/minute continuous infusion for 120 minutes. |
| Andexanet alfa | DRUG | Andexanet alfa will be administered as an intravenous bolus followed by an infusion, however, in Module 3, only a bolus will be given. |
| Rivaroxaban | DRUG | Rivaroxaban will be administered as an oral tablet. |
| Apixaban | DRUG | Apixaban will be administered as an oral tablet. |
| Enoxaparin | DRUG | Enoxaparin will be administered as a subcutaneous injection. |
| Placebo | OTHER | Placebo will replace andexanet and be given as an IV bolus plus infusion in Modules 1 and 2; in Module 3, placebo will be IV bolus only. In Module 4, an oral placebo tablet will replace rivaroxaban and apixaban. |
Key Inclusion Criteria: 1. Acute major bleeding episode that required urgent reversal of anticoagulation; defined by at least one of the following: * Acute bleeding that was potentially life-threatening, or * Acute bleeding associated with a fall in hemoglobin level by ≥2 grams/deciliter (g/...
Andexanet is an investigational monoclonal antibody developed by AstraZeneca PLC (ticker AZN) for the treatment of bleeding. It is being studied in a Phase 3 clinical program in hematology, specifically for patients experiencing acute major bleeding. Andexanet is designed as an inhibitor of TFPI, tissue factor pathway inhibitor.
Andexanet is being developed for the treatment of bleeding, including acute major bleeding. The Phase 3 extension study enrolled participants with acute major bleeding to evaluate the ability of Andexanet alfa to reverse the anticoagulation effect of direct and indirect oral anticoagulants. It remains investigational and is not approved for commercial use.
Andexanet targets TFPI, tissue factor pathway inhibitor. It is classified as an inhibitor of TFPI and is a monoclonal antibody modality. By binding TFPI, Andexanet is designed to modulate the anticoagulation pathway in patients with bleeding, which is the mechanism under study in its Phase 3 clinical program.
Andexanet is developed by AstraZeneca PLC, which trades under the ticker AZN. AstraZeneca is the sponsor of the Phase 3 clinical study evaluating Andexanet alfa in participants with acute major bleeding. The drug remains an investigational asset in the company's hematology pipeline.
Andexanet is in Phase 3 clinical development. Its Phase 3 study, NCT02329327, has been completed and enrolled 479 participants. Andexanet is investigational and has not been approved by the FDA for any indication based on the available development information.
Andexanet has been studied in the Phase 3 trial NCT02329327, titled A Study in Participants With Acute Major Bleeding to Evaluate the Ability of Andexanet Alfa to Reverse the Anticoagulation Effect of Direct and Indirect Oral Anticoagulants (Extension Study). The trial is completed, enrolled 479 participants, and was conducted in the United States, Belgium, Canada, France, Germany, Japan, the Netherlands, Spain, and the United Kingdom.