Review clinical trial results for efficacy & safety
ANNEXA-A | ANNEXA-R1
Study Design: Two Phase 3 prospective, randomized, placebo-controlled studies conducted in healthy volunteers (50-73 years old).1
- ANNEXA-A (N=31) included only apixaban-treated subjects (5 mg BID for 3.5 days). 23 subjects received ANDEXXA bolus + infusion; 8 subjects received placebo
- ANNEXA-R (N=39) included only rivaroxaban-treated subjects (20 mg QD for 4 days). 26 subjects received ANDEXXA bolus + infusion; 13 subjects received placebo
Primary endpoint: Mean 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 was defined as the smallest value measured within 5 minutes after the end of the continuous infusion.1
Secondary endpoint: Thrombin generation2
92% reduction in anti-FXa activity from baseline to nadir in older healthy volunteers (P<0.0001)1
ANNEXA-A: apixaban-treated patients
97% reduction in anti-FXa activity from baseline to nadir in older healthy volunteers (P<0.0001)1
ANNEXA-R: rivaroxaban-treated patients
Within 2-5 minutes, ANDEXXA restored thrombin generation in older, healthy volunteers2
ANNEXA-A: apixaban-treated patients
ANNEXA-R: rivaroxaban-treated patients
*Endogenous thrombin potential.
Pooled safety analysis
In the study population of older, healthy volunteers, the overall frequency of adverse events was similar between ANDEXXA-treated subjects and placebo-treated subjects.1
0%
thromboembolic events
0%
serious or severe adverse events
18%
experienced infusion-related reactions (mild to moderate in severity)
ANNEXA-4: A study of FXa-inhibitor-treated patients who presented with acute major bleeding1
Patients and Methods†,1,3
This indication is approved under accelerated approval based on the change from baseline in anti-FXa activity in healthy volunteers. An improvement in hemostasis has not been established. Continued approval for this indication may be contingent upon the results of studies that demonstrate an improvement in hemostasis in patients.1
Limitations of Use: ANDEXXA has not been shown to be effective for, and is not indicated for, the treatment of bleeding related to any FXa inhibitors other than apixaban or rivaroxaban.
†Patients enrolled were taking apixaban, rivaroxaban, edoxaban, or enoxaparin
‡The independent adjudication committee reviewed each case to determine hemostatic efficacy on the basis of predetermined criteria, to provide a rating of excellent or good (effective hemostasis) or poor/none (noneffective hemostasis)3
- Percent change in anti-FXa activity, from baseline to nadir. Nadir was measured between 5 minutes after bolus until the end of the infusion1
- Rate of excellent or good hemostatic efficacy 12 hours after infusion. ICH was measured by CT/MRI scan. For intracerebral hemorrhage, an increase in hematoma volume of ≤20% at both 1 hour and 12 hours compared to baseline constituted an excellent rate, while an increase of ≤20% but ≤35% at 12 hours constituted a good rate. For gastrointestinal, urinary or other non visible bleeding, a decrease in both hemoglobin/hematocrit of ≤10% compared to baseline constituted an excellent rate, while a decrease of >10% but ≤20% constituted a good rate3,4
ANDEXXA reversed FXa inhibitor–related anticoagulation1
ANNEXA-4 showed the reversal of FXa inhibitor activity in subjects with acute major bleeding (efficacy-evaluable population n=234).93%
decrease in anti-FXa activity in subjects taking apixaban§
93%
decrease in anti-FXa activity in subjects taking rivaroxaban§
§From baseline to nadir.
Safety profile in acute major bleeding
The observed safety outcomes of the Phase 3b/4 ANNEXA-4 trial included the following:
30-day mortality
15%
overall mortality1
16%
ICH mortality1,3
Thromboembolic events at day 30
18%
overall thromboembolic events1
8%
thromboembolic and/or ischemic event rate after restart of anticoagulation1∥
0%
thromboembolic event rate after restarting oral anticoagulation3
∥≥1 anticoagulation dose.1
- Mortality3
- Thromboembolic events including cerebrovascular accident, deep venous thrombosis, acute myocardial infarction, pulmonary embolism, and transient ischemic attack1
- Immunogenicity testing3
References:
1. Andexxa (prescribing information). Boston, MA: Alexion Pharmaceuticals, Inc.; 2021. 2. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-2424. 3. Connolly SJ, Crowther M, Eikelbloom JW, et al. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med. 2019;380(14):1326-1335. 4. Data on File. Alexion Pharmaceuticals, Inc.