Review clinical trial results for efficacy & safety

3D red-blue horshoe-shaped magnet lying flat, to represent Andexxa's power to draw out FXa inhibitors 3D red-blue horshoe-shaped magnet lying flat, to represent Andexxa's power to draw out FXa inhibitors

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

Line graph comparing FXa activity in Andexxa vs placebo in ANNEXA-A clinical trial (healthy volunteers taking apixaban) Line graph comparing FXa activity in Andexxa vs placebo in ANNEXA-A clinical trial (healthy volunteers taking apixaban)

 

97% reduction in anti-FXa activity from baseline to nadir in older healthy volunteers (P<0.0001)1

ANNEXA-R: rivaroxaban-treated patients

Line graph comparing FXa activity in Andexxa vs placebo in ANNEXA-R clinical trial (healthy volunteers taking rivaroxaban) Line graph comparing FXa activity in Andexxa vs placebo in ANNEXA-R clinical trial (healthy volunteers taking rivaroxaban)

Within 2-5 minutes, ANDEXXA restored thrombin generation in older, healthy volunteers2

ANNEXA-A: apixaban-treated patients

Line graph comparing thrombin generation in Andexxa vs placebo in ANNEXA-A trial (healthy volunteers taking apixaban) Line graph comparing thrombin generation in Andexxa vs placebo in ANNEXA-A trial (healthy volunteers taking apixaban)

ANNEXA-R: rivaroxaban-treated patients

Line graph comparing thrombin generation in Andexxa vs placebo in ANNEXA-R trial (healthy volunteers taking rivaroxaban) Line graph comparing thrombin generation in Andexxa vs placebo in ANNEXA-R trial (healthy volunteers taking rivaroxaban)

*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

patients-methods-20201118-mobile patients-methods-20201118

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

Primary efficacy measures

  • 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/thickness of ≤20% compared to baseline constituted an excellent rate, while an increase of >20% but ≤35% 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

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

Safety outcome measures ANNEXA-4 assessed the safety of subjects anticoagulated with FXa inhibitors at 30 days using the following measures:
  • 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]. South San Francisco, CA: Portola Pharmaceuticals Inc.; 2020. 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.