Review clinical trial results for efficacy & safety

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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-mobile patients-methods

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 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

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). 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.

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SELECT IMPORTANT SAFETY INFORMATION

WARNING: THROMBOEMBOLIC RISKS, ISCHEMIC RISKS, CARDIAC ARREST, AND SUDDEN DEATHS

See full prescribing information for complete boxed warning

Treatment with ANDEXXA has been associated with serious and life-threatening adverse events, including:

  • Arterial and venous thromboembolic events

  • Ischemic events, including myocardial infarction and ischemic stroke

  • Cardiac arrest

  • Sudden deaths

Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed.

INDICATION

ANDEXXA (coagulation factor Xa (recombinant), inactivated-zhzo) is a recombinant modified human factor Xa (FXa) protein indicated for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.

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.

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.

Select Important Safety Information
WARNINGS AND PRECAUTIONS

Thromboembolic and Ischemic Risks

The thromboembolic and ischemic risks were assessed in 352 bleeding subjects who received ANDEXXA. Of the 63 subjects who experienced a thrombotic event, the median time to first event was 7 days, and 21 subjects experienced the event within the first three days. A total of 63 (18%) experienced 88 thromboembolic or ischemic events. Of the 352 subjects who received ANDEXXA, 223 received at least one anticoagulation dose within 30 days after treatment. Of these 223, 18 subjects (8%) had a thrombotic event and/or ischemic event after resumption.

Monitor patients treated with ANDEXXA for signs and symptoms of arterial and venous thromboembolic events, ischemic events, and cardiac arrest. To reduce thromboembolic risk, resume anticoagulant therapy as soon as medically appropriate following treatment with ANDEXXA.

The safety of ANDEXXA has not been evaluated in patients who experienced thromboembolic events or disseminated intravascular coagulation within two weeks prior to the life-threatening bleeding event requiring treatment with ANDEXXA. Safety of ANDEXXA also has not been evaluated in patients who received prothrombin complex concentrates, recombinant factor VIIa, or whole blood products within seven days prior to the bleeding event.

Re-elevation or Incomplete Reversal of Anti-FXa Activity

The time course of anti-FXa activity following ANDEXXA administration was consistent among the healthy volunteer studies and the ANNEXA-4 study in bleeding patients. Compared to baseline, there was a rapid and substantial decrease in anti-FXa activity corresponding to the ANDEXXA bolus. This decrease was sustained through the end of the ANDEXXA continuous infusion. The anti-FXa activity returned to the placebo levels approximately two hours after completion of a bolus or continuous infusion. Subsequently, the anti-FXa activity decreased at a rate similar to the clearance of the FXa inhibitors.

Seventy-one subjects were anticoagulated with apixaban and had baseline levels of anti-FXa activity > 150 ng/mL. Nineteen subjects who were anticoagulated with rivaroxaban had elevated baseline anti-FXa activity levels >300 ng/mL. Forty-eight of the 71 apixaban-treated subjects (68%) experienced a > 90% decrease from baseline anti-FXa activity after administration of ANDEXXA. Ten of the 19 rivaroxaban subjects (53%) experienced a > 90% decrease from baseline anti-FXa activity after administration of ANDEXXA.

Use of Heparin Following Administration of ANDEXXA

ANDEXXA may interfere with the anticoagulant effect of heparin. Use of ANDEXXA as an antidote for heparin has not been established. Avoid use of ANDEXXA for the reversal of direct FXa inhibitors (apixaban and rivaroxaban) prior to heparinization as ANDEXXA may cause unresponsiveness to heparin. If anticoagulation is needed, use an alternative anticoagulant to heparin.

ADVERSE REACTIONS

The most common adverse reactions (≥ 5%) in bleeding patients receiving ANDEXXA were urinary tract infections and pneumonia.

The most common adverse reactions (≥ 3%) in healthy subjects treated with ANDEXXA were infusion-related reactions.

Immunogenicity

As with all therapeutic proteins, there is the potential for immunogenicity. Using an electrochemiluminescence (ECL)-based assay, 145 ANDEXXA-treated healthy subjects were tested for antibodies to ANDEXXA as well as antibodies cross-reacting with Factor X (FX) and FXa. Low titers of anti-ANDEXXA antibodies were observed in 26/145 healthy subjects (17%); 6% (9/145) were first observed at Day 30 with 20 subjects (14%) still having titers at the last time point (Days 44 to 48). To date, the pattern of antibody response in patients in the ongoing ANNEXA-4 study has been similar to that observed in healthy volunteers. Of the 236 subjects with available samples, 6.8% (16/236) had antibodies against ANDEXXA. None of these anti-ANDEXXA antibodies were neutralizing. No neutralizing antibodies cross-reacting with FX or FXa were detected in healthy subjects (0/145) or in bleeding patients (0/209) to date.

To report SUSPECTED ADVERSE REACTIONS, call 1-844-259-6783 or contact the FDA by visiting www.fda.gov/medwatch, or calling 1-800-FDA-1088.

Please see full Prescribing Information including Boxed Warning on thromboembolic risks, ischemic risks, cardiac arrest, and sudden death.