|Portola Pharmaceuticals Announces Full Results from the ANNEXA-4 Study of the Factor Xa Inhibitor Reversal Agent Andexxa® in Patients with Life-Threatening Bleeding|
– Excellent or Good Hemostasis Achieved in 82 Percent of Evaluable Patients –
–Thrombotic Event Rate of 9.7 Percent Across All Patients, No Thrombotic Events Observed Among Patients Who Re-started Oral Anticoagulation Therapy –
– Data Presented as a Late-Breaking Oral Presentation at the
Full data from 352 patients (249 of which were evaluable for hemostatic efficacy; all 352 were evaluable for safety) showed that Andexxa rapidly and significantly reversed anti-Factor Xa activity when administered as a bolus, and sustained this reversal when followed by a 120-minute infusion. Anti-Factor Xa activity is a measure of the anticoagulant activity of apixaban, rivaroxaban, edoxaban and enoxaparin, the anticoagulants studied in ANNEXA-4. Among all 352 patients, 64 percent (n=227) were treated for intracranial hemorrhage (ICH) and 26 percent (n=90) were treated for a gastrointestinal bleed. Of those evaluated for efficacy 82 percent (n=204) achieved excellent or good hemostasis (stoppage of bleeding) over the 12-hour period following treatment with Andexxa, as determined by an independent adjudication committee.
Within 30 days of enrollment, thrombotic events occurred in 34 patients (9.7 percent) and death occurred in 49 patients (13.9 percent), consistent with previous ANNEXA-4 trial results and with the high background thrombotic risk of the enrolled patient population. The majority of thrombotic events occurred in patients who delayed or did not re-start anticoagulation therapy with a Factor Xa inhibitor during the follow-up period. Among the 100 patients who re-started oral anticoagulation therapy, no thrombotic events were observed. Two patients experienced an infusion reaction and none developed antibodies to Factor Xa or Factor X or neutralizing antibodies to Andexxa.
“The consistency of the hemostatic efficacy and safety – regardless of age, dose, type of Factor Xa inhibitor and type of bleed – confirms the potential of Andexxa to address life-threatening bleeding associated with the use of the Factor Xa inhibitors apixaban or rivaroxaban,” said Truman J. Milling Jr., M.D., FACEP,
The worldwide use of Factor Xa inhibitors is rapidly growing because of their efficacy and safety profile compared to warfarin and enoxaparin in preventing and treating thromboembolic conditions such as stroke, pulmonary embolism and venous thromboembolism (VTE). This growth has come with a proportional increase in the incidence of hospital admissions and deaths related to bleeding, the major complication of anticoagulation. In the U.S. alone in 2017, there were approximately 140,000 hospital admissions attributable to Factor Xa inhibitor-related bleeding.
“The need for a specific Factor Xa inhibitor reversal agent is clear. As Factor Xa inhibitor use continues to grow, so does the prevalence of life-threatening bleeds such as an ICH, which carries a mortality rate of nearly 50 percent,” said
Andexxa received both U.S. Orphan Drug and
ANNEXA-4 Study Design
IMPORTANT SAFETY INFORMATION FOR ANDEXXA [coagulation factor Xa (recombinant), inactivated-zhzo]
BOXED 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:
Monitor for thromboembolic events and initiate anticoagulation when medically appropriate. Monitor for symptoms and signs that precede cardiac arrest and provide treatment as needed.
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 to demonstrate an improvement in hemostasis in patients.
Limitation of Use
SELECT IMPORTANT SAFETY INFORMATION
Thromboembolic and Ischemic Risk
The thromboembolic and ischemic risks were assessed in 185 patients who received the Generation 1 product and in 124 patients who received the Generation 2 product. The median time to first event was six days, and patients were observed for these events for 30 days following Andexxa infusion. Of the 86 patients who received Generation 1 product and were re-anticoagulated prior to a thrombotic event, 11 (12.7%) patients experienced a thromboembolic event, ischemic event, cardiac event or death.
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
Thirty-eight patients who received the Generation 1 product were anticoagulated with apixaban and had baseline levels of anti-FXa activity > 150 ng/mL. Nineteen of these 38 (50%) patients experienced a > 93% decrease from baseline anti-FXa activity after administration of Andexxa. Eleven patients who were anticoagulated with rivaroxaban had baseline anti-FXa activity levels > 300 ng/mL. Five of the 11 patients experienced a > 90% decrease from baseline anti-FXa activity after administration of Andexxa. Anti-FXa activity levels for patients who received the Generation 2 product were not available.
The most common adverse reactions (≥ 3%) in healthy volunteers treated with Andexxa were infusion-related reactions.
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