Positive Hemostasis in 82 Percent of Evaluable Patients
Portola Pharmaceuticals Announces Full Results from the ANNEXA-4 Study of the Factor Xa Inhibitor Reversal Agent Andexxa® in Patients with Life-Threatening Bleeding
Thu February 7, 2019 4:03 PM|GlobeNewswire|About: PTLA – 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 International Stroke Conference 2019 and Published in The New England Journal of Medicine –
SOUTH SAN FRANCISCO, Calif., Feb. 07, 2019 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals, Inc.® (Nasdaq: PTLA) today announced full results from ANNEXA-4, the Company’s Phase 3b/4 trial of its Factor Xa inhibitor antidote Andexxa® [coagulation factor Xa (recombinant), inactivated-zhzo] in patients experiencing acute major bleeding while taking a Factor Xa inhibitor. Data are being presented as a late-breaking oral presentation today at the International Stroke Conference 2019 and published simultaneously online by The New England Journal of Medicine (NEJM).
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, Seton Dell Medical School Stroke Institute and ANNEXA-4 Executive Committee member. “We now also have new data demonstrating no observed thrombotic events after resumption of oral anticoagulation. This is a particularly significant finding given the clinical importance of re-initiating therapy as soon as possible, even in the wake of a major bleeding event.”
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 John Curnutte, M.D., Ph.D., head of research and development at Portola. “The consistency of the ANNEXA-4 data, the strong response from the international medical societies that have already added Andexxa to their guidelines and the initial demand following the approval of Andexxa in May 2018 highlight its potential to benefit thousands of patients facing life-threatening bleeding associated with the use of rivaroxaban or apixaban.”
Andexxa received both U.S. Orphan Drug and U.S. Food and Drug Administration (FDA) Breakthrough Therapy designations, and was approved on May 3, 2018 under the FDA's Accelerated Approval pathway. Andexxa is the first and only antidote indicated for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding, and it was recently added to the 2019 AHA/ACC/HRS guidelines.
ANNEXA-4 Study Design ANNEXA-4 is a global, single-arm, open-label clinical trial designed to evaluate andexanet alfa in patients who present with an acute major bleed while receiving apixaban, rivaroxaban, edoxaban or enoxaparin. This multi-center, prospective cohort study was not randomized and all participants received andexanet alfa given as a bolus dose over 20-30 minutes followed by a two-hour (120 minute) infusion. Patients received a low or high dose infusion depending on which Factor Xa inhibitor they received and the time since they received the last dose. Patients were evaluated for 30 days following andexanet alfa administration. The co-primary efficacy endpoints are the maximum percent reduction in anti-Factor Xa activity and assessment of hemostasis over 12 hours following the infusion. Hemostatic efficacy was assessed by an independent endpoint adjudication committee using predetermined criteria as either excellent, good or poor/none. The primary safety endpoints were death, thrombotic events and development of antibodies to Andexxa or to native Factor X and Factor Xa.
