Portola Pharmaceuticals Presents New Analysis from the ANNEXA-4 Study of its Factor Xa Inhibitor Reversal Agent Andexxa® in Patients with Acute Gastrointestinal Bleeding
SOUTH SAN FRANCISCO, Calif., Oct. 28, 2019 /PRNewswire/ -- Portola Pharmaceuticals, Inc.® (Nasdaq: PTLA) today announced the presentation of a new exploratory analysis of data from ANNEXA-4, the Company's Phase 3b/4 trial of its Factor Xa inhibitor antidote Andexxa® [coagulation factor Xa (recombinant), inactivated-zhzo], in a key subgroup of patients with acute gastrointestinal (GI) bleeding while taking a Factor Xa inhibitor.
The data will be featured at the American College of Gastroenterology (ACG) 2019 Annual Scientific Meeting in San Antonio, Texas, during a plenary session on Tuesday, October 29, 2019, from 3:25 p.m. CDT to 3:35 p.m. CDT (Location: Stars at Night Ballroom – B4; Plenary Session 3B, Abstract 53).
GI bleeding is a common type of anticoagulant-related bleeding that occurs in the upper or lower GI tract. Among the 352 patients in the ANNEXA-4 study, 90 (26%) were treated for acute GI bleeding and 62 (18%) were evaluable for hemostatic efficacy. Among this subset, 82% (n=51/62) achieved excellent or good hemostasis (stoppage of bleeding) over the 12-hour period following treatment with Andexxa, as determined by an independent adjudication committee. This is consistent with the 82% (n=204/249) reported in the full ANNEXA-4 study across patients with all types of bleeds (e.g., GI, intracranial hemorrhages and other sites of bleeding). Both the exploratory analysis and full study results showed that Andexxa rapidly and potently reversed anti-factor Xa activity.
Patients with GI bleeding were considered efficacy evaluable if they were determined to have major bleeding, as defined by hemodynamic compromise or bleeding associated with a hemoglobin (Hb) drop ≥ 2 g/dL or a baseline Hb ≤ 8 g/dL, and a baseline anti-factor Xa activity ≥ 75 ng/mL (≥ 0.25 IU/mL for enoxaparin patients).
Among the 90 safety evaluable patients with acute GI bleeding, and within 30 days of enrollment, thrombotic events occurred in six patients (7%) and death occurred in 10 patients (11%), consistent with the full ANNEXA-4 study results and the high background thrombotic risk of the enrolled patient population. No thrombotic events were observed among the 40 (44%) patients who re-started oral anticoagulation therapy. By comparison, among the 352 safety evaluable patients in ANNEXA-4 and within 30 days of enrollment, thrombotic events occurred in 34 patients (9.7%) and death occurred in 49 patients (13.9%). All of the thrombotic events occurred in patients who delayed or did not re-start anticoagulation therapy with a Factor Xa inhibitor during the follow-up period.
"Major bleeding associated with use of Factor Xa inhibitors is a serious and life-threatening complication," said Deborah Siegal, M.D., ACG presenter and assistant professor in the Department of Medicine of the Faculty of Health Sciences at McMaster University in Hamilton, Ontario. "This ANNEXA-4 sub-analysis of patients with bleeding in the GI tract – the most common site of anticoagulant-related bleeding – continues to demonstrate the consistency of the hemostatic efficacy and safety of Andexxa."
The use of Factor Xa inhibitors is growing rapidly because of their efficacy and safety profile compared to enoxaparin and warfarin in preventing and treating thromboembolic conditions such as stroke, pulmonary embolism and venous thromboembolism (VTE). This growth has come with a related increase in the incidence of hospital admissions and deaths related to bleeding, the major complication of anticoagulation. In 2017, there were approximately 150,000 hospital admissions attributable to Factor Xa inhibitor-related bleeding and approximately 2,100 bleeding-related deaths per month in the U.S.
"We are pleased that these data continue to highlight the durability of the hemostatic efficacy of Andexxa across patient populations, including those who experience Factor Xa inhibitor-related bleeding in more common sites such as the GI tract," said Scott Garland, Portola's president and chief executive officer. "The presentation of this analysis is part of our long-term strategy to build awareness of the clinical data supporting Andexxa, and become the standard of care for the hundreds of thousands of patients taking Factor Xa inhibitors who may require access to this potentially life-saving medicine."
Andexxa is a recombinant protein specifically designed to bind to Factor Xa inhibitors and rapidly reverse their anticoagulant effect. Andexxa was approved by the FDA in May 2018 as 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. Andexxa received both U.S. Orphan Drug and FDA Breakthrough Therapy designations and was approved under the FDA's Accelerated Approval pathway based on the change from baseline in anti-factor Xa activity in healthy volunteers. It is marketed in Europe as Ondexxya® (andexanet alfa).
ANNEXA-4 Study Design
ANNEXA-4 is a global, prospective, 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 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. Among the safety endpoints were mortality and thrombotic events at 30 days, and the development of antibodies to Andexxa or to native Factor X and Factor Xa.
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
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.
About Portola Pharmaceuticals, Inc.
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SOURCE Portola Pharmaceuticals, Inc.®
Company Codes: NASDAQ-NMS:PTLA