Portola Pharmaceuticals Announces Interim Results from Ongoing Phase 3b/4 ANNEXA-4™ Study of Factor Xa Inhibitor Antidote AndexXa™ (andexanet alfa) in Patients with Acute Major Bleeding
--AndexXa Rapidly Reversed Anticoagulant Effect of Factor Xa Inhibitors; Excellent or Good Hemostasis Was Achieved in 79 Percent of Patients Over 12 Hours--
--Data Presented in Late-Breaking Science Hot Line Session at European Society of Cardiology 2016 Congress and Published in New England Journal of Medicine--
--Webcast with ANNEXA-4 Executive Committee Members Today at 11 a.m. ET--
SOUTH SAN FRANCISCO, Calif., Aug. 30, 2016 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals Inc.® (Nasdaq:PTLA) today announced interim results from the ongoing Phase 3b/4 ANNEXA™-4 study of AndexXa™ (andexanet alfa), a Factor Xa inhibitor antidote. In this study of patients with Factor Xa inhibitor-associated acute major bleeding, a preliminary analysis of interim data from 67 patients (of whom 47 were evaluated for efficacy) showed that AndexXa rapidly and substantially reversed anti-Factor Xa activity (the anticoagulant mechanism of these drugs) when administered as a bolus, and sustained this reversal when followed by a 120-minute infusion. Additionally, 79 percent of these patients achieved excellent or good hemostasis (stoppage of bleeding) over a 12-hour period following infusion. These interim results were presented orally today in a Late-Breaking Science Hot Line session at the European Society of Cardiology (ESC) 2016 Congress in Rome. The interim results were published simultaneously online by The New England Journal of Medicine(NEJM) and are accessible at http://investors.portola.com.
“In this preliminary analysis, AndexXa was effective in rapidly reversing anti-Factor Xa inhibitor activity and restoring normal blood clotting in real-world patients with Factor Xa inhibitor-related bleeding. Based on these interim results, we believe that ANNEXA-4 is on track to achieve its co-primary efficacy endpoints upon study completion,” said Stuart J. Connolly, M.D., ANNEXA-4 Executive Committee chairman and professor in the Department of Medicine of the Faculty of Health Sciences at McMaster University in Hamilton, Ontario. “The hemostatic efficacy results are especially important because no FDA or EMA-approved antidote is available for these patients and no existing therapies, including plasma-derived products for warfarin reversal, have demonstrated reversal of Factor Xa inhibitor activity or clinical efficacy and safety.”
Factor Xa inhibitors are associated with a decreased risk of intracranial hemorrhage compared to warfarin, however the consequences are similar and can be fatal. In large randomized trials, the 30-day mortality rate in Factor Xa inhibitor patients with intracranial hemorrhage (ICH) exceeds 40 percent.
The interim results from all 67 patients who received AndexXa showed that the antidote was not associated with any infusion reactions, and no patients developed antibodies to Factor Xa or Factor X or neutralizing antibodies to AndexXa. During the 30-day follow-up period, thrombotic events occurred in 12 patients (18 percent), and death occurred in 10 patients (15 percent). These events occurred within the range expected in this population given the severity of the bleeding, their underlying thrombotic risk, and the low percentage who restarted anticoagulant therapy following their bleeding episode.
“The ANNEXA-4 interim results are preliminary yet encouraging because the percentage of patients who have achieved excellent or good hemostasis is higher than the co-primary endpoint threshold of above 50 percent defined in the study protocol,” said John Curnutte, M.D. Ph.D., executive vice president, research and development at Portola. “This threshold was determined based on historical benchmarks of hemostatic control achieved with agents in studies of warfarin reversal and on expert opinion. What is also encouraging is that following two reviews that included the patients described in this report, the Data and Safety Monitoring Board recommended that the study proceed as planned.”
ANNEXA-4 Study Design
ANNEXA-4 is a global, single-arm, open-label clinical trial designed to evaluate AndexXa, a U.S. Food and Drug Administration (FDA)-designated Breakthrough Therapy, in patients who present with an acute major bleed while receiving apixaban, rivaroxaban, edoxaban or enoxaparin. For ethical reasons, this multi-center, prospective cohort study is not randomized and all participants receive AndexXa given as a bolus dose over 30 minutes followed by a two-hour infusion. Patients receive a low or high dose depending on which Factor Xa inhibitor they have received and the time they received it. Patients are evaluated for 30 days following AndexXa administration. The co-primary efficacy endpoints are the percent change in anti-Factor Xa activity at two hours and assessment of hemostasis over 12 hours following the infusion. Hemostatic efficacy is assessed by an independent endpoint adjudication committee as either excellent, good or poor/none. To date, ANNEXA-4 has enrolled more than 130 patients of the approximately 270 patients targeted for inclusion.
ANNEXA-4 Interim Results
The interim results included safety data from 67 patients who experienced life-threatening gastrointestinal bleeding (49 percent), intracranial bleeding (42 percent) or bleeding at another site (9 percent) within 18 hours of administration of apixaban (31 patients), rivaroxaban (32 patients) or enoxaparin (4 patients).
The efficacy population included only those 47 patients whose bleed severity met the specific inclusion criteria, as determined by an independent adjudication committee, and whose baseline anti-Factor Xa activity was substantially elevated. The interim efficacy results showed the following:
- AndexXa rapidly and substantially reversed anti-Factor Xa activity, and these levels were sustained for the duration of administration. Following the bolus dose, median anti-Factor Xa activity decreased by 89 percent from baseline for patients on rivaroxaban and by 93 percent for patients on apixaban, and was sustained at similar levels for the duration of the two-hour infusion.
- AndexXa was associated with normalization of blood clotting and cessation of bleeding. The independent adjudication committee determined that 37 of 47 patients (79 percent) achieved excellent or good hemostasis. Among patients with gastrointestinal bleeding, 84 percent had excellent or good hemostasis as did 80 percent of patients with intracranial bleeding. Hemostatic efficacy was similar for patients on apixaban (75 percent) and rivaroxaban (81 percent).
Investor Event Webcast Information
Members of Portola’s senior management team, together with Dr. Stuart J. Connolly, ANNEXA-4 Executive Committee chairman, and Dr. C. Michael Gibson, ANNEXA-4 Executive Committee member, will present and discuss the data during an investor event today, Tuesday, August 30, following the ANNEXA-4 interim results data presentation at the ESC Congress. The investor event will be simultaneously webcast and will take place from 5:00-6:00 p.m. CEST/11 a.m. - 12 p.m. EDT. To access the live and subsequently archived webcast, go to the Investor Relations section of the company's website at http://investors.portola.com. A replay will be available for 30 days following the live event.
About the Need for a Factor Xa Inhibitor Antidote
Annually, 1 to 4 percent of patients treated with Factor Xa inhibitors may experience major bleeding, and an additional 1 percent may require emergency surgery. Commensurate with the increase in the use of Factor Xa inhibitors -- for stroke prevention in atrial fibrillation; treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism; and prevention of DVT following knee or hip replacement surgery -- the number of hospital admissions due to bleeding associated with these agents continues to grow. In the United States, more than 80,000 patients treated with oral Factor Xa inhibitors were admitted to the hospital due to bleeding during 2015. Including patients taking the injectable Factor Xa inhibitor enoxaparin, it is estimated that more than 100,000 U.S. patients could benefit from an antidote annually. Currently, there is no FDA-approved antidote for Factor Xa inhibitors for these patients.
AndexXa, an investigational drug, is a modified human Factor Xa molecule that acts as a decoy to target and sequester with high specificity both oral and injectable Factor Xa inhibitors in the blood. Once bound, the Factor Xa inhibitors are unable to bind to and inhibit native Factor Xa, thus potentially allowing for the restoration of normal hemostatic processes. AndexXa is the first compound being studied as an antidote for Factor Xa inhibitors that directly and specifically reverses anti-Factor Xa activity – the anticoagulant mechanism of these agents.
On August 17, 2016, Portola received a Complete Response Letter (CRL) from the FDA regarding its Biologics License Application (BLA) for AndexXa. The Company plans to meet with the FDA as soon as possible in order to resolve the outstanding questions in the CRL and determine appropriate next steps. In the EU, Portola submitted a Marketing Authorization Application (MAA), which has been validated and is under review by the European Medicines Agency (EMA).
About Portola Pharmaceuticals, Inc.
Portola Pharmaceuticals is a biopharmaceutical company developing product candidates that could significantly advance the fields of thrombosis and other hematologic diseases. The Company is advancing three programs, including betrixaban, an oral, once-daily Factor Xa inhibitor; AndexXa™ (andexanet alfa), a recombinant protein designed to reverse the anticoagulant effect in patients treated with an oral or injectable Factor Xa inhibitor; and cerdulatinib, a Syk/JAK inhibitor in development to treat hematologic cancers. Portola's partnered program is focused on developing selective Syk inhibitors for inflammatory conditions. For more information, visit www.portola.com and follow the Company on Twitter @Portola_Pharma.
Statements contained in this press release regarding matters that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the potential future regulatory approval of andexanet alfa and patient populations that could benefit from a Factor Xa inhibitor reversal agent. Risks that contribute to the uncertain nature of the forward-looking statements include the risk that we may be unable to satisfy regulatory requirements for such approval, we may be unable to manufacture andexanet alfa on a commercial scale, and we will need additional capital to fund our operations. These and other risks and uncertainties are described more fully in our most recent filings with the Securities and Exchange Commission, including our Current Report on 8-K filed on August 19, 2016, and our most recent quarterly report on Form 10-Q, which was filed on August 9, 2016. All forward-looking statements contained in this press release speak only as of the date on which they were made. We undertake no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.
Ana KaporPortola Pharmaceuticalsir@portola.com
Julie NormartW2O Groupjnormart@w2ogroup.com
Portola Pharmaceuticals, Inc.