Portola Reports Q4 EPS -$0.82 Vs Est -$0.90, Announce Positive Phase 3 ANNEXA-R Study

The randomized, double-blind, placebo-controlled Phase 3 ANNEXA-R study is evaluating the safety and efficacy of andexanet alfa in reversing XARELTO®-induced anticoagulation in healthy volunteers ages 50-75 years. Efficacy is being evaluated using biomarker endpoints, with anti-Factor Xa levels as the primary endpoint. Secondary endpoints include plasma levels of free unbound XARELTO® and endogenous thrombin potential (ETP), a measure of thrombin generation. In the first part of the ANNEXA-R study, 41 healthy volunteers were given XARELTO® 20 mg once daily for four days to steady state. They were then randomized in a 2:1 ratio to receive at Cmax either andexanet alfa administered as an 800 mg IV bolus (n=27) or placebo (n=14). Results showed that, for the primary endpoint, andexanet alfa reduced the anti-Factor Xa activity of rivaroxaban from baseline to nadir by >90 percent, a highly significant difference (p<0.0001). For the secondary endpoints: Significantly more andexanet alfa subjects (26 of 27) than placebo subjects (0) had a 90 percent or greater reduction in anti-Factor Xa activity from baseline to nadir (p<0.0001). The free (unbound) XARELTO® concentration from baseline to nadir was reduced significantly by andexanet alfa compared with placebo (p<0.0001). ETP significantly increased from baseline to peak in andexanet alfa subjects compared with placebo subjects (p<0.0001). 26 of 27 andexanet alfa subjects returned to the normal range of thrombin generation within 10 minutes of the end of the bolus administration. In the study, andexanet alfa was well tolerated. There were no serious or severe adverse events, no thrombotic events, and no antibodies to Factor X or Xa were observed. In the second part of the ANNEXA-R study, approximately 40 healthy volunteers will be given XARELTO® 20 mg once daily for four days and will then be randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus followed by a continuous infusion of 8 mg/min for 120 minutes or to placebo. Data from this part of the study are expected in mid-2015. Data Presentation The abstract of the study results was posted today and can be accessed at http://www.abstractsonline.com/pp8/#!/3658. The data will be presented at the American College of Cardiology's (ACC) 64th Annual Scientific Session in San Diego on Monday, March 16, at 11:30 a.m. PT in an oral session titled "Highlighted Original Research: Acute Coronary Syndromes and the Year in Review." About the Need for a Factor Xa Inhibitor Antidote Currently, millions of patients are treated with Factor Xa inhibitors for short-term use or chronic conditions, and the anticoagulant market is expected to continue to grow. Recent patient datai confirm earlier clinical trial results showing that, annually, between 1-4 percent of patients treated with Factor Xa inhibitors may experience major bleeding and an additional 1 percent may require emergency surgery. Development of a specific antidote designed to reverse the anticoagulant activity of Factor Xa inhibitors may provide an important treatment option for patients who experience a major bleeding event or require emergency surgery. About Andexanet Alfa Andexanet alfa 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 allowing for the restoration of normal hemostatic processes. Andexanet alfa has the potential to address numerous clinical scenarios where an antidote is needed by allowing for flexible and controlled reversal. This can be short-acting through the administration of an IV bolus or longer-acting with the addition of an extended infusion. Andexanet alfa is the only compound being studied as a reversal agent for Factor Xa inhibitors that directly and specifically corrects anti-Factor Xa activity -- the anticoagulant mechanism of these agents. Andexanet alfa has been granted orphan drug designation by the FDA for reversing the anticoagulant effect of direct or indirect Factor Xa inhibitors in patients experiencing a serious uncontrolled bleeding event or who require urgent or emergent surgery. About the Andexanet Alfa Clinical Development Program Portola is evaluating andexanet alfa in two randomized, placebo-controlled Phase 3 ANNEXA™ (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors) registration studies using pharmacodynamic endpoints agreed to with the FDA, including anti-Factor Xa inhibitor units, to demonstrate efficacy. The Company reported statistically significant results from the first part of the Phase 3 ANNEXA-A study, which evaluated andexanet alfa administered as a single IV bolus dose with Bristol-Myers Squibb Company and Pfizer Inc.'s direct Factor Xa inhibitor apixaban, and from the first part of the Phase 3 ANNEXA-R study with Bayer HealthCare and Janssen's direct Factor Xa inhibitor rivaroxaban. The second parts of the ANNEXA-A and ANNEXA-R studies are ongoing and are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity. ANNEXA-4, a Phase 4 single-arm confirmatory study in patients receiving apixaban, rivaroxaban, edoxaban or enoxaparin (a low molecular weight heparin and indirect Factor Xa inhibitor) who present with an acute major bleed, is also ongoing. Data from the ANNEXA-A and ANNEXA-R studies, as well as data from a small number of patients from ANNEXA-4, will serve as the clinical basis of a Biologics License Application (BLA), which Portola plans to submit under an Accelerated Approval pathway. Results from four separate Phase 2 proof-of concept studies with apixaban, rivaroxaban, edoxaban and enoxaparin in healthy volunteers demonstrated that andexanet alfa immediately reversed the anticoagulation activity of each Factor Xa inhibitor and that the reversal could be sustained. Andexanet alfa has been shown to be well tolerated in clinical studies, which have included more than 140 healthy volunteers. No thrombotic events or antibodies to Factor Xa or Factor X have been observed. A Phase 2 proof-of-concept study with Portola's investigational Factor Xa inhibitor betrixaban is planned.