The New England Journal of Medicine Publishes Results Of Portola’ Phase 3 ANNEXA Studies Of Andexanet Alfa
Full Data Set From ANNEXA-R Also Presented Today in Late-Breaking Clinical Trial Session at AHA Scientific Sessions 2015
SOUTH SAN FRANCISCO, Calif., Nov. 11, 2015 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) announced that the results of its Phase 3 ANNEXA™ (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors) studies were published online today by The New England Journal of Medicine. ANNEXA-R and ANNEXA-A evaluated the safety and efficacy of andexanet alfa, an investigational reversal agent, which was designated a breakthrough therapy by the U.S. Food and Drug Administration (FDA), for reversing the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban, respectively, in healthy volunteers. Results showed that both ANNEXA Part 1 (bolus only) and Part 2 (bolus plus continuous infusion) met all primary and secondary efficacy endpoints, including the measurement of reversal Anti-Xa activity (p<0.0001) for both rivaroxaban and apixaban.
In Part 1, andexanet alfa given as an IV bolus reversed the anticoagulant effect of the Factor Xa inhibitors to no-effect levels, as measured by anti-Factor Xa activity, within two to five minutes of administration (p<0.0001). In Part 2, andexanet alfa administered as an IV bolus followed by a continuous two-hour infusion sustained that reversal for the duration of the infusion, reducing anticoagulant activity (p<0.0001). Andexanet alfa was well tolerated, with no serious or severe adverse events, no thrombotic events, and no antibodies to Factor X or Xa observed.
Full results of Part 2 of ANNEXA-R also were presented today during a Late Breaking Clinical Trial session at the American Heart Association’s (AHA) Scientific Sessions 2015 in Orlando, Florida, in an abstract entitled: ANNEXA™-R Part 2: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Sustained Reversal of Rivaroxaban-Induced Anticoagulation in Older Subjects by Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa (FXa) Inhibitors.
Commensurate with the increase in use of Factor Xa inhibitors, the number of hospital admissions due to bleeding associated with these agents continues to grow. 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. In the United States alone, during the 12 months ended April 2015, there were over 50,000 rivaroxaban or apixaban treated patients admitted to the hospital due to bleeding1. This number does not account for patients taking the injectable Factor Xa inhibitor enoxaparin or those on a Factor Xa inhibitor undergoing emergency surgery. In the United States, more than 100,000 patients annually may benefit from a reversal agent. Currently, there is no FDA-approved reversal agent for Factor Xa inhibitors for these patients. Portola is developing andexanet alfa, a recombinant protein specifically designed to reverse the anticoagulant activity of Factor Xa inhibitors, as a universal reversal agent for patients anticoagulated with an oral or injectable Factor Xa inhibitor who experience a serious uncontrolled bleeding event or who require urgent or emergency surgery.
Four-factor PCCs, are not approved to reverse the anticoagulant effects of Factor Xa inhibitors, and no known label-enabling studies are ongoing. Additionally, the FDA and the European Medicines Agency do not view four-factor PCCs, which are only approved to reverse the effects of vitamin K and include a black box warning for blood clots, as a standard of care therapy for this patient population.
“The ANNEXA studies demonstrated that andexanet alfa can rapidly reverse the anticoagulant effect of Factor Xa inhibitors for both short and sustained periods with a good safety profile. This is important because it means that andexanet alfa, by allowing for flexible and controlled reversal, could address different clinical scenarios in which a reversal agent is needed,” said John T. Curnutte, M.D., Ph.D., executive vice president, research and development, for Portola. “These positive ANNEXA study results suggest that andexanet alfa, if approved, could become the first universal reversal agent for Factor Xa inhibitors and could also become the new standard of care for managing serious uncontrolled bleeding in patients treated with these novel anticoagulants.”
Design of ANNEXA Studies
The randomized, double-blind, placebo-controlled Phase 3 ANNEXA-R and ANNEXA-A studies evaluated the safety and efficacy of andexanet alfa in reversing the anticoagulant effect of rivaroxaban and apixaban, respectively, in healthy volunteers aged 50-68 years. Efficacy was evaluated using widely accepted coagulation biomarkers. The primary endpoint was reduction in anti-Factor Xa levels; secondary endpoints included reduction in plasma levels of free unbound rivaroxaban or apixaban and restoration of the endogenous thrombin potential (ETP), a measure of thrombin generation.
ANNEXA-R Efficacy Results
In Part 1, 41 healthy volunteers were given rivaroxaban 20 mg once daily for four days and then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or placebo (n=14). Within two to five minutes of completion of the bolus dose, andexanet alfa significantly reversed the anticoagulant activity of rivaroxaban (by 92 percent) compared with placebo (p<0.0001), as measured by anti-Factor Xa activity; significantly reduced the level of free (unbound) rivaroxaban in the plasma compared with placebo (p<0.0001); and fully restored thrombin generation in 96 percent of subjects (p<0.0001 vs. placebo).
In Part 2, 39 healthy volunteers were given rivaroxaban 20 mg once daily for four days and then 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 (n=26) or placebo (n=13). Andexanet alfa significantly reduced anti-Factor Xa activity by 97 percent compared with placebo (p<0.0001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound rivaroxaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound rivaroxaban compared with placebo (p<0.0001). Andexanet alfa also restored thrombin generation to normal in all subjects who received the compound (p<0.0001 vs. placebo).
ANNEXA-A Efficacy Results
In Part 1, 33 subjects were given apixaban 5 mg twice daily for 3.5 days and then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus (n=24) or placebo (n=9). Within two to five minutes of completion of the bolus dose, andexanet alfa significantly reversed the anticoagulant activity of apixaban (by 94 percent) compared with placebo (p<0.0001), as measured by anti-Factor Xa activity; significantly reduced the level of free (unbound) apixaban in the plasma compared with placebo (p<0.0001); and fully restored thrombin generation in 100 percent of subjects (p<0.0001 vs. placebo).
In Part 2, 31 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=24) or placebo (n=8). Andexanet alfa significantly reduced anti-Factor Xa activity by 92 percent compared with placebo (p<0.0001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound apixaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound apixaban compared with placebo (p=0.0002). Andexanet alfa also restored thrombin generation to normal in all subjects who received the compound (p<0.0001 vs. placebo).
ANNEXA Safety Results
Andexanet alfa was well tolerated in both studies. No serious or severe adverse events, no thrombotic events, and no antibodies to Factor X or Xa were reported. All adverse events related to andexanet administration were non-serious and mild.
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 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.
Portola is currently evaluating andexanet alfa in ANNEXA-4, a Phase 4 single-arm, open label 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. Data from a small number of patients from ANNEXA-4, as well as data from ANNEXA-A and ANNEXA-R, will serve as the clinical basis for the Biologics License Application (BLA). A rolling submission of the BLA has been initiated under Accelerated Approval and the submission package is expected to be complete by the end of this year.
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 its three wholly-owned programs using novel biomarker and genetic approaches that may increase the likelihood of clinical, regulatory and commercial success of its potentially life-saving therapies. These programs include betrixaban, an oral, once-daily Factor Xa inhibitor being evaluated in the APEX Phase 3 study for prophylaxis of venous thromboembolism; 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.
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SOUTH SAN FRANCISCO, Calif., Nov. 11, 2015 (GLOBE NEWSWIRE) -- Portola Pharmaceuticals (Nasdaq:PTLA) announced that the results of its Phase 3 ANNEXA™ (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors) studies were published online today by The New England Journal of Medicine. ANNEXA-R and ANNEXA-A evaluated the safety and efficacy of andexanet alfa, an investigational reversal agent, which was designated a breakthrough therapy by the U.S. Food and Drug Administration (FDA), for reversing the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban, respectively, in healthy volunteers. Results showed that both ANNEXA Part 1 (bolus only) and Part 2 (bolus plus continuous infusion) met all primary and secondary efficacy endpoints, including the measurement of reversal Anti-Xa activity (p<0.0001) for both rivaroxaban and apixaban.
In Part 1, andexanet alfa given as an IV bolus reversed the anticoagulant effect of the Factor Xa inhibitors to no-effect levels, as measured by anti-Factor Xa activity, within two to five minutes of administration (p<0.0001). In Part 2, andexanet alfa administered as an IV bolus followed by a continuous two-hour infusion sustained that reversal for the duration of the infusion, reducing anticoagulant activity (p<0.0001). Andexanet alfa was well tolerated, with no serious or severe adverse events, no thrombotic events, and no antibodies to Factor X or Xa observed.
Full results of Part 2 of ANNEXA-R also were presented today during a Late Breaking Clinical Trial session at the American Heart Association’s (AHA) Scientific Sessions 2015 in Orlando, Florida, in an abstract entitled: ANNEXA™-R Part 2: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial Demonstrating Sustained Reversal of Rivaroxaban-Induced Anticoagulation in Older Subjects by Andexanet Alfa (PRT064445), a Universal Antidote for Factor Xa (FXa) Inhibitors.
Commensurate with the increase in use of Factor Xa inhibitors, the number of hospital admissions due to bleeding associated with these agents continues to grow. 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. In the United States alone, during the 12 months ended April 2015, there were over 50,000 rivaroxaban or apixaban treated patients admitted to the hospital due to bleeding1. This number does not account for patients taking the injectable Factor Xa inhibitor enoxaparin or those on a Factor Xa inhibitor undergoing emergency surgery. In the United States, more than 100,000 patients annually may benefit from a reversal agent. Currently, there is no FDA-approved reversal agent for Factor Xa inhibitors for these patients. Portola is developing andexanet alfa, a recombinant protein specifically designed to reverse the anticoagulant activity of Factor Xa inhibitors, as a universal reversal agent for patients anticoagulated with an oral or injectable Factor Xa inhibitor who experience a serious uncontrolled bleeding event or who require urgent or emergency surgery.
Four-factor PCCs, are not approved to reverse the anticoagulant effects of Factor Xa inhibitors, and no known label-enabling studies are ongoing. Additionally, the FDA and the European Medicines Agency do not view four-factor PCCs, which are only approved to reverse the effects of vitamin K and include a black box warning for blood clots, as a standard of care therapy for this patient population.
“The ANNEXA studies demonstrated that andexanet alfa can rapidly reverse the anticoagulant effect of Factor Xa inhibitors for both short and sustained periods with a good safety profile. This is important because it means that andexanet alfa, by allowing for flexible and controlled reversal, could address different clinical scenarios in which a reversal agent is needed,” said John T. Curnutte, M.D., Ph.D., executive vice president, research and development, for Portola. “These positive ANNEXA study results suggest that andexanet alfa, if approved, could become the first universal reversal agent for Factor Xa inhibitors and could also become the new standard of care for managing serious uncontrolled bleeding in patients treated with these novel anticoagulants.”
Design of ANNEXA Studies
The randomized, double-blind, placebo-controlled Phase 3 ANNEXA-R and ANNEXA-A studies evaluated the safety and efficacy of andexanet alfa in reversing the anticoagulant effect of rivaroxaban and apixaban, respectively, in healthy volunteers aged 50-68 years. Efficacy was evaluated using widely accepted coagulation biomarkers. The primary endpoint was reduction in anti-Factor Xa levels; secondary endpoints included reduction in plasma levels of free unbound rivaroxaban or apixaban and restoration of the endogenous thrombin potential (ETP), a measure of thrombin generation.
ANNEXA-R Efficacy Results
In Part 1, 41 healthy volunteers were given rivaroxaban 20 mg once daily for four days and then randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or placebo (n=14). Within two to five minutes of completion of the bolus dose, andexanet alfa significantly reversed the anticoagulant activity of rivaroxaban (by 92 percent) compared with placebo (p<0.0001), as measured by anti-Factor Xa activity; significantly reduced the level of free (unbound) rivaroxaban in the plasma compared with placebo (p<0.0001); and fully restored thrombin generation in 96 percent of subjects (p<0.0001 vs. placebo).
In Part 2, 39 healthy volunteers were given rivaroxaban 20 mg once daily for four days and then 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 (n=26) or placebo (n=13). Andexanet alfa significantly reduced anti-Factor Xa activity by 97 percent compared with placebo (p<0.0001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound rivaroxaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound rivaroxaban compared with placebo (p<0.0001). Andexanet alfa also restored thrombin generation to normal in all subjects who received the compound (p<0.0001 vs. placebo).
ANNEXA-A Efficacy Results
In Part 1, 33 subjects were given apixaban 5 mg twice daily for 3.5 days and then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus (n=24) or placebo (n=9). Within two to five minutes of completion of the bolus dose, andexanet alfa significantly reversed the anticoagulant activity of apixaban (by 94 percent) compared with placebo (p<0.0001), as measured by anti-Factor Xa activity; significantly reduced the level of free (unbound) apixaban in the plasma compared with placebo (p<0.0001); and fully restored thrombin generation in 100 percent of subjects (p<0.0001 vs. placebo).
In Part 2, 31 healthy volunteers were given apixaban 5 mg twice daily for four days and then randomized in a 3:1 ratio to receive either andexanet alfa administered as a 400 mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes (n=24) or placebo (n=8). Andexanet alfa significantly reduced anti-Factor Xa activity by 92 percent compared with placebo (p<0.0001), with reversal persisting for 1 to 2 hours after completion of the infusion. The reduction in free unbound apixaban was sustained with the bolus plus infusion, which significantly reduced the mean plasma concentration of free unbound apixaban compared with placebo (p=0.0002). Andexanet alfa also restored thrombin generation to normal in all subjects who received the compound (p<0.0001 vs. placebo).
ANNEXA Safety Results
Andexanet alfa was well tolerated in both studies. No serious or severe adverse events, no thrombotic events, and no antibodies to Factor X or Xa were reported. All adverse events related to andexanet administration were non-serious and mild.
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 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.
Portola is currently evaluating andexanet alfa in ANNEXA-4, a Phase 4 single-arm, open label 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. Data from a small number of patients from ANNEXA-4, as well as data from ANNEXA-A and ANNEXA-R, will serve as the clinical basis for the Biologics License Application (BLA). A rolling submission of the BLA has been initiated under Accelerated Approval and the submission package is expected to be complete by the end of this year.
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 its three wholly-owned programs using novel biomarker and genetic approaches that may increase the likelihood of clinical, regulatory and commercial success of its potentially life-saving therapies. These programs include betrixaban, an oral, once-daily Factor Xa inhibitor being evaluated in the APEX Phase 3 study for prophylaxis of venous thromboembolism; 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.
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