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Andexanet Alfa Shows Promise in Phase 3 Trials

MAY 06, 2015
Christin L. Melton, ELS
In February 2015, the US Food and Drug Administration (FDA) granted orphan drug designation to andexanet alfa, a novel antidote to drugs taken to inhibit factor Xa (FXa).1 Since then, Portola Pharmaceuticals, the California company developing andexanet alfa, has reported positive results from 2 randomized, double-blind, placebo-controlled, phase 3 trials. Within 10 minutes of administration, andexanet alfa reversed the anticoagulation effects of rivaroxaban (Xarelto) in the ANNEXA-R trial.2,3 It was equally effective at reversing the effects of apixaban (Eliquis) in the ANNEXA-A trial.4,5 Andexanet alfa is the first antidote for FXa inhibitors in development and also has a breakthrough drug designation from the FDA.4

FXa inhibitors are commonly used to prevent clot formation in people with an elevated risk of stroke or venous thromboembolism.5 When patients taking FXa inhibitors experience a serious uncontrolled bleeding event or require an emergency invasive procedure, physicians currently have no fast, effective way to reverse the anticoagulation effects of these drugs. Andexanet alfa is a recombinant protein derived from FXa that works by attracting unbound (free) molecules of direct or indirect FXa inhibitors, thus preventing them from binding to the genuine FXa receptors and exerting their anticoagulation effects.5 Andexanet alfa has no independent ability to affect coagulation.5

The phase 3 ANNEXA-R registration trial (NCT02220725) is an ongoing 2-part study recruiting healthy individuals aged 50 to 75 years.6 In part 1 of the study, 41 participants were randomly assigned 2:1 to andexanet alfa (n = 27) or placebo (n = 14).2 Everyone received oral rivaroxaban 20 mg/day for 4 days before receiving an infusion of 800 mg of andexanet alfa or placebo 4 hours after the last rivaroxaban dose.3 Data presented at the American College of Cardiology’s 64th Annual Scientific Session in March 2015 showed that 26 of 27 individuals in the andexanet alfa arm had at least a 90% reduction in anti-FXa activity from baseline, whereas none of the 14 individuals in the placebo arm did (P <.001).2 Investigators also found a significantly lower mean serum level of unbound rivaroxaban and significantly greater thrombin generation in the andexanet alfa arm versus the placebo arm (both P <.0001). Andexanet alfa was well tolerated, with no serious adverse events reported during the trial.

The phase 3 ANNEX-A trial (NCT02207725) is also a 2-part study in which a similar population is being randomly assigned 2:1 to andexanet alfa versus placebo after 4 days of apixaban therapy.7 Part 1 results (n = 33) were reported in 2014 and associated a 400-mg intravenous bolus dose of andexanet alfa with an approximately 94% reduction from baseline in apixaban activity with 2 to 5 minutes of administration (P <.001). 4 Although no serious adverse events occurred, 3 participants did have mild infusion reactions. Topline results from phase 2 of the ANNEX-A trial (n = 31) were reported in April 2015 and showed that a 2-hour sustained infusion of andexanet alfa (4 mg/min for 120 minutes) subsequent to the intravenous bolos dose produced rapid, persistent reversal of apixaban’s anticoagulant activity with no serious adverse events.4

In a press release, John T. Curnutte, MD, executive vice president of research and development at Portola Pharmaceuticals, said the studies show andexanet alfa can provide short-term or longer reversal of FXa inhibition and noted that the novel drug’s “short half-life allows patients to be recoagulated as needed.”4 Later this year, the company plans to submit data from both studies to the FDA in support of a Biologics License Application under an accelerated approval pathway.

References

1. Portola Pharmaceuticals receives FDA Orphan Drug Designation for andexanet alfa, its breakthrough-designated factor Xa inhibitor antidote [press release]. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsroomArticle&ID=2020507. South San Francisco, CA; February 26, 2015.
2. Portola announces full results from positive phase 3 ANNEXA-R study demonstrating that andexanet alfa rapidly and significantly reversed anticoagulant effect of factor Xa inhibitor Xarelto [press release]. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsroomArticle&ID=2021524. South San Francisco, CA; March 2, 2015.
3. ANNEXA-R: a phase 3 randomized, double-blind, placebo-controlled trial, demonstrating reversal of rivaroxaban-induced anticoagulation in older subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (FXA) inhibitors. J Am Coll Cardiol. 2015;65:10S.  
4. Portola Pharmaceuticals announces new topline data from phase 3 ANNEXA-A trial part 2: breakthrough designated andexanet alfa successfully meets primary endpoint for prolonged reversal of factor Xa inhibitor Eliquis (apixaban) [press release]. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsroomArticle&ID=2033043. South San Francisco, CA; April 8, 2015. Accessed April 17, 2015.
5. Shah N, Rattu MA. Reversal agents for anticoagulants: focus on andexanet alfa. Am Med Student Res J. 2014;1(1):16-28.
6. A study in older subject [sic] to evaluate the safety and ability of andexanet alfa to reverse the anticoagulation effect of rivaroxaban. National Institutes of Health Clinical Trials website. https://clinicaltrials.gov/ct2/show/NCT02220725. Published August 18, 2014. Accessed April 20, 2015.
7. A study in older subjects to evaluate the safety and ability of andexanet alfa to reverse the anticoagulation effect of apixaban. National Institutes of Health Clinical Trials website. https://clinicaltrials.gov/ct2/show/NCT02207725. Updated July 31, 2014. Accessed April 20, 2015.

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