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Great Promise for Factor Xa Inhibitor Antidote: Andexanet Alfa

By: Galina Perel, PharmD Candidate c/o 2016

Andexanet alfa’s has achieved great advancement in part one of the Phase 3 ANNEXA-A study conducted by Portola Pharmaceuticals. The study demonstrated the effects of andexanet alfa being the proposed antidote to the oral anticoagulant Factor Xa inhibitor: apixaban (Eliquis©).1

Apixaban received FDA approval in late 2012 to reduce the risk of blood clots in patients with non-valvular atrial fibrillation, leading to reduction in the risk of stroke.2 Apixaban is a selective inhibitor of both free and bound Factor Xa, a clotting factor composed of serine proteases. Furthermore, apixaban inhibits prothrombinase activity, which converts prothrombin to thrombin via cleavage, and indirectly inhibits platelet aggregation. Due to its mechanism, apixaban alters the coagulation cascade by decreasing thrombin development and formation.3 However, apixaban carries a risk of bleeding, and thus development of an antidote is essential.

Andexanet alfa is a recombinant Factor Xa derivative that works by acting as a decoy for Factor Xa inhibitors. It is not catalytically active due to the mutation of a serine to an alanine in the protease catalytic triad.4 The GLA domain, which is the membrane bound domain of Factor Xa, is removed in andexanet alfa composition, eliminating prothrombin assembly. Once andexanet alfa binds to Factor Xa, it will sequester the Factor Xa inhibitor (apixaban) and reduce its concentration and anticoagulant effects.6 The recombinant Factor Xa derivative binds to apixaban with high affinity, forming a complex that cannot act on the coagulation cascade; it reverses the anticoagulant activity of apixaban, which may be necessitated during emergency surgery or during a major bleeding episode.5

ANNEXA-A is a randomized, double-blind, placebo-controlled study in which the primary endpoint is the percent change in anti-Factor Xa levels, and the secondary endpoints are change in free apixaban concentration and change in thrombin concentration. 4 In part one of the Phase 3 study, there was a total of 33 older healthy participants, with a mean of 61 years of age. Subjects were given apixaban 5 mg twice daily for four days, and then 400 mg IV bolus of andexanet or placebo. All participants completed part one of the study and no adverse effects were reported. The results concluded that there was a >90% of anticoagulation reversal with andexanet and a 94% change in anti Factor Xa levels (p <0.0001). Part one of the study concluded that andexanet alfa restored coagulation levels within 2 minutes of IV administration, with effects lasting up to 2 hours after the time of bolus infusion.5 This study demonstrated that andexanet alfa was successful in terms of safely and effectively reversing anticoagulation caused by apixaban, and concluded that both its primary and secondary endpoints were met with high statistical significance.5 In part two of the study, subjects received apixaban 5 mg twice daily for four days, followed by a 400 mg IV bolus of andexanet and continuous infusion (4 mg/min) of andexanet or placebo for about 2 hours.4,5 Additional results from the study will be evaluated later this year.

“These highly statistically significant phase 3 ANNEXA-A data demonstrate that andexanet alfa has the potential to be the first agent approved as a universal Factor Xa inhibitor antidote,” said John T. Curnutte, M.D., Ph.D., Executive Vice President of Research and Development for Portola.4 Andexanet alfa has been recognized as a breakthrough medication by the FDA with hope to speed up the approval process so it that can be utilized in emergency situations.1,6 Portola Pharmaceuticals has collaborated research with large pharmaceutical companies to perform studies on andexanet alfa and other Factor Xa inhibitors, such as rivaroxaban (Xarelto®), edoxaban (Lixiana®), as well as enoxaparin (Lovenox®).4,6

     FDA approval would allow andexanet alfa to be the necessary developmental drug available on the market for reversal of Factor Xa anticoagulant therapies.


  1. O’Riordan M. Results for Factor Xa inhibitor antidote: ANNEXA-A. http://www.medscape.com/viewarticle/832648. Updated 10/01/2014. Accessed on 03/05/2015.
  2. Walsh S. FDA News Release. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm333634.htm. Updated 12/08/2012. Accessed 03/05/2015.
  3. Apixaban. Medscape Online. http://reference.medscape.com/drug/eliquis-apixaban-999805. Updated on 03/2015. Accessed on 03/05/2015.
  4. News Release. Portola Pharmaceuticals. http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsArticle&ID=1972736. Updated 10/01/2014. Accessed on 03/05/2015.
  5. Crowther M. ANNEXA™-A. American Heart Association. http://my.americanheart.org/professional/Sessions/ScientificSessions/ScienceNews/SS14-Clinical-Science-Special-Reports_UCM_468860_Article.jsp. Updated on 11/2014. Accessed on 03/05/2015.
  6. Mechanism of Action. http://www.portola.com/clinical-development/andexanet-alfa-prt4445-fxa-inhibitor-antidote/. Accessed March 5, 2015.

[pubmed_related keyword1=”andexanet” keyword2=”alfa” keyword3=”inhibitor”]

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