Andexanet Alfa: First Global Approval

Young-A Heo, Young-A Heo

Abstract

Intravenous andexanet alfa [coagulation factor Xa (recombinant), inactivated-zhzo; Andexxa®] is a first-in-class recombinant modified factor Xa protein that has been developed by Portola Pharmaceuticals as a universal antidote to reverse anticoagulant effects of direct or indirect factor Xa inhibitors. In May 2018, andexanet alfa received its first global approval in the USA for use in patients treated with rivaroxaban and apixaban, when reversal of anticoagulant effects is required in life-threatening or uncontrolled bleeding. Intravenous andexanet alfa is under regulatory review in the EU and is undergoing clinical development in Japan. This article summarizes the milestones in the development of andexanet alfa leading to this first global approval for reversing anticoagulation of rivaroxaban and apixaban in adults.

Conflict of interest statement

Funding

The preparation of this review was not supported by any external funding.

Conflict of interest

During the peer review process the manufacturer of the agent under review was offered an opportunity to comment on the article. Changes resulting from any comments received were made by the author on the basis of scientific completeness and accuracy. Young-A Heo is a salaried employee of Adis/Springer, is responsible for the article content and declares no relevant conflicts of interest.

Figures

https://www.ncbi.nlm.nih.gov/pmc/articles/instance/6061403/bin/40265_2018_940_Figa_HTML.jpg
Key milestones in the development of andexanet alfa as a reversal agent for rivaroxaban and apixaban in adults who experience a major bleeding event. BLA biologics license application, MAA marketing authorization application

References

    1. US FDA. FDA approved betrixaban (Bevyxxa, Portola) for the prophylaxis of venous thromboembolism (VTE) in adult patients [media release]. 23 June 2017. .
    1. Kaatz S, Bhansali H, Gibbs J, et al. Reversing factor Xa inhibitors—clinical utility of andexanet alfa. J Blood Med. 2017;8:141–149. doi: 10.2147/JBM.S121550.
    1. Levy JH, Douketis J, Weitz JI. Reversal agents for non-vitamin K antagonist oral anticoagulants. Nat Rev Cardiol. 2018;15(5):273–281. doi: 10.1038/nrcardio.2017.223.
    1. Ansell JE. Reversing the effect of oral anticoagulant drugs: established and newer options. Am J Cardiovasc Drugs. 2016;16(3):163–170. doi: 10.1007/s40256-016-0162-7.
    1. Hu TY, Vaidya VR, Asirvatham SJ. Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab. Vasc Health Risk Manag. 2016;12:35–44.
    1. Portola Pharmaceuticals. U.S. FDA approves Portola Pharmaceuticals Andexxa®, the first and only antidote for the reversal of factor Xa inhibitors [media release]. 3 May 2018.
    1. Goldin M, Hughes GJ, Choudhary Z, et al. Reversal of anticoagulation: therapeutic advances and clinical guidelines. Am J Ther. 2018;25(1):e44–e52. doi: 10.1097/MJT.0000000000000676.
    1. Lippi G, Sanchis-Gomar F, Favaloro EJ. Andexanet: effectively reversing anticoagulation. Trends Pharmacol Sci. 2016;37(6):613–614. doi: 10.1016/j.tips.2016.03.002.
    1. Portola Pharmaceuticals. Andexxa (coagulation factor Xa (recombinant), inactivated-zhzo): US prescribing information. 2018. . Accessed 15 May 2018.
    1. CMC Biologics. CMC Biologics enters into commercial supply agreement with Portola Pharmaceuticals for manufacturing of first-in-class factor Xa inhibitor antidote andexanet alfa [media release]. 2 July 2014.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals announces commercial supply agreement for andexanet alfa with Lonza [media release]. 16 Oct 2014.
    1. Portola Pharmaceuticals. Portola to initiate phase 2 study evaluating the safety and effectiveness of its factor Xa inhibitor antidote PRT4445 in reversing the anticoagulant activity of investigational factor Xa inhibitor edoxaban [media release]. 26 June 2013.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals enters into clinical collaboration agreement with Daiichi Sankyo for phase 3 studies of factor Xa inhibitor antidote, andexanet alfa, and edoxaban [media release]. 7 July 2014.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals enters into clinical collaboration agreement with Daiichi Sankyo to develop andexanet alfa with edoxaban in Japan [media release]. 4 Apr 2016.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals expands clinical collaboration agreement with Daiichi Sankyo worth up to $25 million to develop AndexxaTM (andexanet alfa) in Germany [media release]. 1 Nov 2016.
    1. Portola Pharmaceuticals. Portola, Bristol-Myers Squibb and Pfizer sign clinical collaboration agreement to study Eliquis and Portolas universal factor Xa inhibitor antidote PRT4445 [media release]. 1 Nov 2012.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals enters second clinical collaboration agreement with Bristol-Myers Squibb and Pfizer to study andexanet alfa* (PRT4445), investigational factor Xa inhibitor reversal agent, with Eliquis [media release]. 13 Jan 2014.
    1. Bristol-Myers Squibb, Pfizer. Bristol-Myers Squibb and Pfizer sign collaboration with Portola Pharmaceuticals to develop and commercialize investigational andexanet alfa in Japan [media release]. 1 Feb 2016.
    1. Portola Pharmaceuticals. Portola enters into clinical collaboration agreement with Bayer and Janssen for phase 2 study of universal factor Xa inhibitor antidote, PRT4445, and Xarelto® [media release]. 5 Feb 2013.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals enters into clinical collaboration agreement with Bayer and Janssen for phase 3 studies of andexanet alfa*, investigational factor Xa inhibitor reversal agent, and Xarelto® [media release]. 3 Feb 2014.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals enters into licensing agreements for investigational agent andexanet alfa in Japan worth up to $120 million [media release]. 1 Feb 2016.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals signs $150 million royalty agreement with HealthCare Royalty Partners for development and commercialization of andexanet alfa [media release]. 3 Feb 2017.
    1. Portola Pharmaceuticals. Portola Pharmaceuticals receives $100 million milestone payment from HealthCare Royalty Partners for FDA approval of Andexxa® [media release]. 24 May 2018.
    1. Lu G, DeGuzman FR, Hollenbach SJ, et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013;19(4):446–451. doi: 10.1038/nm.3102.
    1. Lu G, Pine P, Leeds JM, et al. Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model. PLoS One. 2018;13(3):e0195122. doi: 10.1371/journal.pone.0195122.
    1. Lu G, Lin JP, Curnutte JT, et al. Effect of andexanet-TFPI interaction on in vitro thrombin formation and coagulation markers in the TF-pathway [abstract]. In: Blood conference: 59th annual meeting of the American Society of Hematology, ASH. 2017.
    1. Milling TJ, Jr, Kaatz S. Preclinical and clinical data for factor Xa and “universal” reversal agents. Am J Emerg Med. 2016;34(11s):39–45. doi: 10.1016/j.ajem.2016.09.052.
    1. Grottke O, Akman N, Conley PB, et al. The impact of andexanet alfa in a porcine polytrauma model under apixaban anticoagulation: investigation of hemostatic safety and efficacy [abstract no. 20205]. In: Circulation Conference: Resuscitation Science Symposium, ReSS, vol 136, Suppl 1. 2017.
    1. Conley PB, Grottke O, Braunschweig T, et al. Prevention of exanguination under apixaban anticoagulation using andexanet alfa in a polytrauma model [abstract no. 177] Neurocrit Care. 2017;27(Suppl. 2):S198.
    1. Conely PB, Pine P, Deguzman F, et al. Andexanet alfa reduces betrixaban-induced blood loss in a rabbit liver laceration model of acute bleeding [abstract no. P6208] Eur Heart J. 2017;38(Suppl 1):ehx493.
    1. Lu G, Pine P, deGuzman F, et al. Reversal of anticoagulation effects of rivaroxaban and associated bleeding in a rabbit acute hemorrhage model by andexanet alfa vs. coagulation replacement factors. Neurology. 2017;88(16 Suppl) [abstract no. P5.054].
    1. Crowther M, Lu G, Leeds J, et al. Andexanet alfa reverses anticoagulation induced by betrixaban in healthy volunteers [abstract no. 202] Crit Care Med. 2018;46(1 Suppl):83. doi: 10.1097/01.ccm.0000528221.12371.1b.
    1. Crowther M, Lu G, Conley P, et al. Reversal of factor Xa inhibitors-induced anticoagulation in healthy subjects by andexanet alfa [abstract no. 455] Crit Care Med. 2014;42(12 Suppl):A1469. doi: 10.1097/01.ccm.0000457952.01186.20.
    1. Crowther M, Levy GG, Lu G, et al. A phase 2 randomized, double-blind, placebo-controlled trial demonstrating reversal of edoxaban-induced anticoagulation in healthy subjects by andexanet alfa (PRT064445), a universal antidote for factor Xa (FXa) inhibitors [abstract]. In: 56th annual meeting of the American Society of Hematology, ASH. 2014.
    1. Siegal D, Lu G, Leeds JM, et al. Safety, pharmacokinetics, and reversal of apixaban anticoagulation with andexanet alfa. Blood Adv. 2017;1(21):1827–1838. doi: 10.1182/bloodadvances.2017007112.
    1. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413–2424. doi: 10.1056/NEJMoa1510991.
    1. Connolly SJ, Milling TJ, Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016;375(12):1131–1141. doi: 10.1056/NEJMoa1607887.
    1. Connolly S, Milling T, Eikelboom JW, et al. Andexanet alfa in factor Xa inhibitor-associated acute major bleeding [abstract plus slide presentation]. In: American College of Cardiology’s 67th annual scientific session & expo (ACC18). 2018.
    1. Leeds J, Mandema J, Lu G, et al. Pharmacokinetic/pharmacodynamic modeling of andexanet alfa dose in acute major bleeding [abstract no. 33] Crit Care Med. 2018;46(1 Suppl.):17. doi: 10.1097/01.ccm.0000528089.82823.18.

Source: PubMed

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