What is new in the anticoagulant antidote market?


The use of new oral anticoagulants (NOACs) continues to increase. Over the past 4 quarters, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) were in the top 20 of fastest-growing drugs in the United States. They offer advantages compared to warfarin such as a rapid onset of action, no dietary modifications, fewer drug–drug interactions, and do not require routine coagulation monitoring.

The use of new oral anticoagulants (NOACs) continues to increase. Over the past 4 quarters, rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) were in the top 20 of fastest-growing drugs in the United States.1 They offer advantages compared to warfarin such as a rapid onset of action, no dietary modifications, fewer drug–drug interactions, and do not require routine coagulation monitoring.

AHA: Rivaroxaban linked to fewer hospitalization days compared to warfarin in NVAF patients

Both rivaroxaban and apixaban are direct factor Xa inhibitors. An additional agent, dabigatran etexilate mesylate (Pradaxa, Boehringer Ingelheim) inhibits thrombin (factor IIa) and has the same advantages as rivaroxaban and apixaban. It is estimated that these 3 agents will constitute about 36% (by prescription volume) of the US anticoagulant market by 2020.2 One significant drawback of using the NOACs, however, is the current lack of an antidote to reverse the anticoagulant effects of these agents in the case of a major spontaneous bleed or prior to emergency surgery. It is estimated that between 1% and 5% of patients taking factor Xa inhibitors may experience a spontaneous major bleed or require emergency surgery.3

VIDEO: New Anticoagulants for AF

Fresh frozen plasma, prothrombin complex concentrates (PCCs), and PCCs with added activated factor VIIa have been used to try to reverse the anticoagulant effects and stop bleeding in patients on factor Xa and IIa inhibitors. Data on these reversal therapies are limited and have been studied only in animal models or healthy volunteers. Additionally, they can be prothrombotic, causing problems if too much is given.4–6

There are, however, currently 3 anticoagulant reversal agents (antidotes) in phase 2 or 3 clinical trials. The first agent, andexanet alfa, is a recombinant, modified factor Xa molecule. Andexanet alfa acts as a factor Xa decoy that targets and sequesters with high specificity both direct and indirect factor Xa inhibitors in the blood. Initial results have been released from the phase 3 trial, ANNEXA-A (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors–Apixaban). A total of 24 healthy volunteers were randomized to an intravenous (IV) 400-mg bolus dose of andexanet, and 9 patients were given placebo. The anticoagulant activity of apixaban was reversed by 94% (P<.0001) 2 to 5 minutes after the bolus dose of andexanet, measured by the biomarker end point, anti-factor Xa activity. The second part of the study will test a 400-mg IV bolus followed by a continuous infusion of 4 mg/min for 120 minutes, with results expected in early 2015. No serious or thrombotic adverse events were reported. Mild infusion reactions were reported by 3 volunteers.3



Two additional phase 3 studies using andexanet alfa as an antidote for rivaroxaban and edoxaban (investigational factor Xa inhibitor, Daiichi Sankyo) are ongoing or planned. In phase 2 studies, andexanet alfa has been shown to reverse the anticoagulant activity of enoxaparin (a low-molecular weight heparin that indirectly acts on factor X and factor IIa), rivaroxaban, and apixaban.7

Andexanet alfa has been designated as a breakthrough therapy by FDA, and plans are under way to pursue an accelerated approval pathway. A phase 3b/4 study will be initiated to evaluate clinical outcomes before filing the biologics license application (BLA). It is anticipated that a BLA filing with FDA will occur in 2015. 

Idarucizumab is a selective and specific monoclonal antibody fragment being studied as an antidote to dabigatran. A phase 3 study evaluating idarucizumab in patients in actual clinical settings, RE-VERSE AD began this year. A total of 250 patients are expected to be recruited to receive a 1-time IV administration of idarucizumab 5 g. The trial is expected to complete in 2017.8,9

Phase 1 data have shown that a 1-time IV dose of idarucizumab reverses the anticoagulant activity (measured by thrombin time) of dabigatran in healthy, male volunteers.10 In a substudy of the phase 1 data, idarucizumab was shown to restore wound-site formation of fibrin as measured by fibrinopeptide A production.11 No prothrombotic events have been reported. Adverse effects of mild intensity including erythema, migraine, feeling hot, and headache were reported by 10 subjects. 

A phase 1 double-blind, placebo-controlled, cross-over study in 46 patients aged 45 to 80 years, with some patients having mild-to-moderate renal failure, showed that an IV infusion of idarucizumab 5 g restored dabigatran-induced prolonged blood clotting time to baseline levels. Twenty-four hours after the idarucizumab infusion, dabigatran was restarted in healthy volunteers. Prolonged blood clotting time was again seen. A second infusion of idarucizumab once more reversed the dabigatran-induced anticoagulation. Transient, dose-related increases in urinary protein levels were seen in patients receiving idarucizumab. No other adverse events were reported.12

Idarucizumab has been granted breakthrough therapy designation by FDA. Boehringer Ingelheim plans to pursue an accelerated approval pathway for the drug when filing the BLA for idarucizumab.13



PER-977 is a small synthetic molecule that binds to factor X and factor IIa inhibitors and heparin. Perosphere has signed an agreement with Daiichi Sankyo to initiate a phase 3 clinical study evaluating PER-977 as an antidote to edoxaban.14 Phase 1/2 studies have shown that a single IV administration of PER-977 100 to 300 mg restored hemostasis to baseline levels. This was measured by whole blood clotting time. Adverse events included transient mild perioral and facial flushing, dysgeusia, and 1 report of moderate headache. PER-977 has also been shown to be effective in reversing the effects of enoxaparin. Additional phase 2 studies are ongoing.15

Because PER-977 is a small molecule, Perosphere plans to submit a new drug application (NDA) for the drug. Perosphere plans to pursue an accelerated approval pathway and file the NDA for PER-977 in June 2015.14

In a 1-year time frame between 2012 and 2013, about 650,000 people were admitted to hospitals or had an emergency room visit due to bleeding from a factor Xa or IIa inhibitor.15 Having a reversal agent that could be given once in these settings would be highly advantageous in improving the quality and safety of care for such patients in the future. 



1. King S. FirstWord Lists – Pharma's fastest growing drugs. November 16, 2014. http://www.firstwordpharma.com/node/1246255#axzz3JSBnxJHH. Accessed December 19, 2014.

2. Cowen and Company. Therapeutic Categories Outlook, Comprehensive Study. October 2014.

3. Portola Pharmaceuticals. Portola, Bristol-Myers Squibb and Pfizer announce statistically significant results from the first part of the phase 3 ANNEXA(TM)-A studies of investigational andexanet alfa with Eliquis (apixaban). November 17, 2014.  http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsroomArticle&ID=1990181.  Accessed December 19, 2014.

4. Ebright J, Mousa SA. Oral anticoagulants and status of antidotes for the reversal of bleeding risk. Clin Appl Thromb Hemost. August 12, 2014 [Epub].

5. Fawole A, Daw HA, Crowther MA. Practical management of bleeding due to the anticoagulants dabigatran, rivaroxaban, and apixaban. Cleve Clin J Med. 2013;80(7):443–451.

6. Hughes S. Promising data on antidotes to new anticoagulants. December 20, 2013.  http://www.medscape.com/viewarticle/818169. Accessed December 19, 2014.

7. Portola Pharmaceuticals. Portola Pharmaceuticals announces positive phase 2 data with FDA-designated breakthrough therapy andexanet alfa and enoxaparin. June 11, 2014.  http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-newsroomArticle&ID=1939000.  Accessed December 19, 2014.

8. Boehringer Ingelheim. Boehringer Ingelheim initiates U.S. sites in first-ever global phase III trial of investigational antidote in patients taking Pradaxa® (dabigatran etexilate mesylate). November 10, 2014. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/11-10-14-boehringer-ingelheim-initiates-us-sites-first-ever-global-phase-iii-trial-investigational-antidote-patients-taking-pradaxa-dabigatran-etexilate-mesylate.html. Accessed December 19, 2014.

9. ClinicalTrials.gov. Reversal of dabigatran anticoagulant effect with idarucizumab. Verified December 2014. http://www.clinicaltrials.gov/ct2/show/NCT02104947. Accessed December 19, 2014.

10. Boehringer Ingelheim. Data from first phase I study of antidote for Pradaxa (dabigatran etexilate mesylate). Presented at American Heart Association Scientific Sessions. November 18, 2013. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2013/11-18-2013-data-first-phase-study-antidote-pradaxa-dabigatran-etexilate-mesylate-american-heart-association-scientific-sessions.html. Accessed December 19, 2014.

11. Boehringer Ingelheim. New data show idarucizumab* restores wound-site formation of fibrin, a key component of blood clotting, in healthy volunteers given Pradaxa (dabigatran etexilate mesylate). November 18, 2014. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/11-18-14-new-data-show-idarucizumab-restores-wound-site-formation-fibrin-key-component-blood-clotting-healthy-volunteers-given-pradaxa-dabigatran-etexilate-mesylate.html. Accessed December 19, 2014. 

12. Boehringer Ingelheim. New data show idarucizumab* reverses anticoagulant effects of dabigatran (Pradaxa) in middle-aged, elderly and renally impaired volunteers. December 8, 2014. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/12-08-14-new-data-show-idarucizumab-reverses-anticoagulant-effects-dabigatran-pradaxa-middle-aged-elderly-renally-impaired-volunteers.html. Accessed December 19, 2014.

13. Boehringer Ingelheim. Boehringer Ingelheim’s investigational antidote for Pradaxa (dabigatran etexilate mesylate) receives FDA breakthrough therapy designation. June 26, 2014. http://us.boehringer-ingelheim.com/news_events/press_releases/press_release_archive/2014/06-26-14-boehringer-ingelheim-investigational-antidote-pradaxa-dabigatran-etexilate-mesylate-fda-breakthrough-therapy-designation.html. Accessed December 19, 2014.

14. Perosphere. Perosphere and Daiichi Sankyo enter into a clinical trial collaboration agreement for phase 3 studies of PER977 to investigate reversal of the anticoagulant activity of the investigational factor Xa-inhibitor edoxaban. October 6, 2014.  http://perosphere.com/content/media/documents/PerosphereandDaiichiSankyoEnterintoaClinicalTrialAgreementforPhase3.pdf. Accessed December 19, 2014.

15. Perosphere. Perosphere’s anticoagulant reversal agent clinical trial results published in the New England Journal of Medicine. November 5, 2014. http://perosphere.com/content/media/documents/PerospherePressReleaseNEJMLettertoEditor05Nov2014.pdf. Accessed December 19, 2014.

Dr Taylor is a clinical pharmacist with Catamaran.

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