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An Antidote to Factor Xa Inhibitors at Last!


Andexanet alfa is a recombinant factor Xa molecule that binds to and sequesters factor Xa inhibitors in the blood, making them unavailable to bind to native factor Xa.

The Achilles heel of the novel oral anticoagulants has been the inability to reverse the anticoagulant effects of these agents, unlike vitamin K inhibitors, which can be reversed with the administration of fresh frozen plasma. Finally, there is some encouraging early phase clinical trial data available that suggest an antidote may soon be available.

Interim findings of a phase 2 study of an investigational antidote, andexanet alfa, were recently announced by Porthola Pharmaceuticals.1 Six healthy volunteers were administered the antidote intravenously (as a 420-mg bolus followed by a 2-hour infusion) and demonstrated rapid and nearly complete (92%) reversal of the anticoagulation effects of apixaban only 2 minutes after the infusion was completed. This effect lasted up to 2 hours with 91% reversal of activity of apixaban. Previous bolus dosing data from the company (90 mg, 210 mg, 420 mg) presented at the International Society on Thrombosis and Haemostatsis in Amsterdam in July 2013 reported similar results, which confirmed that this relationship seems to be dose-dependent.

There were no significant adverse effects and no drug discontinuations were noted during the results of the latest phase 2 trial. The pooled phase 1 and phase 2 clinical trial data thus far for this agent (n=65) have revealed no antibody generation against the antidote, no problems with excess clotting, and only 1 case of pneumonia, which occurred during phase 1.
Andexanet alfa (PRT4445) is a recombinant modified factor Xa molecule that serves as a factor Xa decoy to bind and sequester factor Xa inhibitors in the blood so they are unavailable to bind native factor Xa. Unlike native factor Xa, the recombinant molecule does not participate in other biological functions, such as cleavage of prothrombin to active thrombin. However, it does restore hemostasis by allowing native factor Xa to be free from circulating factor Xa inhibitors.

The antidote is now an option for patients receiving oral factor Xa inhibitors who may require emergency surgery and need rapid reversal of the effects of oral factor Xa inhibitors. It remains to be seen whether the efficacy of this antidote will be maintained in critically ill patients with life-threatening hemorrhage and whether there will be any adverse events associated with its administration. Additional large-scale phase 2 and phase 3 data are needed before this antidote can be widely adopted into clinical practice. 

Portola Pharmaceuticals Announces First Phase 2 Results Demonstrating Extended Duration Infusion With Andexanet Alfa (PRT4445*) Provides Prolonged Reversal of Anticoagulation Activity of Factor Xa Inhibitor Eliquis(R). Rapid and Nearly Complete Reversal of Anticoagulation Effect of Eliquis(R) (apixaban) Sustained for Duration of Infusion [press release]. South San Francisco: Globe Newswire; October 14, 2013.

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