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Factor Xa inhibitor antidote Andexanet alfa reverses anticoagulant activity of Apixaban


Pharmacodynamic and safety data from a Phase 2 proof-of-concept study of its investigational factor Xa inhibitor antidote Andexanet alfa ( PRT4445 ) in healthy volunteers who were administered the factor Xa inhibitor Apixaban ( Eliquis ). Results showed greater than a 95% reversal of the anticoagulant activity of Apixaban was achieved within two minutes of intravenously administered high-dose Andexanet alfa.
In the study, Andexanet alfa was well tolerated, with no serious adverse events or immunologic effects observed. The data were presented at the XXIV Congress of the International Society on Thrombosis and Haemostasis ( ISTH) in Amsterdam.

Major bleeding events occur infrequently in patients taking factor Xa inhibitors ( 1-4% per year in several clinical studies involving patients taking a factor Xa inhibitor on a chronic basis ), and standard measures are currently employed to manage these events. However, there is presently no approved antidote or reversal agent that is specifically intended for use against factor Xa inhibitors. Development of Andexanet alfa, specifically designed to reverse the activity of factor Xa inhibitors, may provide an antidote for patients who experience an uncontrolled major bleeding event or require emergency surgery.

Portola is studying Andexanet alfa with Apixaban in the Phase 2 study. This is the first in a series of phase 2 studies that are evaluating the safety and pharmacodynamic activity of Andexanet alfa in healthy volunteers who have been administered one of several factor Xa inhibitors.
Portola Pharmaceuticals is evaluating Andexanet alfa and Rivaroxaban ( Xarelto ) in a separate phase 2 study.

The lack of an effective antidote is restricting the use of factor Xa inhibitors to patients at low risk for bleeding or requiring surgery.

In the randomized, placebo-controlled, double-blind, cohort dose-escalation phase 2 study, 27 healthy volunteers were treated on days 1-6 with Apixaban 5 mg twice a day ( to steady state ) and then randomized in a 6:3 ratio to intravenous Andexanet alfa ( in three different dose cohorts, 90 mg, 210 mg or 420 mg ) or saline on day 6, three hours after receiving the last Apixaban dose.
Pharmacodynamic and safety data were collected through day 48 and pharmacokinetic data through day 10.

Results have demonstrated a dose-dependent reversal of the anticoagulant activity of Apixaban. Two minutes after administration of 420 mg Andexanet alfa ( n=6 ), the anticoagulant activity of Apixaban decreased by greater than 95% as measured by anti-factor Xa activity. Similarly, the 210 mg dose reduced anti-factor Xa activity by 80% compared with saline ( n=9 ). The reversal of anti-factor Xa activity correlated with a reduction in the level of free, unbound Apixaban in the plasma consistent with the mechanism of action of Andexanet alfa.

Safety data for all 27 healthy volunteers after 48 days of follow-up showed no thrombotic events, serious adverse events or premature discontinuations of Andexanet alfa. The incidence of adverse events with Andexanet alfa was similar to that with the control. No antibodies were generated against Andexanet alfa, endogenous factor Xa or factor X.

Andexanet alfa is a novel recombinant protein designed to reverse the anticoagulant activity in patients treated with a factor Xa inhibitor who suffer an uncontrolled bleeding episode or need to undergo emergency surgery. Andexanet alfa is similar to native factor Xa, but has been modified to restrict its biological activity to the reversal of the anticoagulant effects of factor Xa inhibitors. Andexanet alfa acts as a factor Xa decoy that binds and sequestors direct factor Xa inhibitors in the blood. Once bound to Andexanet alfa, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa. The native factor Xa is then available to participate in the coagulation process and restore hemostasis. ( Xagena )

Source: Portola Pharmaceuticals, 2013

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