Credit: Kevin MacKenzie
An intravenous (IV) bolus of the factor Xa inhibitor antidote andexanet alfa can significantly and immediately reverse the steady-state anticoagulation activity of rivaroxaban in healthy subjects, according to initial results of the phase 3 ANNEXA-R study.
Portola Pharmaceuticals, the company developing andexanet alfa, recently announced these results from the first part of the study.
The company expects to present the full data set on March 16 at the American College of Cardiology’s 64th Annual Scientific Session & Expo in San Diego.
The second part of the ANNEXA-R study, in which researchers are evaluating a bolus plus a continuous infusion of andexanet alfa to sustain reversal, is ongoing.
Portola is developing andexanet alfa as a universal antidote for patients treated with oral and injectable factor Xa inhibitors who are experiencing a major bleeding episode or who require emergency surgery.
Andexanet alfa acts as a factor Xa decoy that targets and sequesters both oral and injectable factor Xa inhibitors in the blood. Once bound, the factor Xa inhibitors are unable to bind to and inhibit native factor Xa, thus allowing for the restoration of normal hemostatic processes.
ANNEXA-R details
This randomized, double-blind, placebo-controlled study is an evaluation of andexanet alfa in reversing rivaroxaban-induced anticoagulation in healthy volunteers ages 50 to 75 years.
In the first part of the study, 41 subjects received rivaroxaban at 20 mg once daily for 4 days. Then, they were randomized in a 2:1 ratio to receive either andexanet alfa administered as an 800 mg IV bolus (n=27) or to placebo (n=14).
Results showed that andexanet alfa significantly and immediately reversed the anticoagulation activity of rivaroxaban. Furthermore, andexanet alfa appeared to be well tolerated.
For the second part of the ANNEXA-R study, researchers plan to enroll about 40 healthy volunteers and give them rivaroxaban at 20 mg once daily for 4 days.
Then, subjects will be randomized to receive either placebo or andexanet alfa administered as an 800 mg IV bolus, followed by a continuous infusion of 8 mg/min for 120 minutes. Data from this part of the study are expected in mid-2015.
Andexanet alfa development
Andexanet alfa is the only compound being studied as a reversal agent for factor Xa inhibitors that directly and specifically corrects anti-factor Xa activity.
Portola is evaluating andexanet alfa in randomized, placebo-controlled phase 3 ANNEXA registration studies using pharmacodynamic endpoints agreed to with the US Food and Drug Administration (FDA), such as anti-factor Xa inhibitor units, to demonstrate efficacy.
Researchers recently reported statistically significant results from the first part of the phase 3 ANNEXA-A study, in which researchers evaluated andexanet alfa administered as a single IV bolus dose with the direct factor Xa inhibitor apixaban.
The second part of the study is ongoing. It’s an evaluation of an IV bolus plus a continuous infusion of andexanet alfa to sustain the reversal of anticoagulation activity.
“The statistically significant phase 3 ANNEXA-R study data, together with results presented previously with apixaban, provide compelling evidence that this ground-breaking agent could serve as a universal antidote for factor Xa inhibitor anticoagulants,” said John T. Curnutte, MD, PhD, executive vice president, research and development for Portola.
“Andexanet alfa is unique among the other reversal agents in development in that it has been the only agent to immediately and significantly reverse all of the key pharmacodynamic measurements of coagulation that have been agreed to with the FDA for accelerated approval. These include anti-factor Xa levels, thrombin generation, and unbound anticoagulant (free-fraction). This has been demonstrated with all of the factor Xa inhibitors studied to date—apixaban, rivaroxaban, edoxaban, and enoxaparin.”
