ANTIDOTES FOR NOVEL ANTICOAGULANT DRUGS

SAN FRANCISCO, CA — The makers of a novel antidote that reverses the anticoagulant effects of the factor Xa inhibitors announced today that the second part of a phase 3 study testing the agent met its primary end point^[1].

The antidote, an intravenous bolus of andexanet alfa (Portola Pharmaceuticals, San Francisco, CA), produced a "rapid reversal" of the anticoagulant effect of apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) in the ANNEXA-A study, according to the company. The first part of the study, in which 33 healthy volunteers were treated with apixaban 5 mg twice daily for 4 days and then randomized to andexanet alfa 400 mg or placebo, was previously reported by heartwire .

In the second part of the trial, 31 healthy volunteers were again treated with apixaban 5 mg twice daily for 4 days and randomized to andexanet alfa 400 mg plus a continuous infusion of 4 mg/min for 120 minutes or to placebo.

The full results of the ANNEXA-A study will be presented at an upcoming scientific meeting, but the company said the study met the primary and secondary end points with a degree of high statistical significance. In the trial, the reversal of the anticoagulant effect of apixaban with andexanet alfa was measured by anti–factor Xa activity, an end point the US Food and Drug Administration (FDA) and the European Medicines Agency have agreed is an acceptable primary end point.

The FDA has designated andexanet alfa a breakthrough therapy, which is meant to help accelerate the development and review of drugs for serious or life-threatening conditions. The designation is given when early evidence suggests the agent represents a substantial improvement over existing therapies on one or more significant end points.

Unlike bleeding caused by warfarin, which can be reversed using low-dose vitamin K1, there is nothing yet available for reversing bleeding caused by the novel oral anticoagulants or for stopping the anticoagulant effects of the drugs in patients who need emergency surgery.

n the past few months, Portola also announced positive data from the ANNEXA-R study. In that trial, andexanet alfa significantly reversed the anticoagulant effect of rivaroxaban (Xarelto, Bayer Pharma/Janssen Pharmaceuticals). It is currently being tested in patients treated with edoxaban (Savaysa, Daiichi-Sankyo), the newest oral anticoagulant approved by the FDA, but those results are not yet known.

Boehringer Ingelheim is in the process of developing an antidote specific to its own drug, dabigatran (Pradaxa), a direct thrombin inhibitor. That antidote, idarucizumab, also has FDA breakthrough status