The drugmaker Portola Pharmaceuticals Inc. announced that on August 17, 2016, the Biologics License Application (BLA) of its new Xarelto antidote AndexXa™ (Andexanet alfa) has been rejected. AndexXa acts by substituting the human Factor Xa, stopping the action of Factor Xa inhibitors such as rivaroxaban. This mechanism is called a suicide inhibition since it prevents the action of those anticoagulants restoring the normal hemostatic process and reversing a potentially lethal bleeding accident. Andexanet alfa is the first compound that possesses this type of activity so far and it can potentially reverse the action of other Novel Oral Anticoagulants (NOACs) such as apixaban (Eliquis) and edoxaban, as well as indirect Factor Xa inhibitors such as enoxaparin.
Since an antidote to these anticoagulants is actually lacking, many patients who used them suffered grievous injuries or even died of internal bleeding. During the last year, at least 80,000 patients were admitted to the hospital to receive emergency treatment after being prescribed an oral Factor Xa inhibitor just in the United States. For this reason, Portola Pharmaceutical submitted the new medication to the Food and Drug Administration (FDA) as a Breakthrough Therapy to grant it a quicker review. However, the regulator provided a negative answer to the company in its recent Complete Response Letter (CRL). Members of the FDA’s committee required the company to provide additional manufacturing information, as well as additional data before the antidote’s label could include enoxaparin and edoxaban among the agents whose action it could reverse.
To fully evaluate the efficacy and safety of Andexanet alfa, Portola issued two Phase 3 studies called ANNEXA which were published at the end of 2015 in the New England Journal of Medicine. These clinical trials determined the ability of the compound in reversing the blood-thinning activity of Xarelto and Eliquis in otherwise healthy elderly subjects. If the antidote is eventually approved, FDA granted Portola the Orphan Drug designation for their new drug. The drugmaker could then market it exclusively for subsequent seven years. Bill Lis, CEO of Portola, explained that the company fully understand the urgency of releasing to the market a new drug which may save hundreds of lives, and told during a conference that they are going to re-submit it to the regulator’s approval within the current year.
Article by Claudio Butticè, Pharm.D.
REFERENCES
- Yahoo Finance. Portola Pharmaceuticals Receives Complete Response Letter from FDA for Biologics License Application for AndexXa™ (andexanet alfa). GlobeNewswire, August 18, 2016. (Accessed August 2016)
- Portola Pharmaceuticals. Andexanet alfa: FXa Inhibitor Antidote. www.portola.com (Accessed September 2016)
- Deborah M. Siegal, et al. Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity. N Engl J Med 2015; 373:2413-2424. December 17, 2015DOI: 10.1056/NEJMoa1510991
- Jean M. Connors, Antidote for Factor Xa Anticoagulants. N Engl J Med 2015; 373:2471-2472. December 17, 2015DOI: 10.1056/NEJMe1513258
