Boehringer Ingelheim is poised to benefit from the FDA’s rejection of Andexxa.
By Jack Allen, Analyst
31 August 2016
I am an analyst at Datamonitor Healthcare based in the New York office, where I am currently a member of the cardiovascu...
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Boehringer Ingelheim’s Pradaxa (dabigatran) is expected to experience an increase in uptake as a result of the rejection of Portola Pharmaceuticals’ factor Xa inhibitor antidote, Andexxa (andexanet alfa), by the US Food and Drug Administration (FDA). This rejection will extend the period of market advantage experienced by Pradaxa as the only approved novel oral anticoagulant (NOAC) with an approved reversal agent, allowing the drug to outcompete its rival NOACs.
On 17 August 2016, Portola Pharmaceuticals received a complete response letter (CRL) from the FDA in response to its Biologic License Application for Andexxa, an antidote in development for the rapid reversal of the anticoagulant effects of factor Xa inhibitors (Xarelto [rivaroxaban; Bayer/Johnson & Johnson], Eliquis [apixaban; Bristol-Myers Squibb/Pfizer], Savaysa [edoxaban; Daiichi Sankyo], and enoxaparin) in emergency situations. The lack of a reversal agent for these drugs is a major concern for physicians, as they are unable to reverse the anticoagulation effects of these medications in cases of emergency bleeding or surgery. This concern is thought to have hindered the uptake of the NOAC class (Pradaxa, Xarelto, Eliquis, and Savaysa) in the cardiovascular market. In 2015, Pradaxa became the first molecule in the class to secure an antidote with the approval of Praxbind (idarucizumab; Boehringer Ingelheim) (Pharmaprojects, 2016). This gave Pradaxa a market advantage over the other NOACs by allowing physicians to safely reverse the effects of Pradaxa in emergency situations. The rejection of Andexxa will extend the term of Pradaxa’s market advantage, thereby increasing its uptake.
The FDA raised three major areas of concern in its rejection of Andexxa. Its most prominent concern was the need for the validation of quality assays during the antidote’s manufacturing process. The FDA also requested additional data on the use of the antidote in patients taking edoxaban and enoxaparin, and wanted to see additional analysis of the ANNEXA-4 trial, an ongoing Phase IV trial enrolling patients with acute major bleeds.
The bulk of the FDA’s manufacturing concerns were related to the full validation of quality assays to tighten specifications and account for all isoforms of Andexxa in each step of the process. The FDA also requested that Portola continues to track the properties of the drug with the additional, more detailed biochemical assays that the company had designed and implemented. Portola had entered into a contract with CMC Biologics for the initial manufacturing of the drug, prior to filing for its approval with the FDA (Portola, 2016).
The other two concerns raised by the FDA focused on the clinical investigation of Andexxa. The first clinical concern raised was the lack of sufficient data on the use of Andexxa in patients taking Savaysa and enoxaparin to support the class label for the medication pursued by Portola, which would designate the antidote as the reversal agent for all factor Xa inhibitors. The FDA specifically requested more data investigating an infusion of Andexxa after the initial bolus of the reversal agent in healthy patients taking Savaysa and enoxaparin (Portola, 2016). This request was not unexpected, as Portola had only submitted Phase II data in these patient groups.
The FDA’s second clinical concern was the need for more information from the ongoing ANNEXA-4 trial of Andexxa in patients with acute major bleeding. The FDA requested that Portola split the ANNEXA-4 data into surgical and bleeding patient cohorts (as was done in the pivotal trial of Praxbind), and that the company provide additional data including propensity scoring, stroke outcomes, and intracranial bleeding (Portola, 2016).
Portola officials responded to all three areas of concern on a conference call with investors on 18 August 2016. In response to the manufacturing concerns, Portola said it has all of the information requested in its suite of assays, but will need time to validate the assays and compile its documents prior to resubmission. Portola officials also outlined how they plan to respond to the FDA’s clinical concerns. The company discussed how it is considering filing for initial approval of Andexxa, based on a limited label restricting use of the drug to Xarelto and Eliquis patients. This would allow Portola to get Andexxa on the market as fast as possible, without the need for additional clinical trials investigating the antidote in Savaysa and enoxaparin patients. Portola could then file for label expansions after post-marketing studies investigating the use of Andexxa in Savaysa and enoxaparin patients had been completed. However, since the FDA raised this issue in the CRL, Portola officials will need to investigate whether the agency requires these studies be done pre-approval, before pursuing this approach. If the FDA does require that these trials are completed prior to the approval of Andexxa, Portola will need some time to collect these data. Portola also indicated that it has most of the ANNEXA-4 data requested by the FDA. However, it noted that it will take some time to compile and communicate this information to the FDA (Portola, 2016).
The rejection of Andexxa will continue to extend Pradaxa’s advantage over key NOAC competitors Xarelto, Eliquis, and Savaysa. This advantage will have a significant impact on market dynamics in the anticoagulant class, until Portola is able to resubmit to the FDA and secure approval of Andexxa. Portola officials hope that they will be able to address the FDA’s concerns and resubmit before the end of the year, but cautioned that they need to speak with the FDA to fully assess the work needed prior to resubmission (Portola, 2016).
Portola (2016) Portola Pharmaceuticals Conference Call regarding CRL from FDA for BLA for AndexXa. Available from: http://investors.portola.com/phoenix.zhtml?c=198136&p=irol-EventDetails&EventId=5235907 [Accessed 23 August 2016].
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