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Date: 2018-12-31

Type of information: Granting of a Market Authorisation in the US

Product name: AndexXa®(US)/ Ondexxya™ (EU)

Compound: andexanet alfa

Therapeutic area: Cardiovascular diseases - Hematological diseases

Action mechanism:

  • protein. Andexanet alfa, an FDA-designated breakthrough therapy, is a first-in-class recombinant, modified Factor Xa molecule. It is being developed as an antidote for patients receiving a Factor Xa inhibitor who suffer a major bleeding episode or who may require emergency surgery. Andexanet alfa acts as a Factor Xa decoy that targets and sequesters with high specificity both direct and indirect 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. Andexanet alfa has the potential to address numerous clinical scenarios by allowing for flexible and controlled reversal, which can be short-acting through the administration of an IV bolus or longer-acting with the addition of an extended infusion.

Company: Portola Pharmaceuticals (USA - CA)

Disease:

  • reversing of the anticoagulant effect of direct or indirect factor Xa inhibitors in patients experiencing a serious uncontrolled bleeding event or who require urgent or emergent surgery

Latest news:

  • • On December 31, 2018, Portola Pharmaceuticals announced that the FDA has approved the company's Prior Approval Supplement (PAS) for its large-scale, second generation Andexxa® [coagulation factor Xa (recombinant), inactivated-zhzo], allowing for broad commercial launch in the United States .Andexxa® received both U.S. Orphan Drug and FDA Breakthrough Therapy designations and was initially approved on May 3, 2018 under the FDA's Accelerated Approval pathway. It is the first and only antidote indicated for patients treated with rivaroxaban or apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding.
  • • On December 11, 2018, Portola Pharmaceuticals announced  that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has extended the review period for the marketing authorization application for Ondexxya™ (andexanet alfa), and cancelled the Oral Explanation scheduled for Wednesday, December 12, 2018 . An opinion is now expected by February 28, 2019 . The CHMP informed Portola that it will provide a list of outstanding questions related to the data package the company submitted for Ondexxya™ last quarter, which will require additional responses from the company. The preliminary timetable provided to the company by the CHMP sets a deadline of January 29, 2019 for responses to the questions followed by a 30-day assessment period for the CHMP to review the Company's responses.
  • • On May 3, 2018, Portola Pharmaceuticals announced that the FDA has approved Andexxa®[coagulation factor Xa (recombinant), inactivated-zhzo], the first and only antidote indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. Andexxa® received both U.S. Orphan Drug and FDA Breakthrough Therapy designations and was approved under the FDA's Accelerated Approval pathway based on the change from baseline in anti-Factor Xa activity in healthy volunteers. Continued approval for this indication may be contingent upon post-marketing study results to demonstrate an improvement in hemostasis in patients.
    Figure 1
    Rivaroxaban
    Fig 1
    Figure 2
    Apixaban
    Fig 2
      The approval of Andexxa® is supported by data from two Phase 3 ANNEXA studies (ANNEXA-R and ANNEXA-A) published in The New England Journal of Medicine , which evaluated the safety and efficacy of Andexxa® in reversing the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban in healthy volunteers (Figure 1 and Figure 2, respectively). As described in the label, results demonstrated that Andexxa rapidly and significantly reversed anti-Factor Xa activity (the anticoagulant mechanism of these medicines). The median decrease in anti-Factor Xa activity from baseline was 97 percent for rivaroxaban and 92 percent for apixaban.
  • Interim data from the ongoing ANNEXA-4 single-arm, open-label study in patients with major bleeding also were assessed by the FDA as part of its review and approval. Data from 185 evaluable patients showed that Andexxa rapidly and significantly reversed anti-Factor Xa activity when administered as a bolus and sustained this reversal when followed by a 120-minute infusion. The median decrease from baseline was 90 percent for rivaroxaban and 93 percent for apixaban.
  • The post-marketing requirement is a clinical trial that randomizes patients to receive either Andexxa or usual care (the type of care the enrolling institution would provide in the absence of Andexxa). This study is scheduled to be initiated in 2019 and be reported in 2023.
  • Consistent with the company's prior plan, Portola expects to launch Andexxa under an Early Supply Program with Generation 1 product in early June. Broader commercial launch is anticipated in early 2019 upon FDA approval of its Generation 2 manufacturing process.
  • The MAA for andexanet alfa is also under review by the European Medicines Agency . The Committee for Medicinal Products for Human Use (CHMP) communicated a positive trend vote on the MAA in February 2018 . A formal opinion from the CHMP is expected by the end of 2018, and the European Commission is expected to issue a decision in early 2019.
  • • On February 20, 2018, Portola Pharmaceuticals announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has communicated a positive trend vote on the Marketing Authorisation Application (MAA) for andexanet alfa, a Factor Xa-inhibitor reversal agent. Portola is seeking conditional approval for andexanet alfa for the reversal of the anticoagulant effects of the Factor Xa inhibitors apixaban and rivaroxaban in patients experiencing uncontrolled or life-threatening bleeding.
  • • On December, 22, 2017, Portola Pharmaceuticals announced that the FDA will extend its review of the Biologics License Application (BLA) for AndexXa® (andexanet alfa) by 90 days. The company recently submitted additional data requested by the agency for the ongoing ANNEXA-4 study as part of the continuing review process, which constitutes an amendment to the submission. Therefore, the agency has instituted an extension to allow more time for a thorough review of the information provided and to work with the company on labeling and post-marketing commitments. In correspondence dated and issued today, the FDA communicated that the action date will move from February 3, 2018 to May 4, 2018 .
  • Andexanet alfa is also under review by the European Medicines Agency (EMA). A final decision by the European Commission on the marketing authorization application (MAA) for andexanet alfa is anticipated in the first half of 2018.
  • • On August 15, 2017, Portola Pharmaceuticals announced that the  FDA has found its resubmitted Biologics License Application (BLA) for AndexXa® (andexanet alfa) to be acceptable for review, with an action due date of February 2, 2018.  The resubmission includes supplemental information primarily related to analytics and manufacturing, as requested by the FDA in a complete response letter issued to Portola last year.
  • • On August 3, 2017,  Portola Pharmaceuticals announced that it has resubmitted its Biologics License Application (BLA) to the FDA for AndexXa® (andexanet alfa). The resubmission includes supplemental information primarily related to manufacturing, as requested by the FDA in a complete response letter issued to Portola in August 2016 (see below).•
  • • On August 19, 2016, Portola Pharmaceuticals announced that the MAA for IndexXa™ (andexanet alfa) has been submitted to the EMA, completed the validation period, and has been accepted for review.  Portola is seeking conditional approval of IndexXa™ in the EU through the centralized procedure. With the acceptance of the application, the EMA’s Committee for Medicinal Products for Human Use (CHMP) will now begin the centralized review procedure under a standard 210-day review period. Portola’s MAA submission is based on data from two Phase 3 Annexa™ studies that evaluated the safety and efficacy of andexanet alfa in reversing the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban in healthy volunteers. Results of the ANNEXA studies were published by The New England Journal of Medicine. The MAA also included limited adjudicated efficacy and safety data from initial patients enrolled in the ongoing ANNEXA-4 study. Portola is currently evaluating andexanet alfa in this global, Phase 3b/4 single-arm, open-label study in patients receiving apixaban, rivaroxaban, edoxaban or enoxaparin who present with an acute major bleed. The study is enrolling patients in the United States, Canada and the EU.
  • • On August 17, 2016, Portola Pharmaceuticals announced that it has received a Complete Response Letter (CRL) from the FDA regarding its Biologics License Application (BLA) for AndexXa™ (andexanet alfa). In the CRL, the FDA requested that Portola provide additional information primarily related to manufacturing. The agency also asked for additional data to support inclusion of edoxaban and enoxaparin in the label, and indicated it needs to finalize its review of the clinical amendments to Portola’s post-marketing commitments that recently were submitted.
  • • On February 17, 2016, Portola Pharmaceutical announced that the Center for Biologics Evaluation and Research (CBER) of the FDA has accepted the Biologics License Application (BLA) for andexanet alfa for filing under a priority review. Portola submitted the BLA in December 2015 under an Accelerated Approval pathway. The FDA is expected to take action on the application by the Prescription Drug User Fee Act (PDUFA) action date of August 17, 2016.
  • The BLA is based on data from preclinical, Phase 1 and 2, manufacturing and Phase 3 studies. The Phase 3 Annexa™ (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of FXa Inhibitors) studies evaluated the safety and efficacy of andexanet alfa in reversing the anticoagulant activity of the Factor Xa inhibitors rivaroxaban and apixaban in healthy volunteers. Results of those studies were published by The New England Journal of Medicine in November 2015.
  • • On February 23, 2015, the FDA has granted orphan drug designation for andexanet alfa for reversing the anticoagulant effect of direct or indirect factor Xa inhibitors in patients experiencing a serious uncontrolled bleeding event or who require urgent or emergent surgery

Patents:

Submission of marketing authorization application USA : 2015-12-00/2017-08-03

Submission of marketing authorization application UE: 2016-08-19

Withdrawal of marketing authorization application USA:

Withdrawal of marketing authorization application UE:

US authorization: 2018-05-03

UE authorization:

Favourable opinion UE:

Favourable opinion USA:

Orphan status USA: 2015-02-23

Orphan status UE:

Pediatric exclusivit _USA:

Pediatric exclusivity UE:

OTC status:

Other news:

Is general: Yes