Andexanet alfa

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Andexanet alfa
other names
  • Recombinant coagulation factor Xa (inactivated)
Mass / length primary structure 40,987.57 Da
Identifier
External IDs
Drug information
ATC code V03 AB38
DrugBank DB14562
Drug class Antidote

Andexanet alfa (manufacturer: Portola Pharmaceuticals ) is a protein that is structurally related to human coagulation factor factor Xa and is produced using biotechnology . It cancels the effects of certain anti-coagulants and thus acts as an antidote . Andexanet alfa is approved in the United States and the EU for the treatment of uncontrollable bleeding during therapy with rivaroxaban or apixaban . Lt. Pharmaceutical newspaper andexanet alfa can be considered a leap innovation , which means something like a "groundbreaking invention".

background

For the prophylaxis of thrombosis and pulmonary embolism after major surgery and stroke in atrial fibrillation and other heart diseases in recent years become increasingly direct oral anticoagulants (DOAK) as apixaban (trade name Eliquis ), rivaroxaban ( Xarelto ), edoxaban ( Lixiana ) or dabigatran ( Pradaxa ) used. These have the advantage over heparin derivatives such Certoparin ( mono Embolex ), dalteparin ( Fragmin ), enoxaparin ( Clexane ), nadroparin , reviparin or tinzaparin ( Innohep ) the advantage without painful injections to be taken orally and compared to vitamin K antagonists such as warfarin (trade name Falithrom , Marcumar ), acenocumarol or warfarin have the advantage of not needing regular laboratory tests for coagulation. The disadvantage up to now has been that in the event of an excessive bleeding tendency, acute bleeding or an acute indication for surgery, there was no possibility of canceling the anticoagulant effect of the DOACs. Andexanet alfa partially closes this gap.

Mechanism of action

Andexanet alfa is a recombinant and modified version of activated human coagulation factor X. It binds direct factor Xa inhibitors with the same affinity as natural factor Xa. This neutralizes the anticoagulant effect of direct factor Xa inhibitors and restores adequate hemostasis . Andexanet alfa is ineffective as an antidote to factor IIa inhibitors such as dabigatran .

properties

The light chain consists of 105, the heavy chain of 254 amino acids. The serine in the active center of the molecule has been replaced by alanine , which means that the protein is no longer able to activate prothrombin by cleavage. The ability of the protein to integrate into the prothrombinase complex was eliminated by the removal of the γ-carboxyglutamic acid (Gla) domain. This eliminates any potential anticoagulant effect. Andexanet alfa is made in CHO cells .

application

Andexanet alfa is administered intravenously. It has a half-life of 5-7 hours. It is approved as an antidote to rivaroxaban and apixaban. It has no effect on dabigatran etexilate, the only currently approved DOAC that is not a factor Xa inhibitor. After administration of Andexanet alfa, commercial anti-FXa tests are not meaningful because the contained FXa inhibitor dissociates from Andexanet alfa. Treatment monitoring should be based on other parameters to prevent erroneous underestimation of the cancellation activity.

Side effects

Common side effects are pneumonia and urinary tract infections.

Since Andexanet alfa abolishes the anticoagulant effect of DOACs, diseases can occur that are supposed to be prevented by DOACs:

Cardiac arrest and sudden death can occur as a result of these disorders .

Admission

Andexanet alfa was developed by Portola Pharmaceuticals and was granted orphan drug status in the United States in February 2015 , followed by FDA approval on May 3, 2018 . The marketing authorization holder is Portola Pharmaceuticals, Inc. The marketing authorization is granted to patients treated with rivaroxaban or apixaban when cessation of anticoagulant therapy is urgently required because of life-threatening or uncontrolled bleeding. This indication was carried out as an accelerated approval based on changes in anti-factor Xa activity in healthy volunteers. An improvement in hemostasis has not been sufficiently demonstrated. This evidence is to be provided later with currently ongoing clinical studies. The drug is currently only available to a limited extent.

In February 2019 adopted Committee for Medicinal Products of the European Medicines Agency (EMA) a positive recommendation for the approval of Andexanet alfa ( Ondexxya ) in the EU. However, since the data situation is incomplete, the approval should be subject to conditions and the manufacturer should be asked to provide further data, for example on dosage and the risk of clot formation. This recommendation was complied with at the end of April 2019, i.e. H. it was approved by the European Commission for the European member states.

ANNEXA-4 study

In a multicentre, prospective, single-arm study , Andexanet Alfa was tested on 352 patients with severe bleeding who were taking apixaban (194 patients), rivaroxaban (128 patients), edoxaban (20 patients) or enoxaparin (heparin derivative, 15 patients) within the last 18 hours checked. The mean age of the patients was 77 years and had intracranial bleeding (64%) or gastrointestinal bleeding (26%). Treatment consisted of a bolus of 400 or 800 mg of Andexanet Alfa in 15 to 30 minutes followed by an infusion of 480 or 960 mg over two hours. In the apixaban group the anti-factor Xa activity decreased from 149.7 to 11.1 ng per ml, in the rivaroxaban group from 211.8 to 14.2 ng per ml. In 204 of 249 cases evaluated, a good or excellent hemostasis can be determined. In 10% of the cases, thrombosis occurred in the first 30 days, seven patients suffered a heart attack , 14 an ischemic stroke.

Web links

Trade names

Andexxa (USA), Ondexxya (EU)

Individual evidence

  1. ↑ New Drugs 2019 Pharmaceutical Newspaper of December 16, 2019, accessed on December 17, 2019
  2. ↑ Genmin Lu, Francis R. DeGuzman, Sanjay Lakhotia, Stanley J Hollenbach, David R Phillips and Uma Sinha: Recombinant Antidote for Reversal of Anticoagulation by Factor Xa inhibitor. In: Blood . tape 112 , 2008, p. 983 .
  3. ↑ Elie Dolgin: Antidotes edge closer to reversing effects of new blood thinners. In: Nature Medicine . tape 19 , 2013, pp. 251 .
  4. ↑ Genmin Lu, Francis R. DeGuzman, Stanley J. Hollenbach, Mark J. Karbarz, Keith Abe: A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa . In: Nature Medicine . tape 19 , no. 4 , 2013, p. 446-451 , doi : 10.1038 / nm.3102 , PMID 23455714 .
  5. ^ H Spreitzer: New active ingredients - Andexanet Alfa . In: Österreichische Apothekerzeitung . No. 26 , 2013, p. 40 .
  6. ↑ International Nonproprietary Names for Pharmaceutical Substances (INN) - Recommended International Nonproprietary Names: List 72
  7. ↑ a b c ANDEXXA® (coagulation factor Xa (recombinant), inactivated-zhzo) Lyophilized Powder for Solution For Intravenous Injection. Prescribing information. Portola Pharmaceuticals, Inc., South San Francisco, 2018, accessed April 8, 2019 .
  8. ↑ a b AHFS Monographs Andexxa. Drugs.com, January 28, 2019, accessed April 9, 2019 .
  9. ^ Paul Ehrlich Institute - Homepage - Rote-Hand-Brief: Ondexxya - Andexanet alfa (June 18, 2020). Accessed July 30, 2020 .
  10. ↑ Elie Dolgin: Antidotes edge closer to reversing effects of new blood thinners . In: Nature Medicine . tape 19 , no. 3 , 2013, p. 251 , doi : 10.1038 / nm0313-251 , PMID 23467222 .
  11. ↑ Search Orphan Drug Designations and Approvals, Coagulation factor Xa (recombinant), inactivated-zhzo , accessed April 15, 2019.
  12. ↑ EPAR - Overview of Ondexxya and why it is approved in the EU. (PDF). EMA, April 2019.
  13. ↑ a b European Commission Grants Conditional Marketing Authorization for Portola Pharmaceuticals' Ondexxya ™ (andexanet alfa), the First and Only Antidote for the Reversal of Factor Xa Inhibitors , PM Portola, April 26, 2019, accessed April 29, 2019.
  14. ^ Deborah M. Siegal, John T Curnutte, Stuart J Connolly, Genmin Lu, Pamela B Conley: Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity . In: New England Journal of Medicine . tape 373 , no. 25 , December 17, 2015, p. 2413-2424 , doi : 10.1056 / NEJMoa1510991 .
  15. ↑ First antidote for reversal of anticoagulation with factor Xa inhibitors apixaban and rivaroxaban , press release of the European Medicines Agency dated March 1, 2019.
  16. ↑ Overview of Ondexxya and why it is approved in the EU , EMA April 2019, accessed on July 16, 2019.
  17. ↑ Ondexxya - andexanet alfa , EMA, accessed on August 8, 2019.
  18. ↑ Accelerated approval for Antidot , Pharmazeutische Zeitung, March 1, 2019, accessed April 29, 2019.
  19. ↑ Stuart J Connolly, Mark Crowther, John W Eikelboom, C Michael Gibson, John T Curnutte: Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors . In: New England Journal of Medicine . tape 380 , no. 14 , April 4, 2019, p. 1326-1335 , doi : 10.1056 / NEJMoa1814051 .