Chemistry:Andexanet alfa

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Andexanet alfa
Clinical data
Trade namesAndexxa, Ondexxya, others
Other namesCoagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445
AHFS/Drugs.comMonograph
License data
Routes of
administration		Intravenous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
MetabolismNot studied
Elimination half-life5 h to 7 h
Identifiers
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL

Andexanet alfa, sold under the trade name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding.[1] It has not been found to be useful for other factor Xa inhibitors.[2] It is given by injection into a vein.[2]

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clots, heart attacks, strokes, or cardiac arrest.[2] It works by binding to rivaroxaban and apixaban.[2]

It was approved for medical use in the United States in May 2018.[1] It was developed by Portola Pharmaceuticals.[3]

Medical uses

Andexanet alfa is used to stop life-threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban.[1]

There are no randomised clinical trials as of 2019. Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity.[4] The only published clinical trial is a prospective, open label, single group study.[5] This study reports results on 352 people and demonstrates a reduction of anti-Xa-activity while also showing an excellent or good hemostatic efficacy in 82%. While people who were expected to die in 30 days were excluded from the study, 14% of participants died. There was no relationship between hemostatic efficacy and reduced anti-Xa-activity.[6] The FDA has demanded a randomised clinical trial: the first results are not expected before 2023.[7]

Adverse effects

Common side effects include pneumonia and urinary tract infections.[2] Severe side effects may include blood clots or cardiac arrest.[2]

Andexanet alfa has a boxed warning that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths.[1]

Pharmacology

Mechanism of action

Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa).[8] Andexanet alfa differs from native FXa due to the removal of a 34 residue fragment that contains the Gla domain. This modification reduces andexanet alfa's anticoagulant potential. Additionally, a serine to alanine (S419A) mutation in the active site eliminates its activity as a prothrombin to thrombin catalyst, but still allows the molecule to bind to FXa inhibitors.[9] FXa inhibitors bind to andexanet alfa with the same affinity as to natural FXa. As a consequence in the presence of andexanet alfa natural FXa is partially freed, which can lead to effective hemostasis.[3][10] In other words, it acts as a decoy receptor. Andexanet alfa reverses effect of all anticoagulants that act directly through FXa or by binding antithrombin III. The drug is not effective against factor IIa inhibitor dabigatran.[11] Its activity is measured using the anti-Xa test, which is utilized to determine the amount of available factor Xa for coagulation[12]

History

It was approved in the United States in 2018 based on data from two phase III studies on reversing the anticoagulant activity of FXa inhibitors rivaroxaban and apixaban in healthy volunteers.[4] As a condition of its accelerated approval there is a study being conducted comparing it to other currently used reversal agents ("usual care").[5][13]

Society and culture

Economics

Initial pricing (AWP) is $58,000 per reversal (800 mg bolus + 960 mg infusion, $3,300 per 100 mg vial) which is higher than reversal agents for other DOAC agents (idarucizumab for use in dabigatran reversal is $4,200 per reversal).[14]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "Andexxa- andexanet alfa injection, powder, lyophilized, for solution". 21 September 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ae7f0c50-ff2d-49e5-8e10-4efa861556e6. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Andexxa Monograph for Professionals". https://www.drugs.com/monograph/andexxa.html. Retrieved 19 December 2018. 
  3. ↑ 3.0 3.1 Dolgin E (March 2013). "Antidotes edge closer to reversing effects of new blood thinners". Nature Medicine 19 (3): 251. doi:10.1038/nm0313-251. PMID 23467222. 
  4. ↑ 4.0 4.1 "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity". New England Journal of Medicine 373 (25): 2413–24. December 2015. doi:10.1056/NEJMoa1510991. PMID 26559317. 
  5. ↑ 5.0 5.1 "Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors". New England Journal of Medicine 380 (14): 1326–1335. April 2019. doi:10.1056/NEJMoa1814051. PMID 30730782. 
  6. ↑ Justin Morgenstern, "Andexanet Alfa: More garbage science in the New England Journal of Medicine", First10EM blog, February 11, 2019. Available at: https://first10em.com/andexanet-alfa/.
  7. ↑ "A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor". 11 January 2022. https://clinicaltrials.gov/ct2/show/NCT03661528. 
  8. ↑ Lu, Genmin; DeGuzman, Francis R.; Lakhotia, Sanjay; Hollenbach, Stanley J.; Phillips, David R.; Sinha, Uma (2008-11-16). "Recombinant Antidote for Reversal of Anticoagulation by Factor Xa Inhibitors.". Blood 112 (11): 983. doi:10.1182/blood.V112.11.983.983. ISSN 0006-4971. 
  9. ↑ Kaatz, Scott; Bhansali, Hardik; Gibbs, Joseph; Lavender, Robert; Mahan, Charles E.; Paje, David G. (2017-09-13). "Reversing factor Xa inhibitors – clinical utility of andexanet alfa" (in English). Journal of Blood Medicine 8: 141–149. doi:10.2147/JBM.S121550. PMID 28979172. PMC 5602457. https://www.dovepress.com/reversing-factor-xa-inhibitors-clinical-utility-of-andexanet-alfa-peer-reviewed-fulltext-article-JBM. 
  10. ↑ "A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa". Nature Medicine 19 (4): 446–51. March 2013. doi:10.1038/nm.3102. PMID 23455714. 
  11. ↑ H. Spreitzer (23 December 2013). "Neue Wirkstoffe – Andexanet Alfa" (in German). Österreichische Apothekerzeitung (26/2013): 40. 
  12. ↑ Flaherty, Devon (October 1, 2019). "Andexanet Alfa for Urgent Reversal of Apixaban Before Aortic Surgery Requiring Cardiopulmonary Bypass: A Case Report". A&A Practice 13 (7): 271–273. doi:10.1213/XAA.0000000000001052. PMID 31265446. https://journals.lww.com/aacr/Abstract/2019/10010/Andexanet_Alfa_for_Urgent_Reversal_of_Apixaban.8.aspx. 
  13. ↑ Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor. 11 January 2022. https://clinicaltrials.gov/ct2/show/NCT03661528?cond=NCT03661528&draw=2&rank=1. 
  14. ↑ "Lexi Comp Drug Information Online". 24 May 2018. http://www.wolterskluwercdi.com/. 

Further reading

External links



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