Andexanet alfa

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Andexanet alfa
Clinical data
Trade names Andexxa, Ondexxya, others
Other namesCoagulation factor Xa (recombinant), inactivated-zhzo, PRT06445, r-Antidote, PRT4445
AHFS/Drugs.com Monograph
License data
Pregnancy
category
Routes of
administration 		Intravenous injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life 5 h to 7 h
Identifiers
  • Andexanet alfa
CAS Number
IUPHAR/BPS
DrugBank
ChemSpider
  • none
UNII
KEGG
ChEMBL

Andexanet alfa, sold under the brand name Andexxa among others, is an antidote for the medications rivaroxaban and apixaban, when reversal of anticoagulation is needed due to uncontrolled bleeding. [8] It has not been found to be useful for other factor Xa inhibitors. [9] It is given by injection into a vein. [9]

Contents

Common side effects include pneumonia and urinary tract infections. [9] Severe side effects may include blood clots, heart attacks, strokes, or cardiac arrest. [9] It works by binding to rivaroxaban and apixaban. [9]

It was approved for medical use in the United States in May 2018. [8] It was developed by Portola Pharmaceuticals. [10]

Medical uses

Andexanet alfa is used to stop life-threatening or uncontrollable bleeding in people who are taking rivaroxaban or apixaban. [8]

Studies in healthy volunteers show that the molecule binds factor Xa inhibitors and counters their anti-Xa-activity. [11] The first published clinical trial was a prospective, open label, single group study. [12] 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. [13] The FDA demanded a randomised clinical trial [14] which resulted in publication in 2024. [15] The ANNEXA-I trial included 530 patients with intracerebral hemorrhage who were receiving factor Xa inhibitors. Andexanet resulted in better control of hematoma expansion than usual care, but was associated with thrombotic events, including ischemic stroke. ANNEXA-I did not have sufficient power or information to draw conclusions about the effect of andexanet on mortality, clinical deterioration, or the need for rescue therapy. [16]

Adverse effects

Common side effects include pneumonia and urinary tract infections. [9] Severe side effects may include blood clots or cardiac arrest. [9]

Andexanet alfa has a boxed warning that it is associated with arterial and venous blood clots, ischemic events, cardiac arrest, and sudden deaths. [8]

Pharmacology

Mechanism of action

Andexanet alfa is a biologic agent, a recombinant modified version of human activated factor X (FXa). [17] 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. [18] 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. [10] [19] 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. [20] Its activity is measured using the anti-Xa test, which is utilized to determine the amount of available factor Xa for coagulation [21]

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. [11] As a condition of its accelerated approval, the ANNEXA-I study was conducted comparing it to other currently used reversal agents ("usual care"). [12] [22]

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). [23]

Related Research Articles

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces the coagulation of blood, prolonging the clotting time. Some occur naturally in blood-eating animals, such as leeches and mosquitoes, which help keep the bite area unclotted long enough for the animal to obtain blood.

<span class="mw-page-title-main">Warfarin</span> Anticoagulant medication

Warfarin, sold under the brand name Coumadin among others, is an anticoagulant medication. While the drug is described as a "blood thinner", it does not reduce viscosity but rather inhibits coagulation. Accordingly, it is commonly used to prevent blood clots in the circulatory system such as deep vein thrombosis and pulmonary embolism, and to protect against stroke in people who have atrial fibrillation, valvular heart disease, or artificial heart valves. Less commonly, it is used following ST-segment elevation myocardial infarction (STEMI) and orthopedic surgery. It is usually taken by mouth, but may also be administered intravenously. It is a vitamin K antagonist.

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and, in the treatment of venous thromboembolism, and the treatment of myocardial infarction.

<span class="mw-page-title-main">Factor VII</span> Mammalian protein found in humans

Coagulation factor VII is a protein involved in coagulation and, in humans, is encoded by gene F7. It is an enzyme of the serine protease class. Once bound to tissue factor released from damaged tissues, it is converted to factor VIIa, which in turn activates factor IX and factor X.

<span class="mw-page-title-main">Intracerebral hemorrhage</span> Type of intracranial bleeding that occurs within the brain tissue itself

Intracerebral hemorrhage (ICH), also known as hemorrhagic stroke, is a sudden bleeding into the tissues of the brain, into its ventricles, or into both. An ICH is a type of bleeding within the skull and one kind of stroke. Symptoms can vary dramatically depending on the severity, acuity, and location (anatomically) but can include headache, one-sided weakness, numbness, tingling, or paralysis, speech problems, vision or hearing problems, memory loss, attention problems, coordination problems, balance problems, dizziness or lightheadedness or vertigo, nausea/vomiting, seizures, decreased level of consciousness or total loss of consciousness, neck stiffness, and fever.

<span class="mw-page-title-main">Rivaroxaban</span> Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

<span class="mw-page-title-main">Dabigatran</span> Anticoagulant medication

Dabigatran, sold under the brand name Pradaxa among others, is an anticoagulant used to treat and prevent blood clots and to prevent stroke in people with atrial fibrillation. Specifically it is used to prevent blood clots following hip or knee replacement and in those with a history of prior clots. It is used as an alternative to warfarin and does not require monitoring by blood tests. In a meta analysis of 7 different studies, there was no benefit of dabigatran over warfarin in preventing ischemic stroke; however, dabigatran were associated with a lower hazard for intracranial bleeding compared with warfarin, but also had a higher risk of gastrointestinal bleeding relative to warfarin. It is taken by mouth.

Prothrombin complex concentrate (PCC), also known as factor IX complex, sold under the brand name Kcentra among others, is a combination medication made up of blood clotting factors II, IX, and X(3-factor PCC) or, when also containing factor VII as does Kcentra, 4-factor PCC. It is used to treat and prevent bleeding in hemophilia B if pure factor IX is not available. It may also be used for reversal of warfarin therapy. It is given by slow injection into a vein. Another product, activated prothrombin complex concentrate or FEIBA, may be used for acquired hemophilia.

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.

Direct factor Xa inhibitors (xabans) are anticoagulants, used to both treat and prevent blood clots in veins, and prevent stroke and embolism in people with atrial fibrillation (AF).

<span class="mw-page-title-main">Vitamin K antagonist</span> Group of substances

Vitamin K antagonists (VKA) are a group of substances that reduce blood clotting by reducing the action of vitamin K. The term "vitamin K antagonist" is technically a misnomer, as the drugs do not directly antagonize the action of vitamin K in the pharmacological sense, but rather the recycling of vitamin K. Vitamin K antagonists (VKAs) have been the mainstay of anticoagulation therapy for more than 50 years.

The management of atrial fibrillation (AF) is focused on preventing temporary circulatory instability, stroke and other ischemic events. Control of heart rate and rhythm are principally used to achieve the former, while anticoagulation may be employed to decrease the risk of stroke. Within the context of stroke, the discipline may be referred to as stroke prevention in atrial fibrillation (SPAF). In emergencies, when circulatory collapse is imminent due to uncontrolled rapid heart rate, immediate cardioversion may be indicated.

<span class="mw-page-title-main">Edoxaban</span> Anticoagulant medication

Edoxaban, sold under the brand name Lixiana among others, is an anticoagulant medication and a direct factor Xa inhibitor. It is taken by mouth.

<span class="mw-page-title-main">Betrixaban</span> Chemical compound

Betrixaban is an oral anticoagulant drug which acts as a direct factor Xa inhibitor. Betrixaban is FDA approved for venous thrombosis prevention in adults hospitalized for an acute illness who are at risk for thromboembolic complications. Compared to other directly acting oral anticoagulants betrixaban has relatively low renal excretion and is not metabolized by CYP3A4.

<span class="mw-page-title-main">Apixaban</span> Anticoagulant medication

Apixaban, sold under the brand name Eliquis, is an anticoagulant medication used to treat and prevent blood clots and to prevent stroke in people with nonvalvular atrial fibrillation through directly inhibiting factor Xa. It is used an alternative to warfarin to prevent blood clots following hip or knee replacement and in those with a history of prior clots. and does not require monitoring by blood tests or dietary restrictions. It is taken by mouth.

<span class="mw-page-title-main">Darexaban</span> Chemical compound

Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

<span class="mw-page-title-main">Ciraparantag</span> Chemical compound

Ciraparantag (aripazine) is a drug under investigation as an antidote for a number of anticoagulant drugs, including factor Xa inhibitors, dabigatran, and heparins.

Four drugs from the class of direct Xa inhibitors are marketed worldwide. Rivaroxaban (Xarelto) was the first approved FXa inhibitor to become commercially available in Europe and Canada in 2008. The second one was apixaban (Eliquis), approved in Europe in 2011 and in the United States in 2012. The third one edoxaban was approved in Japan in 2011 and in Europe and the US in 2015. Betrixaban (Bevyxxa) was approved in the US in 2017.

Portola Pharmaceuticals is an American clinical stage biotechnology company that researches, develops, and commercializes drugs. The company focuses primarily on drugs used in the treatment of thrombosis and hematological malignancies. Founded in 2003 and headquartered in South San Francisco, California, Portola Pharmaceuticals is a member of the NASDAQ Biotechnology Index.

References

  1. 1 2 "Andexxa APMDS". Therapeutic Goods Administration (TGA). 12 July 2023. Retrieved 10 September 2023.
  2. ↑ "Andexxa (AstraZeneca Pty Ltd)". Therapeutic Goods Administration (TGA). 28 July 2023. Archived from the original on 11 September 2023. Retrieved 10 September 2023.
  3. ↑ "AusPAR: Andexxa". Therapeutic Goods Administration (TGA). 19 December 2023. Retrieved 31 March 2024.
  4. ↑ "Details for: Ondexxya". Health Canada . 16 June 2023. Archived from the original on 3 March 2024. Retrieved 3 March 2024.
  5. ↑ "Summary Basis of Decision (SBD) for Ondexxya". Health Canada . Retrieved 11 December 2023.
  6. ↑ "Notice: Multiple additions to the Prescription Drug List (PDL) [2023-08-30]". Health Canada . 26 October 2023. Archived from the original on 3 January 2024. Retrieved 3 January 2024.
  7. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 October 2023.
  8. 1 2 3 4 5 "Andexxa- andexanet alfa injection, powder, lyophilized, for solution". DailyMed. 21 September 2020. Archived from the original on 18 November 2020. Retrieved 12 November 2020.
  9. 1 2 3 4 5 6 7 "Andexxa Monograph for Professionals". Drugs.com. Archived from the original on 19 December 2018. Retrieved 19 December 2018.
  10. 1 2 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. S2CID   13340319.
  11. 1 2 Siegal DM, Curnutte JT, Connolly SJ, Lu G, Conley PB, Wiens BL, et al. (December 2015). "Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity". The New England Journal of Medicine. 373 (25): 2413–2424. doi: 10.1056/NEJMoa1510991 . PMID   26559317.
  12. 1 2 Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al. (April 2019). "Full Study Report of Andexanet Alfa for Bleeding Associated with Factor Xa Inhibitors". The New England Journal of Medicine. 380 (14): 1326–1335. doi: 10.1056/NEJMoa1814051 . PMC   6699827 . PMID   30730782.
  13. ↑ Morgenstern J (11 February 2019). "Andexanet Alfa: More garbage science in the New England Journal of Medicine". First10EM blog. Archived from the original on 1 March 2021. Retrieved 5 February 2020.
  14. ↑ Clinical trial number NCT03661528 for "A Randomized Clinical Trial of Andexanet Alfa in Acute Intracranial Hemorrhage in Patients Receiving an Oral Factor Xa Inhibitor " at ClinicalTrials.gov
  15. ↑ Connolly SJ, Sharma M, Cohen AT, Demchuk AM, Członkowska A, Lindgren AG, Molina CA, Bereczki D, Toni D, Seiffge DJ, Tanne D, Sandset EC, Tsivgoulis G, Christensen H, Beyer-Westendorf J, Coutinho JM, Crowther M, Verhamme P, Amarenco P, Roine RO, Mikulik R, Lemmens R, Veltkamp R, Middeldorp S, Robinson TG, Milling TJ Jr, Tedim-Cruz V, Lang W, Himmelmann A, Ladenvall P, Knutsson M, Ekholm E, Law A, Taylor A, Karyakina T, Xu L, Tsiplova K, Poli S, Kallmünzer B, Gumbinger C, Shoamanesh A; ANNEXA-I Investigators. Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage. N Engl J Med. 2024 May 16;390(19):1745-1755. doi: 10.1056/NEJMoa2313040. PMID: 38749032.
  16. ↑ Smith WS, Hemphill JC. Reversing Oral Anticoagulation in Intracerebral Hemorrhage. N Engl J Med. 2024 May 16;390(19):1815-1816. doi: 10.1056/NEJMe2403726. PMID: 38749038.
  17. ↑ Lu G, DeGuzman FR, Lakhotia S, Hollenbach SJ, Phillips DR, Sinha U (16 November 2008). "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.
  18. ↑ Kaatz S, Bhansali H, Gibbs J, Lavender R, Mahan CE, Paje DG (13 September 2017). "Reversing factor Xa inhibitors - clinical utility of andexanet alfa". Journal of Blood Medicine. 8: 141–149. doi: 10.2147/JBM.S121550 . PMC   5602457 . PMID   28979172.
  19. ↑ Lu G, DeGuzman FR, Hollenbach SJ, Karbarz MJ, Abe K, Lee G, et al. (April 2013). "A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa". Nature Medicine. 19 (4): 446–451. doi:10.1038/nm.3102. PMID   23455714. S2CID   11235887.
  20. ↑ Spreitzer H (23 December 2013). "Neue Wirkstoffe – Andexanet Alfa". Österreichische Apothekerzeitung (in German) (26/2013): 40.
  21. ↑ Flaherty D, Connors JM, Singh S, Sylvester KW, Rimsans J, Cornella L (October 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. S2CID   195788543.
  22. ↑ Clinical trial number NCT03661528 for "Trial of Andexanet in ICH Patients Receiving an Oral FXa Inhibitor" at ClinicalTrials.gov
  23. ↑ "Lexi Comp Drug Information Online". 24 May 2018. Archived from the original on 5 October 2020. Retrieved 24 May 2018.

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