Tafamidis

Tafamidis
Names
Trade namesVyndaqel, Vyndamax, others
Other namesTafamidis meglumine
IUPAC name
  • 2-(3,5-Dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
Clinical data
Main usesFamilial amyloid polyneuropathy (transthyretin amyloidosis)[1]
Side effectsAbdominal pain, diarrhea, infection[2]
Pregnancy
category
  • AU: D[3]
  • US: N (Not classified yet)[4]
    Routes of
    use    		By mouth
    Typical dose20 to 80 mg OD[2][1]
    External links
    AHFS/Drugs.comMonograph
    Legal
    License data
    Legal status
    • AU: S4 (Prescription only) [3]
    • UK: POM (Prescription only) [5]
    • US: ℞-only [6]
    • EU: Rx-only [7]
    • In general: ℞ (Prescription only)
    Chemical and physical data
    FormulaC14H7Cl2NO3
    Molar mass308.11 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C(O)c3ccc1nc(oc1c3)-c2cc(Cl)cc(Cl)c2
    InChI
    • InChI=1S/C14H7Cl2NO3/c15-9-3-8(4-10(16)6-9)13-17-11-2-1-7(14(18)19)5-12(11)20-13/h1-6H,(H,18,19) ☒N
    • Key:TXEIIPDJKFWEEC-UHFFFAOYSA-N ☒N

    Tafamidis, sold under the brand names Vyndaqel among others, is a medication used to treat transthyretin-mediated amyloidosis.[1] It is taken by mouth.[2] It can be stopped after liver transplantation.[2]

    Common side effects include abdominal pain, diarrhea, and infection.[2] Use during pregnancy is believed to harm the baby.[8] It works by stabilizing the protein transthyretin, thus decreasing the formulation amyloids.[7]

    Tafamidis was approved for medical use in Europe in 2011 and the United States in 2019.[7][1] In the United Kingdom a month of 20 mg per day costs the NHS about £10,700 as of 2021.[2] This amount in the United States costs about 4,900 USD.[9]

    Medical use

    Tafamidis is used to delay disease progression in adults with transthyretin amyloidosis (ATTR) whose disease leads to loss of nerve function (ATTR with polyneuropathy, ATTR-PN) or to heart disease (ATTR with cardiomyopathy, ATTR-CM).[10][5][11][6] It is taken by mouth.[5][6]

    Women should not get pregnant while taking it and should not breast feed while taking it. People with FAP who have received a liver transplant should not take it.[5]

    Dosage

    It is used at a dose of 20 to 80 mg once per day as the tafamidis meglumine (Vyndaqel) formulation and as 61 mg per day as the tafamidis (Vyndamax) formulation.[1][7]

    Side effects

    More than 10% of people in trials had one or more of urinary tract infections, vaginal infections, upper abdominal pain, or diarrhea.[5]

    Interactions

    Tafamidis does not appear to interact with cytochrome P450 but does inhibit BCRP, so is likely to affect availability of drugs including methotrexate, rosuvastatin, and imatinib, and inhibits OAT1 and OAT3 so is likely to interact with NSAIDs and other drugs that rely on those transporters.[5]

    Pharmacology

    Tafamidis is a pharmacological chaperone that stabilizes the correctly folded tetrameric form of the transthyretin (TTR) protein by binding in one of the two thyroxine-binding sites of the tetramer.[11] In people with FAP, the individual monomers fall away from the tetramer, misfold, and aggregate; the aggregates harm nerves.[11]

    The maximum plasma concentration is achieved around two hours after dosing; in plasma it is almost completely bound to proteins. Based on preclinical data, it appears to be metabolized by glucuronidation and excreted via bile; in humans, around 59% of a dose is recovered in feces, and approximately 22% in urine.[5]

    Chemistry

    The chemical name of tafamidis is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The molecule has two crystalline forms and one amorphous form; it is manufactured in one of the possible crystalline forms. It is marketed as a meglumine salt. It is slightly soluble in water.[12]

    History

    The laboratory of Jeffery W. Kelly at The Scripps Research Institute began looking for ways to inhibit TTR fibril formation in the 1990s.[13]: 210  Tafamidis was eventually discovered by Kelly's team using a structure-based drug design strategy; the chemical structure was first published in 2003.[14][15] In 2003, Kelly co-founded a company called FoldRx with Susan Lindquist of MIT and the Whitehead Institute[15][16] and FoldRx developed tafamidis up through submitting an application for marketing approval in Europe in early 2010.[14] FoldRx was acquired by Pfizer later that year.[14]

    Tafamidis was approved by the European Medicines Agency (EMA) in November 2011, to delay peripheral nerve impairment in adults with transthyretin-related hereditary amyloidosis.[11] The U.S. Food and Drug Administration (FDA) rejected the application for marketing approval in 2012, on the basis that the clinical trial did not show efficacy based on a functional endpoint, and the FDA requested further clinical trials.[17] In May 2019, the FDA approved two tafamidis preparations, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis), for the treatment of transthyretin-mediated cardiomyopathy (ATTR-CM).[10] The drug was approved in Japan in 2013; regulators there made the approval dependent on further clinical trials showing better evidence of efficacy.[18]

    The FDA approved tafamidis meglumine based primarily on evidence from a clinical trial (NCT01994889) of 441 adults.[19] The trial was conducted at 60 sites in Belgium, Brazil, Canada, Czech Republic, Spain, France, Greece, Italy, Japan, Netherlands, Sweden, Great Britain, and the United States.[19]

    There was one trial that evaluated the benefits and side effects of tafamidis for the treatment of ATTR-CM.[19] In the trial, people with ATTR‑CM were randomly assigned to receive either tafamidis (either 20 or 80 mg) or placebo for 30 months.[19] About 90% of people in the trial were taking other drugs for heart failure (consistent with the standard of care).[19]

    The EMA designated tafamidis an orphan medicine[7] and the FDA designated tafamidis meglumine an orphan drug.[20] The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.[21]

    Society and culture

    Tafamidis was approved for the treatment of ATTR with loss of nerve function (ATTR-PN) in the European Union in 2011, and in Japan in 2013.[7][18] In the United States, it was rejected for the treatment of ATTR-PN. The reason for this is that the FDA saw insufficient evidence for its efficacy in this form of ATTR.[22][10]

    Tafamidis can also be used to treat a different form of ATTR that leads to heart disease (ATTR with cardiomyopathy, ATTR-CM). It was approved for the treatment of this form of the disease in the United States in 2019 and in the European Union in 2020. In the United States, there are two approved preparations for the treatment of ATTR-CM: tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax).[10][23][19] The two preparations have the same active moiety, tafamidis, but they are not substitutable on a milligram to milligram basis.[10]

    Tafamidis (Vyndamax) and tafamidis meglumine (Vyndaqel) were approved for medical use in Australia in March 2020.[24]

    References

    1. 1 2 3 4 5 "Tafamidis Monograph for Professionals". Drugs.com. Archived from the original on 9 July 2021. Retrieved 7 August 2021.
    2. 1 2 3 4 5 6 BNF (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. p. 428. ISBN 978-0-85711-369-6.
    3. 1 2 "Vyndamax and Vyndaqel Australian prescription medicine decision summary". Therapeutic Goods Administration (TGA). 17 July 2020. Archived from the original on 29 August 2021. Retrieved 16 August 2020.
    4. ↑ "Tafamidis Use During Pregnancy". Drugs.com. 6 September 2019. Archived from the original on 11 July 2021. Retrieved 16 August 2020.
    5. 1 2 3 4 5 6 7 "Vyndaqel 20 mg soft capsules - Summary of Product Characteristics". Electronic Medicines Compendium. Archived from the original on 2 April 2018. Retrieved 2 April 2018.
    6. 1 2 3 "Vyndaqel- tafamidis meglumine capsule, liquid filled Vyndamax- tafamidis capsule, liquid filled". DailyMed. 30 August 2019. Archived from the original on 1 April 2020. Retrieved 24 November 2019.
    7. 1 2 3 4 5 6 "Vyndaqel EPAR". European Medicines Agency (EMA). 16 October 2019. Archived from the original on 25 November 2019. Retrieved 24 November 2019.
    8. ↑ "Tafamidis Use During Pregnancy". Drugs.com. Archived from the original on 11 July 2021. Retrieved 16 September 2021.
    9. ↑ "Vyndaqel Prices, Coupons & Patient Assistance Programs". Drugs.com. Retrieved 16 September 2021.
    10. 1 2 3 4 5 "FDA approves new treatments for heart disease caused by a serious rare disease, transthyretin mediated amyloidosis". U.S. Food and Drug Administration (FDA). 14 September 2019. Archived from the original on 14 September 2019. Retrieved 24 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
    11. 1 2 3 4 Said, G; Grippon, S; Kirkpatrick, P (1 March 2012). "Tafamidis". Nature Reviews. Drug Discovery. 11 (3): 185–6. doi:10.1038/nrd3675. PMID 22378262.
    12. ↑ "Assessment report: Vyndaqel tafamidis meglumine Procedure No.: EMEA/H/C/002294" (PDF). EMA. 2011. Archived (PDF) from the original on 17 June 2018. Retrieved 2 August 2021. See EMA index page Archived 20 June 2018 at the Wayback Machine for updates.
    13. ↑ Labaudiniere, Richard (2014). "Chapter 9: Discovery and Development of Tafamidis for the Treatment of TTR Familial Amyloid Polyneuropathy". In Pryde, David C; Palmer, Michael J (eds.). Orphan Drugs and Rare Diseases. RSC Drug Discovery Series No. 38. Royal Society of Chemistry. ISBN 978-1-84973-806-4.
    14. 1 2 3 Jones, Dan (29 October 2010). "Modifying protein misfolding". Nature Reviews Drug Discovery. 9 (11): 825–827. doi:10.1038/nrd3316. PMID 21030987. S2CID 30702908.
    15. 1 2 Borman, Stu (25 January 2010). "Attacking Amyloids". Chemical & Engineering News. 88 (4): 30–32. doi:10.1021/cen-v088n004.p030.
    16. ↑ Breznitz, Shiri M.; O'Shea, Rory P.; Allen, Thomas J. (March 2008). "University Commercialization Strategies in the Development of Regional Bioclusters". Journal of Product Innovation Management. 25 (2): 129–142. doi:10.1111/j.1540-5885.2008.00290.x.
    17. ↑ Grogan, Kevin (19 June 2012). "FDA rejects Pfizer rare disease drug tafamidis". Pharma Times. Archived from the original on 2 June 2021. Retrieved 2 August 2021.
    18. 1 2 "Report on the Deliberation Results" (PDF). Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare. 2 September 2013. Archived (PDF) from the original on 12 July 2017. Retrieved 2 August 2021.
    19. 1 2 3 4 5 6 "Drug Trial Snapshots: Vyndaqel/Vyndamax". U.S. Food and Drug Administration (FDA). 28 May 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
    20. ↑ "Tafamidis meglumine Orphan Drug Designation and Approval". U.S. Food and Drug Administration (FDA). 3 May 2019. Archived from the original on 19 December 2019. Retrieved 18 December 2019. Public Domain This article incorporates text from this source, which is in the public domain.
    21. ↑ "New Drug Therapy Approvals 2019". U.S. Food and Drug Administration. 31 December 2019. Archived from the original on 16 September 2020. Retrieved 15 September 2020.
    22. ↑ "FDA rejects Pfizer rare disease drug tafamidis". PharmaTimes online. 19 June 2012. Archived from the original on 2 June 2021. Retrieved 2 June 2021.
    23. ↑ "Drug Approval Package: Vyndaquel & Vyndamax". U.S. Food and Drug Administration (FDA). 13 June 2019. Archived from the original on 25 November 2019. Retrieved 24 November 2019. Public Domain This article incorporates text from this source, which is in the public domain.
    24. ↑ "AusPAR: Tafamidis and Tafamidis meglumine". Therapeutic Goods Administration (TGA). 10 September 2020. Archived from the original on 27 October 2020. Retrieved 23 September 2020.
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