Tafamidis

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Tafamidis
Tafamidis skeletal.svg
Clinical data
Trade names Vyndaqel
License data
Routes of
administration
Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
Chemical and physical data
Formula C14H7Cl2NO3
Molar mass 308.116 g/mol
3D model (JSmol)
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Tafamidis (trade name Vyndaqel)[1] is a drug used to delay loss of peripheral nerve function in adults with familial amyloid polyneuropathy (FAP), an orphan disease. It works by stabilizing the protein, transthyretin, which is normally made up of four strands. In people with FAP these strands separate and form clumps that harm nerves. The drug was approved by the European Medicines Agency in 2011, rejected by the US FDA in 2012, and approved in Japan in 2013.

Medical use[edit]

Tafamidis is used to delay impairment of peripheral nerve function in adults with familial amyloid polyneuropathy (FAP).[2][3] It is taken by mouth.[2]

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.[2]

Adverse effects[edit]

More than 10% of people in clinical trials had one or more of urinary tract infections, vaginal infections, upper abdominal pain, or diarrhea.[2]

Interactions[edit]

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.[2]

Pharmacology[edit]

Tafamidis functions as a 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.[3] In people with FAP, the individual monomers fall away from the tetomer, misfold, and aggregate; the aggregates harm nerves.[3]

The maximum plasma concentration is achieved around 2 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.[2]

Chemistry[edit]

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.[4]

History[edit]

The laboratory of Jeffery W. Kelly began looking for ways to inhibit TTR fibril formation in the 1990s.[5]:210 Tafamidis was eventually discovered by Kelly's team using a structure-based drug design strategy; the chemical structure was first published in 2003.[6][7] In 2003 Kelly co-founded a company called FoldRx with Susan Lindquist of MIT and the Whitehead Institute[7][8] and FoldRx developed tafamidis up through submitting an application for marketing approval in Europe in early 2010.[6] FoldRx was acquired by Pfizer later that year.[6]

During its development tafamidis was called Fx-1006A, FX1006A, PF-06291826, and PF-6291826.[1]

Tafamidis was approved by the European Medicines Agency in November 2011 to delay peripheral nerve impairment in adults with transthyretin-related hereditary amyloidosis.[3] The FDA rejected the application for marketing approval in the US 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.[9] The drug was approved in Japan in 2013; regulators there made the approval dependent on further clinical trials showing better evidence of efficacy.[10]

As of 2018 Pfizer had continued running clinical trials in order to obtain FDA approval.[11]

References[edit]

  1. ^ a b "Tafamidis meglumine - Pfizer". AdisInsight. Retrieved 2 April 2018. 
  2. ^ a b c d e f "Vyndaqel 20 mg soft capsules - Summary of Product Characteristics". Electronic Medicines Compendium. Retrieved 2 April 2018. 
  3. ^ a b c d Said, G; Grippon, S; Kirkpatrick, P (1 March 2012). "Tafamidis". Nature Reviews. Drug Discovery. 11 (3): 185–6. doi:10.1038/nrd3675. PMID 22378262. 
  4. ^ "Assessment report: Vyndaqel tafamidis meglumine Procedure No.: EMEA/H/C/002294" (PDF). EMA. 2011.  See EMA index page for updates.
  5. ^ 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. Orphan Drugs and Rare Diseases. RSC Drug Discovery Series No. 38. Royal Society of Chemistry. ISBN 978-1-84973-806-4. 
  6. ^ a b c Jones, Dan (29 October 2010). "Modifying protein misfolding". Nature Reviews Drug Discovery. 9 (11): 825–827. doi:10.1038/nrd3316. 
  7. ^ a b Borman, Stu (25 January 2010). "Attacking Amyloids". Chemical & Engineering News. 88 (4): 30–32. doi:10.1021/cen-v088n004.p030. 
  8. ^ 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. 
  9. ^ Grogan, Kevin (19 June 2012). "FDA rejects Pfizer rare disease drug tafamidis". Pharma Times. 
  10. ^ "Report on the Deliberation Results" (PDF). Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau Ministry of Health, Labour and Welfare. September 2, 2013. 
  11. ^ Al Idrus, Amirah (March 29, 2018). "With Pfizer's 'pipeline surprise,' there's a new kid on the ATTR block". FierceBiotech.