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Title: Tafamidis  
Author: World Heritage Encyclopedia
Language: English
Subject: Transthyretin-related hereditary amyloidosis, ATC code N07, Chemical chaperone, Familial amyloid neuropathy, Xaliproden
Collection: Drugs Acting on the Nervous System, Orphan Drugs
Publisher: World Heritage Encyclopedia


Systematic (IUPAC) name
2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
Clinical data
Trade names Vyndaqel
Legal status
  • Prescription only
Routes Oral
CAS number  N
ATC code N07
ChemSpider  N
Chemical data
Formula C14H7Cl2NO3 
Mol. mass 308.116 g/mol

Tafamidis (INN, or Fx-1006A,[1] trade name Vyndaqel) is a drug for the amelioration of transthyretin-related hereditary amyloidosis (also familial amyloid polyneuropathy, or FAP), a rare but deadly neurodegenerative disease.[2][3] The drug was approved by the European Medicines Agency in November 2011 and by the Japanese Pharmaceuticals and Medical Devices Agency in September 2013.[4]

The marketed drug, a meglumine salt, has completed an 18 month placebo controlled phase II/III clinical trial,[5][6] and an 18 month extension study which provides evidence that tafamidis slows progression of Familial amyloid polyneuropathy.[7] Tafamidis (20 mg once daily) is used in adult patients with an early stage (stage 1) of familial amyloidotic polyneuropathy.[8][9]

Tafamidis was discovered in the Jeffery W. Kelly Laboratory at The Scripps Research Institute[10] using a structure-based drug design strategy[11] and was developed at FoldRx pharmaceuticals, a biotechnology company led by Richard Labaudiniere that was acquired by Pfizer in 2010.

Tafamidis functions by kinetic stabilization of the correctly folded tetrameric form of the transthyretin (TTR) protein.[12] In patients with FAP, this protein dissociates in a process that is rate limiting for aggregation including amyloid fibril formation, causing failure of the autonomic nervous system and/or the peripheral nervous system (neurodegeneration) initially and later failure of the heart. Kinetic Stabilization of tetrameric transthyretin in familial amyloid polyneuropathy patients provides the first pharmacologic evidence that the process of amyloid fibril formation causes this disease, as treatment with tafamidis dramatically slows the process of amyloid fibril formation and the degeneration of post-mitotic tissue. Sixty % of the patients enrolled in the initial clinical trial have the same or an improved neurologic impairment score after six years of taking tafamidis, whereas 30% of the patients progress at a rate ≤ 1/5 of that predicted by the natural history. Importantly, all of the V30M FAP patients remain stage 1 patients after 6 years on tafamidis out of four stages of disease progression. {Data presented orally by Professor Coelho in Brazil in 2013][7]

The process of wild type transthyretin amyloidogenesis also appears to cause senile systemic amyloidosis leading to cardiomyopathy as the prominent phenotype [13] Some mutants of transthyretin, including V122I primarily found in individuals of African descent, are destabilizing enabling heterotetramer dissociation, monomer misfolding, and subsequent misassembly of transthyretin into a variety of aggregate structures [14] including amyloid fibrils[15] leading to familial amyloid cardiomyopathy.[16] While there is clinical evidence from a small number of patients that tafamidis slows the progression of the transthyretin cardiomyopathies, this has yet to be demonstrated in a placebo controlled clinical trial. Pfizer is currently enrolling a placebo-controlled clinical trial to evaluate the ability of tafamidis to slow the progression of familial amyloid cardiomyopathy (mutant and wild type TTR aggregation) and senile systemic amyloidosis, a cardiomyopathy caused by the aggregation of wild type TTR.

Regulatory Process

Tafamidis was approved for use in Europe by the European Medicines Agency in November 2011, specifically for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). In September 2013 Tafamidis was approved for use in Japan by the Pharmaceuticals and Medical Devices Agency, specifically for the treatment of transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP (all mutations). It is currently being considered for approval by the United States Food and Drug Administration (FDA) for the treatment of early stage transthyretin-related hereditary amyloidosis or familial amyloid polyneuropathy or FAP.

In June 2012, the FDA Peripheral and Central Nervous System Drugs Advisory Committee voted “yes” (13-4 favorable vote) when asked if the findings of the pivotal clinical study with tafamidis were “sufficiently robust to provide substantial evidence of efficacy for a surrogate endpoint that is reasonably likely to predict a clinical benefit”. The Advisory Committee voted "no" 4-13 to reject the drug–both primary endpoints were met in the intent to treat population and were just missed in the efficacy evaluable population, presumably because more patients than expected in the efficacy evaluable population were selected for liver transplantation during the course of the trial, not owing to treatment failure.


  1. ^ Bulawa, C.E.; Connelly, S.; DeVit, M.; Wang, L. Weigel, C.;Fleming, J. Packman, J.; Powers, E.T.; Wiseman, R.L.; Foss, T.R.; Wilson, I.A.; Kelly, J.W.; Labaudiniere, R. “Tafamidis, A Potent and Selective Transthyretin Kinetic Stabilizer That Inhibits the Amyloid Cascade” Proc. Natl. Acad. Sci. 2012 109, 9629-9634.
  2. ^ Ando, Y., and Suhr, O.B. (1998). Autonomic dysfunction in familial amyloidotic polyneuropathy (FAP). Amyloid 5, 288-300.
  3. ^ Benson, M.D. (1989). Familial Amyloidotic polyneuropathy. Trends in neurosciences 12, 88-92.
  4. ^
  5. ^ NCT00409175 Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis
  6. ^ Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Lozeron, P.; Suhr, O.B.; Campistol, J.M.; Conceiçao, I.; Schmidt, H.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Wilson, A.; Grogan, D.R. “Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial” Neurology 2012, 79, 785-792.
  7. ^ a b Coelho, T.; Maia, L.F.; Martins da Silva, A.; Cruz, M.W.; Planté-Bordeneuve, V.; Suhr, O.B.; Conceiçao, I.; Schmidt, H. H. J.; Trigo, P. Kelly, J.W.; Labaudiniere, R.; Chan, J., Packman, J.; Grogan, D.R. “Long-term Effects of Tafamidis for the Treatment of Transthyretin Familial Amyloid Polyneuropathy” J. Neurology 2013 260, 2802-2814.
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  9. ^ Coelho, T. (1996). Familial amyloid polyneuropathy: new developments in genetics and treatment. Current Opinion in Neurology 9, 355-359.
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  11. ^ Connelly, S., Choi, S., Johnson, S.M., Kelly, J.W., and Wilson, I.A. (2010). Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses. Current Opinion in Structural Biology 20, 54-62.
  12. ^ Hammarstrom, P.; Wiseman, R. L.; Powers, E.T.; Kelly, J.W. "Prevention of Transthyretin Amyloid Disease by Changing Protein Misfolding Energetics" Science 2003, 299, 713-716
  13. ^ Westermark, P., Sletten, K., Johansson, B., and Cornwell, G.G., 3rd (1990). Fibril in senile systemic amyloidosis is derived from normal transthyretin. Proc Natl Acad Sci U S A 87, 2843-2845.
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  16. ^ Jacobson, D.R., Pastore, R.D., Yaghoubian, R., Kane, I., Gallo, G., Buck, F.S., and Buxbaum, J.N. (1997). Variant-sequence transthyretin (isoleucine 122) in late-onset cardiac amyloidosis in black Americans. The New England Journal of Medicine 336, 466-473.
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