Tafamidis

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Tafamidis
Systematic (IUPAC) name
2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
Clinical data
Trade namesVyndaqel
Pregnancy cat. ?
Legal status Prescription only
RoutesOral
Identifiers
CAS number594839-88-0 N
ATC codeN07XX08
PubChemCID 11001318
UNII8FG9H9D31J YesY
Chemical data
FormulaC14H7Cl2NO3 
Mol. mass308.116 g/mol
 N (what is this?)  (verify)
 
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Tafamidis
Systematic (IUPAC) name
2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid
Clinical data
Trade namesVyndaqel
Pregnancy cat. ?
Legal status Prescription only
RoutesOral
Identifiers
CAS number594839-88-0 N
ATC codeN07XX08
PubChemCID 11001318
UNII8FG9H9D31J YesY
Chemical data
FormulaC14H7Cl2NO3 
Mol. mass308.116 g/mol
 N (what is this?)  (verify)

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.[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.

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.

Regulatory Process

Tafamidis was approved for use in the European Union in November 2011. Tafamidis 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 4-13 to reject drug the drug, stating there was little data supporting drug efficacy. The drug did not prevent neurologic deterioration or improve neurologic functional scores (both primary outcomes). However, the committee voted 13-4 that the existing data supported a secondary endpoint of reducing the number of patients who chose liver transplantation. The FDA requested a second clinical trial, which is likely to be completed in early 2014.[17]

References

  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. ^ http://www.businesswire.com/news/home/20111117005505/en/Pfizer%E2%80%99s-Vyndaqel%C2%AE-tafamidis-Therapy-Approved-European-Union
  5. ^ ClinicalTrials.gov 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. ^ Massachusetts General Hospital: Origami Medicine
  8. ^ Andrade, C. (1952). A peculiar form of peripheral neuropathy; familiar atypical generalized amyloidosis with special involvement of the peripheral nerves. Brain : a journal of neurology 75, 408-427.
  9. ^ Coelho, T. (1996). Familial amyloid polyneuropathy: new developments in genetics and treatment. Current Opinion in Neurology 9, 355-359.
  10. ^ Razavi, H.; Palaninathan, S.K. Powers, E.T.; Wiseman, R.L.; Purkey, H.E.; Mohamadmohaideen, N.N.; Deechongkit, S.; Chiang, K.P.; Dendle, M.T.A.; Sacchettini, J.C.; Kelly, J.W. "Benzoxazoles as Transthyretin Amyloid Fibril Inhibitors: Synthesis, Evaluation and Mechanism of Action" Angew. Chem. Int. Ed. 2003, 42, 2758-2761.
  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.
  14. ^ Sousa, M.M., Cardoso, I., Fernandes, R., Guimaraes, A., and Saraiva, M.J. (2001). Deposition of transthyretin in early stages of familial amyloidotic polyneuropathy: evidence for toxicity of nonfibrillar aggregates. The American Journal of Pathology 159, 1993-2000.
  15. ^ Colon, W., and Kelly, J.W. (1992). Partial denaturation of transthyretin is sufficient for amyloid fibril formation in vitro. Biochemistry 31, 8654-8660.
  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.
  17. ^ http://www.bioworld.com/content/fda-delivers-crl-pfizers-rare-disease-drug-vyndaqel-0