Tafamidis

Jump to navigation Jump to search
Tafamidis
Clinical data
Trade namesVyndaqel
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC14H7Cl2NO3
Molar mass308.116 g/mol
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

WikiDoc Resources for Tafamidis

Articles

Most recent articles on Tafamidis

Most cited articles on Tafamidis

Review articles on Tafamidis

Articles on Tafamidis in N Eng J Med, Lancet, BMJ

Media

Powerpoint slides on Tafamidis

Images of Tafamidis

Photos of Tafamidis

Podcasts & MP3s on Tafamidis

Videos on Tafamidis

Evidence Based Medicine

Cochrane Collaboration on Tafamidis

Bandolier on Tafamidis

TRIP on Tafamidis

Clinical Trials

Ongoing Trials on Tafamidis at Clinical Trials.gov

Trial results on Tafamidis

Clinical Trials on Tafamidis at Google

Guidelines / Policies / Govt

US National Guidelines Clearinghouse on Tafamidis

NICE Guidance on Tafamidis

NHS PRODIGY Guidance

FDA on Tafamidis

CDC on Tafamidis

Books

Books on Tafamidis

News

Tafamidis in the news

Be alerted to news on Tafamidis

News trends on Tafamidis

Commentary

Blogs on Tafamidis

Definitions

Definitions of Tafamidis

Patient Resources / Community

Patient resources on Tafamidis

Discussion groups on Tafamidis

Patient Handouts on Tafamidis

Directions to Hospitals Treating Tafamidis

Risk calculators and risk factors for Tafamidis

Healthcare Provider Resources

Symptoms of Tafamidis

Causes & Risk Factors for Tafamidis

Diagnostic studies for Tafamidis

Treatment of Tafamidis

Continuing Medical Education (CME)

CME Programs on Tafamidis

International

Tafamidis en Espanol

Tafamidis en Francais

Business

Tafamidis in the Marketplace

Patents on Tafamidis

Experimental / Informatics

List of terms related to Tafamidis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

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 12 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 Kelly co-founded with Susan Lindquist. FoldRx was led by Richard Labaudiniere when it 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 (ClinicalTrials.gov identifier: NCT01994889).

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). Tafamidis is also approved for use in Argentina and Mexico by the relevant authorities. 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 efficacy evaluable population (n=87) and were just missed in the intent to treat population (n=125), apparently because more patients than expected in the intent to treat population were selected for liver transplantation during the course of the trial, not owing to treatment failure, but because their name rose to the top of the transplant list. However, these patients were classified as treatment failures in the conservative analysis used.

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. ↑ Clinical trial number NCT00409175 for "Safety and Efficacy Study of Fx-1006A in Patients With Familial Amyloidosis" at ClinicalTrials.gov
  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. ↑ 7.0 7.1 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.
  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.

Template:Other nervous system drugs

Retrieved from "https://www.wikidoc.org/index.php?title=Tafamidis&oldid=1086569"