Ataluren

Ataluren
Names
IUPAC name
3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
Other names
PTC124
Identifiers
775304-57-9 N
3D model (Jmol) Interactive image
ChEMBL ChEMBL256997 YesY
ChemSpider 9394889 YesY
ECHA InfoCard 100.132.097
7341
KEGG D09323 YesY
PubChem 11219835
UNII K16AME9I3V YesY
Properties
C15H9FN2O3
Molar mass 284.24 g/mol
Pharmacology
M09AX03 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

Ataluren, formerly known as PTC124, is a pharmaceutical drug for the treatment of Duchenne muscular dystrophy, Cystic Fibrosis, and potentially other genetic disorders involving prematurely truncated proteins. It was designed by PTC Therapeutics and is sold under the trade name Translarna in the European Union.

Medical uses

Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,[1][2] such as some people with cystic fibrosis and Duchenne muscular dystrophy. It is approved for the use in Duchenne in the European Union.

Mechanism of action

Ataluren makes ribosomes less sensitive to premature stop codons (referred to as "read-through") by promoting insertion of certain near-cognate tRNA at the site of nonsense codons with no apparent effects on downstream transcription, mRNA processing, stability of the mRNA or the resultant protein, thereby making a functional protein similar to the non-mutated endogenous product.[3] Ataluren incorporates amino acids Gln, Lys, and Tyr at UAA and UAG codons and of Trp, Arg, and Cys at UGA codons; interestingly, the moderate read-through of Ataluren is observed only at premature termination signals, but not at the normal termination signal of the full-length protein.[3] This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. Studies have demonstrated that PTC124/Ataluren treatment increases expression of full-length dystrophin protein in human and mouse primary muscle cells containing the premature stop codon mutation for Duchenne muscular dystrophy and rescues striated muscle function.[1] Studies in mice with the premature stop codon mutation for cystic fibrosis demonstrated increased CFTR protein production and function.[4] Extending on this work, a mechanistic study with yeast and human cells has elucidated the details of Ataluren-mediated nonstandard codon-anticodon base pairings which result in specific amino acid substitutions at specific codon positions in the CFTR protein.[3] The European Medicines Agency review on the approval of ataluren concluded that "the non-clinical data available were considered sufficient to support the proposed mechanism of action and to alleviate earlier concerns on the selectivity of ataluren for premature stop codons." [5]

In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.[6] Ataluren appears to be most effective for the stop codon 'UGA'.[1]

History

Clinical trials

In 2010, PTC Therapeutics released preliminary results of its phase 2b clinical trial for Duchenne muscular dystrophy, with participants not showing a significant improvement in the six minute walk distance after the 48 weeks of the trial.[7] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug.

Phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.[8][9] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.[10]

Approval

On 23 May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA).[11] Translarna was first available in Germany, the first EU country to launch the new medicine. It has since become available across France, Italy, Denmark, Spain and a number of other European countries. [12]

In August 2014, ataluren received market authorization from the European Commission to treat patients with nonsense mutation Duchenne muscular dystrophy. A confirmatory phase III clinical trial is ongoing.[12] The drug does not yet have approval by the US Food and Drug Administration.

In February 2016, FDA declined to approve or even discuss PTC Therapeutics application for ataluren because it deemed the data presented by the developer "insufficient to warrant a review".[13]

In July 2016, NHS England agreed a Managed Access Agreement (MAA) for Translarna providing reimbursed patient access to Translarna in England via a five-year MAA. This followed a positive recommendation from the National Institute for Health and Care Excellence (NICE) in April 2016, subject to PTC and NHS England finalizing the terms of the MAA. NICE issued its final guidance later in July with implementation of the MAA for patients following within two months. [14]

In November 2016, PTC Therapeutics announced it had achieved agreement on pricing and reimbursement terms in both Sweden and Romania, as well as an agreement on terms with AIFA, the Italian Medicines Agency, for commercial access for Italian patients including for those on reimbursed early access. [15]

See also

References

  1. 1 2 3 Welch EM, Barton ER, Zhuo J, Tomizawa Y, Friesen WJ, Trifillis P, et al. (May 2007). "PTC124 targets genetic disorders caused by nonsense mutations". Nature. 447 (7140): 87–91. Bibcode:2007Natur.447...87W. doi:10.1038/nature05756. PMID 17450125.
  2. ↑ Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (April 2007). "Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers". Journal of Clinical Pharmacology. 47 (4): 430–44. doi:10.1177/0091270006297140. PMID 17389552.
  3. 1 2 3 Roy B, Friesen, WJ, Tomizawa Y, Leszyk JD, Zhuo J, Johnson B, Dakka J, Trotta CR, Xue X, Mutyam V, Keeling KM, Mobley JA, Rowe SM, Bedwell DM, Welch EM, Jacobson A (October 2016). "Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression". Proceedings of the National Academy of Sciences of the United States of America. doi:10.1073/pnas.1605336113.
  4. ↑ Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM (February 2008). "PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model". Proceedings of the National Academy of Sciences of the United States of America. 105 (6): 2064–9. doi:10.1073/pnas.0711795105. PMID 18272502.
  5. ↑ Haas M, Vlcek V, Balabanov P, Salmonson T, Bakchine S, Markey G, Weise M, Schlosser-Weber G, Brohmann H, Yerro CP, Mendizabal MR, Stoyanova-Beninska V, Hillege HL (January 2015). "European Medicines Agency review of ataluren for the treatment of ambulant patients aged 5 years and older with Duchenne muscular dystrophy resulting from a nonsense mutation in the dystrophin gene". Neuromuscular Disorders. 25 (1): 5–13. doi:10.1016/j.nmd.2014.11.011. PMID 25497400.
  6. ↑ Wilschanski M (February 2013). "Novel therapeutic approaches for cystic fibrosis". Discovery Medicine. 15 (81): 127–33. PMID 23449115.
  7. ↑ "PTC Therapeutics and Genzyme Corporation announce preliminary results from the phase 2b clinical trial of ataluren for nonsense mutation Duchenne/Becker muscular dystrophy (NASDAQ:PTCT)". Ptct.client.shareholder.com. Retrieved 2013-11-28.
  8. ↑ Wilschanski M, Miller LL, Shoseyov D, Blau H, Rivlin J, Aviram M, Cohen M, Armoni S, Yaakov Y, Pugatsch T, Pugatch T, Cohen-Cymberknoh M, Miller NL, Reha A, Northcutt VJ, Hirawat S, Donnelly K, Elfring GL, Ajayi T, Kerem E (July 2011). "Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis". The European Respiratory Journal. 38 (1): 59–69. doi:10.1183/09031936.00120910. PMID 21233271.
  9. ↑ Sermet-Gaudelus I, Boeck KD, Casimir GJ, Vermeulen F, Leal T, Mogenet A, Roussel D, Fritsch J, Hanssens L, Hirawat S, Miller NL, Constantine S, Reha A, Ajayi T, Elfring GL, Miller LL (November 2010). "Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis". American Journal of Respiratory and Critical Care Medicine. 182 (10): 1262–72. doi:10.1164/rccm.201001-0137OC. PMID 20622033.
  10. ↑ "PTC Therapeutics Completes Enrollment of Phase 3 Trial of Ataluren in Patients with Cystic Fibrosis (NASDAQ:PTCT)". Ptct.client.shareholder.com. 2010-12-21. Retrieved 2013-11-28.
  11. ↑ http://www.marketwatch.com/story/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23
  12. 1 2 "PTC Therapeutics Announces Launch of Translarna™ (ataluren) in Germany". marketwatch.com. 3 Dec 2014. Retrieved 27 Dec 2014.
  13. ↑ http://uk.reuters.com/article/us-ptc-therapeutics-fda-idUKKCN0VW1FG
  14. ↑ http://www.england.nhs.uk/2016/07/drug-treatment/
  15. ↑ http://seekingalpha.com/article/4018622-ptc-therapeutics-ptct-ceo-stuart-peltz-q3-2016-results-earnings-call-transcript

External links

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