3D model (JSmol)
|Molar mass||284.24 g/mol|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|what is ?)(|
Ataluren, formerly known as PTC124, is a pharmaceutical drug for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics and is sold under the trade name Translarna in the European Union.
People who are pregnant or breast feeding should not take ataluren.
More than 10% of people taking ataluren in clinical trials experienced vomiting; more than 5% experienced diarrhea, nausea, headache, upper abdominal pain, and flatulence; between 1% and 5% of people experienced decreased appetite and weight loss, high levels of triglycerides, high blood pressure, cough, nosebleeds, abdominal discomfort, constipation, rashes, pain in their arms, legs, and chest muscles, blood in their urine, urinary incontinence, and fever.
Aminoglycosides should not be given to someone taking ataluren, as they interfere with its mechanism of action. Caution should be used with drugs that induce UGT1A9, or that are substrates of OAT1, OAT3, or OATP1B3.
Ataluren is thought to make 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. It seems to work particularly well for the stop codon 'UGA'.
Studies have demonstrated that 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. Studies in mice with the premature stop codon mutation for cystic fibrosis demonstrated increased CFTR protein production and function. 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.
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." 
Ataluren was discovered by scientists at PTC Therapeutics in a collaboration with Lee Sweeney's lab at the University of Pennsylvania, which was initially funded in part by Parent Project Muscular Dystrophy. The team used phenotypic screening of a chemical library to identify compounds that increased the amount of protein expressed by mutated genes, who then optimized one of the hits in the screen to create this drug. As with the results of many cell-based screens, the biological target of ataluren is not known.
Phase I clinical trials started in 2004.
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. This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug.
In May 2014 ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) and received market authorization from the European Commission to treat people with nonsense mutation Duchenne muscular dystrophy in August 2014; a confirmatory phase III clinical trial was required. By December it was on the market in Germany, France, Italy, Denmark, Spain and a number of other European countries.
In February 2016, FDA declined to accept PTC Therapeutics new drug application for ataluren, which was based on a clinical trial in which ataluren missed its primary endpoint; PTC appealed and the FDA declined again in October 2016.
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.
- Biostrophin and rimeporide, other drugs against Duchenne muscular dystrophy
- Ivacaftor and lumacaftor, other drugs against cystic fibrosis in development by Vertex Pharmaceuticals
- "Translarna - Summary of Product Characteristics". UK Electronic Medicines Compendium. 24 April 2017. Retrieved 18 June 2017.
- Karijolich, J; Yu, YT (August 2014). "Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review).". International journal of molecular medicine. 34 (2): 355–62. PMC . PMID 24939317.
- Pace, Andrea; Buscemi, Silvestre; Piccionello, Antonio Palumbo; Pibiri, Ivana (2015). "3. Recent Advances in the Chemistry of 1,2,4-Oxadiazoles". In Scriven, Eric F.V.; Ramsden, Christopher A. Advances in Heterocyclic Chemistry. Academic Press. p. 127. ISBN 9780128028742.
- Roberts, Roland G. (25 June 2013). "A Read-Through Drug Put through Its Paces". PLoS Biology. 11 (6): e1001458. doi:10.1371/journal.pbio.1001458.
- Devitt, Liz (25 June 2013). "Researchers question ‘read-through’ mechanism of muscular dystrophy drug ataluren : Spoonful of Medicine". Nature Medicine: Spoonful of Medicine.
- "Press Release: Questions Raised About Process Used to Identify Experimental Drug for Genetic Disease". NIH via Drug Discovery & Development. 3 February 2009.
- Schmitz, A; Famulok, M (3 May 2007). "Chemical biology: ignore the nonsense.". Nature. 447 (7140): 42–3. PMID 17450128. doi:10.1038/nature05715.
- 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. 113: 12508–12513. PMC . PMID 27702906. doi:10.1073/pnas.1605336113.
- Welch, EM; Barton, ER; Zhuo, J; Tomizawa, Y; Friesen, WJ; Trifillis, P; Paushkin, S; Patel, M; Trotta, CR; Hwang, S; Wilde, RG; Karp, G; Takasugi, J; Chen, G; Jones, S; Ren, H; Moon, YC; Corson, D; Turpoff, AA; Campbell, JA; Conn, MM; Khan, A; Almstead, NG; Hedrick, J; Mollin, A; Risher, N; Weetall, M; Yeh, S; Branstrom, AA; Colacino, JM; Babiak, J; Ju, WD; Hirawat, S; Northcutt, VJ; Miller, LL; Spatrick, P; He, F; Kawana, M; Feng, H; Jacobson, A; Peltz, SW; Sweeney, HL (3 May 2007). "PTC124 targets genetic disorders caused by nonsense mutations.". Nature. 447 (7140): 87–91. PMID 17450125. doi:10.1038/nature05756.
- 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. PMC . PMID 18272502. doi:10.1073/pnas.0711795105.
- 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. PMID 25497400. doi:10.1016/j.nmd.2014.11.011.
- "Press release: PTC Therapeutics Announces $15.4 Million NIH Research Grant for Duchenne Muscular Dystrophy | Evaluate". PTC, University of Pennsylvania, and the NIH via Evaluate Group. July 10, 2007.
- "Press Release: PTC Therapeutics Initiates Clinical Trials of PTC124 for Cystic Fibrosis and Duchenne Muscular Dystrophy". PTC Therapeutics, Inc via P&T Community. July 13, 2004.
- "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.
- "PTC Therapeutics Announces Launch of Translarna™ (ataluren) in Germany". marketwatch.com. 3 Dec 2014. Retrieved 27 Dec 2014.
- Pagliarulo, Ned (October 17, 2016). "FDA snubs PTC appeal for Duchenne drug". BioPharma Dive.
- "Drug Company Ends Ataluren Program for CF Nonsense Mutations". Cystic Fibrosis Foundation. March 3, 2017.
- DeFrancesco, Laura (9 May 2017). "Drug pipeline: 1Q17". Nature Biotechnology. 35 (5): 400–400. doi:10.1038/nbt.3874.
- Aslam, AA; Higgins, C; Sinha, IP; Southern, KW (19 January 2017). "Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis.". The Cochrane database of systematic reviews. 1: CD012040. PMID 28102546. doi:10.1002/14651858.CD012040.pub2.