Ataluren Explained

Verifiedfields:changed
Watchedfields:changed
Tradename:Translarna
Routes Of Administration:By mouth
Atc Prefix:M09
Atc Suffix:AX03
Legal Uk:POM
Legal Eu:Rx-only
Cas Number:775304-57-9
Pubchem:11219835
Iuphar Ligand:7341
Drugbank:DB05016
Chemspiderid:9394889
Unii:K16AME9I3V
Kegg:D09323
Chebi:94805
Chembl:256997
Synonyms:PTC124
Iupac Name:3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
C:15
H:9
F:1
N:2
O:3
Smiles:Fc3ccccc3c1nc(no1)c2cc(ccc2)C(=O)O
Stdinchi:1S/C15H9FN2O3/c16-12-7-2-1-6-11(12)14-17-13(18-21-14)9-4-3-5-10(8-9)15(19)20/h1-8H,(H,19,20)
Stdinchikey:OOUGLTULBSNHNF-UHFFFAOYSA-N

Ataluren, sold under the brand name Translarna, is a medication for the treatment of Duchenne muscular dystrophy. It was designed by PTC Therapeutics.

Medical use

Ataluren is used in the European Union to treat people with Duchenne muscular dystrophy who have a nonsense mutation in the dystrophin gene, can walk, and are more than five years old.[1]

Contraindications

People who are pregnant or breast feeding should not take ataluren.[1]

Adverse effects

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.[1]

Interactions

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.[1]

Pharmacology

While a large number of studies failed to identify the biological target of ataluren,[2] [3] [4] it was discovered to bind and stabilize firefly luciferase, thus explaining the mechanism by which it created a false positive effect on the read through assay.[5] [6]

Ataluren is thought to make ribosomes less sensitive to premature stop codons (an effect 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.[7] 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.[8] 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."[9]

Chemistry

Ataluren is an oxadiazole; its chemical name is 3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid.

History

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.[10] The team used phenotypic screening of a chemical library to identify compounds that increased the amount of protein expressed by mutated genes, and then optimized one of the hits in the screen to create this drug.[11] [12] [13] As with the results of many cell-based screens, the biological target of ataluren is not known.[14]

Phase I clinical trials started in 2004.[15]

In 2010, PTC Therapeutics released preliminary results of its phase IIb 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.[16]

In May 2014, ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA)[17] and received market authorization from the European Commission to treat people with nonsense mutation Duchenne muscular dystrophy in August 2014;[18] 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 Union countries.[19]

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.[20]

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.[21]

In March 2017, PTC terminated development of ataluren for cystic fibrosis due to lack of efficacy in the phase III trials.[22] [23] [24]

Society and culture

Legal status

In June 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency recommended not renewing the conditional marketing authorization for Translarna, a medicine for treating people with Duchenne muscular dystrophy.[25] [26] [27]

Notes and References

  1. Web site: Translarna - Summary of Product Characteristics. UK Electronic Medicines Compendium. 18 June 2017. 24 April 2017. 15 July 2017. https://web.archive.org/web/20170715082409/http://www.medicines.org.uk/emc/medicine/33294. live.
  2. Karijolich J, Yu YT . Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review) . International Journal of Molecular Medicine . 34 . 2 . 355–362 . August 2014 . 24939317 . 4094583 . 10.3892/ijmm.2014.1809 .
  3. News: Devitt L . Researchers question 'read-through' mechanism of muscular dystrophy drug ataluren : Spoonful of Medicine. Nature Medicine: Spoonful of Medicine. 25 June 2013. 18 June 2017. 16 May 2017. https://web.archive.org/web/20170516092514/http://blogs.nature.com/spoonful/2013/06/researchers-question-read-through-mechanism-of-muscular-dystrophy-drug-ataluren.html. live.
  4. Schmitz A, Famulok M . Chemical biology: ignore the nonsense . Nature . 447 . 7140 . 42–43 . May 2007 . 17450128 . 10.1038/nature05715 . 29789135 . free . 2007Natur.447...42S .
  5. Auld DS, Thorne N, Maguire WF, Inglese J . Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression . Proceedings of the National Academy of Sciences of the United States of America . 106 . 9 . 3585–3590 . March 2009 . 19208811 . 2638738 . 10.1073/pnas.0813345106 . free . 2009PNAS..106.3585A .
  6. Auld DS, Lovell S, Thorne N, Lea WA, Maloney DJ, Shen M, Rai G, Battaile KP, Thomas CJ, Simeonov A, Hanzlik RP, Inglese J . Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124 . Proceedings of the National Academy of Sciences of the United States of America . 107 . 11 . 4878–4883 . March 2010 . 20194791 . 2841876 . 10.1073/pnas.0909141107 . 4 November 2018 . live . free . 2010PNAS..107.4878A . https://web.archive.org/web/20230823040400/https://kuscholarworks.ku.edu/bitstream/handle/1808/8633/1.%20Auld%20et%20al_PNAS_combined100108%20copy.pdf?sequence=1 . 23 August 2023 .
  7. 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 . 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 . 44 . 12508–12513 . November 2016 . 27702906 . 5098639 . 10.1073/pnas.1605336113 . free . 2016PNAS..11312508R .
  8. Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM . 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 . 2064–2069 . February 2008 . 18272502 . 2538881 . 10.1073/pnas.0711795105 . free . 2008PNAS..105.2064D .
  9. 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 . 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 . January 2015 . 25497400 . 10.1016/j.nmd.2014.11.011 . 41468577 .
  10. News: 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. 10 July 2007. 18 June 2017. 23 August 2023. https://web.archive.org/web/20230823041012/https://www.evaluate.com/. live.
  11. News: Press Release: Questions Raised About Process Used to Identify Experimental Drug for Genetic Disease. NIH via Drug Discovery & Development. 3 February 2009. 18 June 2017. 7 October 2017. https://web.archive.org/web/20171007120009/https://www.dddmag.com/news/2009/02/questions-raised-about-process-used-identify-experimental-drug-genetic-disease. live.
  12. Roberts RG . A read-through drug put through its paces . PLOS Biology . 11 . 6 . e1001458 . 25 June 2013 . 23824301 . 3692443 . 10.1371/journal.pbio.1001458 . free .
  13. 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 . PTC124 targets genetic disorders caused by nonsense mutations . Nature . 447 . 7140 . 87–91 . May 2007 . 17450125 . 10.1038/nature05756 . 4423529 . 2007Natur.447...87W .
  14. Book: Pace A, Buscemi S, Piccionello AP, Pibiri I . Scriven EF, Ramsden CA . Advances in Heterocyclic Chemistry. 2015. Academic Press. 978-0-12-802874-2. 127. 3. Recent Advances in the Chemistry of 1,2,4-Oxadiazoles.
  15. PTC Therapeutics, Inc. Initiates Phase 2 Study Of PTC124 In Duchenne Muscular Dystrophy . BioSpace . 27 January 2006 . 22 August 2023.
  16. PTC Therapeutics, Inc. and Genzyme Corporation Announce Preliminary Results from the Phase 2b Clinical Trial of Ataluren; Primary Endpoint Does Not Reach Statistical Significance within Duration of Study . BioSpace . 3 March 2010 . 22 August 2023.
  17. Web site: PTC Therapeutics Receives Positive Opinion from CHMP for Translarna (ataluren). MarketWatch. 30 May 2019. 30 May 2019. https://web.archive.org/web/20190530010018/https://www.marketwatch.com/press-release/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23. live.
  18. Web site: Translarna EPAR . European Medicines Agency (EMA) . 17 September 2018 . 29 September 2020 . 29 October 2020 . https://web.archive.org/web/20201029153952/https://www.ema.europa.eu/en/medicines/human/EPAR/translarna . live .
  19. Web site: PTC Therapeutics Announces Launch of Translarna (ataluren) in Germany. MarketWatch. 3 December 2014. 27 December 2014. 27 December 2014. https://web.archive.org/web/20141227081609/http://www.marketwatch.com/story/ptc-therapeutics-announces-launch-of-translarnatm-ataluren-in-germany-2014-12-03. live.
  20. News: Pagliarulo. Ned. FDA snubs PTC appeal for Duchenne drug. BioPharma Dive. 17 October 2016. 18 June 2017. 28 January 2017. https://web.archive.org/web/20170128093923/http://www.biopharmadive.com/news/fda-snubs-ptc-appeal-for-duchenne-drug/428417/. live.
  21. Web site: NHS England successfully negotiates access to new drug treatment for children with duchenne muscular dystrophy. NHS England .
  22. News: Drug Company Ends Ataluren Program for CF Nonsense Mutations. Cystic Fibrosis Foundation. 3 March 2017.
  23. DeFrancesco L . Drug pipeline: 1Q17 . Nature Biotechnology . 35 . 5 . 400 . May 2017 . 28486449 . 10.1038/nbt.3874 . 205284732 . free .
  24. Aslam AA, Sinha IP, Southern KW . Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis . The Cochrane Database of Systematic Reviews . 2023 . 3 . CD012040 . March 2023 . 36866921 . 9983356 . 10.1002/14651858.CD012040.pub3 .
  25. Web site: EMA recommends non-renewal of authorisation of Duchenne muscular dystrophy medicine Translarna . European Medicines Agency . 15 September 2023 . 29 June 2024.
  26. Web site: EMA recommends non-renewal of authorisation of Duchenne muscular dystrophy medicine Translarna . European Medicines Agency . 28 June 2024 . 29 June 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  27. Web site: Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 24-27 June 2024 . European Medicines Agency . 28 June 2024 . 12 July 2024 . 12 July 2024 . https://web.archive.org/web/20240712152232/https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-24-27-june-2024 . live .

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