Ataluren

{{Short description|Duchenne muscular dystrophy medication}} {{Use dmy dates|date=August 2023}} {{cs1 config |name-list-style=vanc |display-authors=6}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = | image = Ataluren.svg | image_class = skin-invert-image | width = | alt = | image2 = Ataluren ball-and-stick model.png | image_class2 = bg-transparent | width2 = | alt2 = | caption =

<!-- Clinical data --> | pronounce = | tradename = Translarna | Drugs.com = {{drugs.com|international|ataluren}} | MedlinePlus = | DailyMedID = <!-- DailyMed may use generic or brand name (generic name preferred) --> | pregnancy_AU = <!-- A / B1 / B2 / B3 / C / D / X --> | pregnancy_AU_comment = | pregnancy_category= | routes_of_administration = By mouth | class = | ATC_prefix = M09 | ATC_suffix = AX03 | ATC_supplemental =

<!-- Legal status --> | legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled --> | legal_AU_comment = | legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F --> | legal_BR_comment = | legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII --> | legal_CA_comment = | legal_DE = <!-- Anlage I, II, III or Unscheduled --> | legal_DE_comment = | legal_NZ = <!-- Class A, B, C --> | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = <ref name=UKlabel /> | legal_US = <!-- OTC / Rx-only / Schedule I, II, III, IV, V --> | legal_US_comment = | legal_EU = Rx-only | legal_EU_comment = <ref name="Translarna EPAR" /> | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV --> | legal_UN_comment = | legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data --> | bioavailability = | protein_bound = | metabolism = | metabolites = | onset = | elimination_half-life = | duration_of_action = | excretion =

<!-- Identifiers --> | CAS_number_Ref = {{cascite|changed}} | CAS_number = 775304-57-9 | CAS_supplemental = | PubChem = 11219835 | IUPHAR_ligand = 7341 | DrugBank_Ref = | DrugBank = DB05016 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 9394889 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = K16AME9I3V | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D09323 | ChEBI_Ref = | ChEBI = 94805 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 256997 | NIAID_ChemDB = | PDB_ligand = | synonyms = PTC124

<!-- Chemical and physical data --> | 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_Ref = {{stdinchicite|correct|chemspider}} | 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) | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = OOUGLTULBSNHNF-UHFFFAOYSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''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.<ref name=UKlabel>{{cite web|title=Translarna - Summary of Product Characteristics|url=https://www.medicines.org.uk/emc/medicine/33294|publisher=UK Electronic Medicines Compendium|access-date=18 June 2017|date=24 April 2017|archive-date=15 July 2017|archive-url=https://web.archive.org/web/20170715082409/http://www.medicines.org.uk/emc/medicine/33294|url-status=live}}</ref>

==Contraindications== People who are pregnant or breast feeding should not take ataluren.<ref name=UKlabel/>

==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.<ref name=UKlabel/>

== 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.<ref name=UKlabel/>

==Pharmacology== While a large number of studies failed to identify the biological target of ataluren,<ref>{{cite journal | vauthors = Karijolich J, Yu YT | title = Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review) | journal = International Journal of Molecular Medicine | volume = 34 | issue = 2 | pages = 355–362 | date = August 2014 | pmid = 24939317 | pmc = 4094583 | doi = 10.3892/ijmm.2014.1809 }}</ref><ref name=Pace/><ref name=Roberts/><ref>{{cite news| vauthors = Devitt L |title=Researchers question 'read-through' mechanism of muscular dystrophy drug ataluren: Spoonful of Medicine|url=http://blogs.nature.com/spoonful/2013/06/researchers-question-read-through-mechanism-of-muscular-dystrophy-drug-ataluren.html|work=Nature Medicine: Spoonful of Medicine|date=25 June 2013|access-date=18 June 2017|archive-date=16 May 2017|archive-url=https://web.archive.org/web/20170516092514/http://blogs.nature.com/spoonful/2013/06/researchers-question-read-through-mechanism-of-muscular-dystrophy-drug-ataluren.html|url-status=live}}</ref><ref name=NIH2009/><ref>{{cite journal | vauthors = Schmitz A, Famulok M | title = Chemical biology: ignore the nonsense | journal = Nature | volume = 447 | issue = 7140 | pages = 42–43 | date = May 2007 | pmid = 17450128 | doi = 10.1038/nature05715 | s2cid = 29789135 | doi-access = free | bibcode = 2007Natur.447...42S }}</ref> 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.<ref>{{cite journal | vauthors = Auld DS, Thorne N, Maguire WF, Inglese J | title = Mechanism of PTC124 activity in cell-based luciferase assays of nonsense codon suppression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 9 | pages = 3585–3590 | date = March 2009 | pmid = 19208811 | pmc = 2638738 | doi = 10.1073/pnas.0813345106 | doi-access = free | bibcode = 2009PNAS..106.3585A }}</ref><ref>{{cite journal | vauthors = Auld DS, Lovell S, Thorne N, Lea WA, Maloney DJ, Shen M, Rai G, Battaile KP, Thomas CJ, Simeonov A, Hanzlik RP, Inglese J | title = Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124 | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 11 | pages = 4878–4883 | date = March 2010 | pmid = 20194791 | pmc = 2841876 | doi = 10.1073/pnas.0909141107 | url = https://kuscholarworks.ku.edu/bitstream/1808/8633/1/1.%20Auld%20et%20al_PNAS_combined100108%20copy.pdf | access-date = 4 November 2018 | url-status = live | doi-access = free | bibcode = 2010PNAS..107.4878A | archive-url = https://web.archive.org/web/20230823040400/https://kuscholarworks.ku.edu/bitstream/handle/1808/8633/1.%20Auld%20et%20al_PNAS_combined100108%20copy.pdf?sequence=1 | archive-date = 23 August 2023 }}</ref>

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.<ref name=Roy_2016>{{cite journal | vauthors = 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 | title = Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 44 | pages = 12508–12513 | date = November 2016 | pmid = 27702906 | pmc = 5098639 | doi = 10.1073/pnas.1605336113 | doi-access = free | bibcode = 2016PNAS..11312508R }}</ref> It seems to work particularly well for the stop codon 'UGA'.<ref name=Pace/><ref name=Welch_2007/>

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.<ref name=Welch_2007/> Studies in mice with the premature stop codon mutation for cystic fibrosis demonstrated increased CFTR protein production and function.<ref>{{cite journal | vauthors = Du M, Liu X, Welch EM, Hirawat S, Peltz SW, Bedwell DM | title = PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 105 | issue = 6 | pages = 2064–2069 | date = February 2008 | pmid = 18272502 | pmc = 2538881 | doi = 10.1073/pnas.0711795105 | doi-access = free | bibcode = 2008PNAS..105.2064D }}</ref> 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.<ref name="Roy_2016" />

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."<ref>{{cite journal | vauthors = 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 | title = 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 | journal = Neuromuscular Disorders | volume = 25 | issue = 1 | pages = 5–13 | date = January 2015 | pmid = 25497400 | doi = 10.1016/j.nmd.2014.11.011 | s2cid = 41468577 }}</ref>

==Chemistry== Ataluren is an oxadiazole; its chemical name is 3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid.<ref name=Pace/>

==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.<ref>{{cite news|title=Press release: PTC Therapeutics Announces $15.4 Million NIH Research Grant for Duchenne Muscular Dystrophy {{!}} Evaluate|url=http://www.evaluategroup.com/Universal/View.aspx?type=Story&id=132834|work=PTC, University of Pennsylvania, and the NIH via Evaluate Group|date=10 July 2007|access-date=18 June 2017|archive-date=23 August 2023|archive-url=https://web.archive.org/web/20230823041012/https://www.evaluate.com/|url-status=live}}</ref> 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.<ref name=NIH2009>{{cite news|title=Press Release: Questions Raised About Process Used to Identify Experimental Drug for Genetic Disease|url=https://www.dddmag.com/news/2009/02/questions-raised-about-process-used-identify-experimental-drug-genetic-disease|work=NIH via Drug Discovery & Development|date=3 February 2009|access-date=18 June 2017|archive-date=7 October 2017|archive-url=https://web.archive.org/web/20171007120009/https://www.dddmag.com/news/2009/02/questions-raised-about-process-used-identify-experimental-drug-genetic-disease|url-status=live}}</ref><ref name=Roberts>{{cite journal | vauthors = Roberts RG | title = A read-through drug put through its paces | journal = PLOS Biology | volume = 11 | issue = 6 | article-number = e1001458 | date = 25 June 2013 | pmid = 23824301 | pmc = 3692443 | doi = 10.1371/journal.pbio.1001458 | doi-access = free }}</ref><ref name=Welch_2007>{{cite journal | vauthors = 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 | title = PTC124 targets genetic disorders caused by nonsense mutations | journal = Nature | volume = 447 | issue = 7140 | pages = 87–91 | date = May 2007 | pmid = 17450125 | doi = 10.1038/nature05756 | s2cid = 4423529 | bibcode = 2007Natur.447...87W }}</ref> As with the results of many cell-based screens, the biological target of ataluren is not known.<ref name=Pace>{{cite book | vauthors = Pace A, Buscemi S, Piccionello AP, Pibiri I | veditors = Scriven EF, Ramsden CA |series=Advances in Heterocyclic Chemistry|date=2015|publisher=Academic Press|isbn=978-0-12-802874-2|page=127|url=https://books.google.com/books?id=hViZBQAAQBAJ&pg=PA127|title=3. Recent Advances in the Chemistry of 1,2,4-Oxadiazoles}}</ref>

Phase I clinical trials started in 2004.<ref>{{cite press release | title=PTC Therapeutics, Inc. Initiates Phase 2 Study Of PTC124 In Duchenne Muscular Dystrophy | website=BioSpace | date=27 January 2006 | url=https://www.biospace.com/article/ptc-therapeutics-inc-initiates-phase-2-study-of-ptc124-in-duchenne-muscular-dystrophy-/ | access-date=22 August 2023 | archive-date=23 August 2023 | archive-url=https://web.archive.org/web/20230823040253/https://www.biospace.com/article/ptc-therapeutics-inc-initiates-phase-2-study-of-ptc124-in-duchenne-muscular-dystrophy-/ }}</ref>

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.<ref>{{cite press release | title=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 | website=BioSpace | date=3 March 2010 | url=https://www.biospace.com/article/ptc-therapeutics-inc-and-genzyme-corporation-announce-preliminary-results-from-the-phase-2b-clinical-trial-of-ataluren-primary-endpoint-does-not-re/ | access-date=22 August 2023 | archive-date=24 August 2023 | archive-url=https://web.archive.org/web/20230824002534/https://www.biospace.com/article/ptc-therapeutics-inc-and-genzyme-corporation-announce-preliminary-results-from-the-phase-2b-clinical-trial-of-ataluren-primary-endpoint-does-not-re/ }}</ref>

In May 2014, ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA)<ref>{{cite web|url=https://www.marketwatch.com/press-release/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23|title=PTC Therapeutics Receives Positive Opinion from CHMP for Translarna (ataluren)|website=MarketWatch|access-date=30 May 2019|archive-date=30 May 2019|archive-url=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|url-status=live}}</ref> and received market authorization from the European Commission to treat people with nonsense mutation Duchenne muscular dystrophy in August 2014;<ref name="Translarna EPAR">{{cite web | title=Translarna EPAR | website=European Medicines Agency (EMA) | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/translarna | access-date=29 September 2020 | archive-date=29 October 2020 | archive-url=https://web.archive.org/web/20201029153952/https://www.ema.europa.eu/en/medicines/human/EPAR/translarna | url-status=live }}</ref> a confirmatory phase III clinical trial was required.<ref name="market"/> By December it was on the market in Germany, France, Italy, Denmark, Spain and a number of other European Union countries.<ref name="market">{{cite web| url= http://www.marketwatch.com/story/ptc-therapeutics-announces-launch-of-translarnatm-ataluren-in-germany-2014-12-03| website= MarketWatch| title= PTC Therapeutics Announces Launch of Translarna (ataluren) in Germany| date= 3 December 2014| access-date= 27 December 2014| archive-date= 27 December 2014| archive-url= https://web.archive.org/web/20141227081609/http://www.marketwatch.com/story/ptc-therapeutics-announces-launch-of-translarnatm-ataluren-in-germany-2014-12-03| url-status= live}}</ref>

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.<ref>{{cite news|last1=Pagliarulo|first1=Ned|title=FDA snubs PTC appeal for Duchenne drug|url=http://www.biopharmadive.com/news/fda-snubs-ptc-appeal-for-duchenne-drug/428417/|work=BioPharma Dive|date=17 October 2016|access-date=18 June 2017|archive-date=28 January 2017|archive-url=https://web.archive.org/web/20170128093923/http://www.biopharmadive.com/news/fda-snubs-ptc-appeal-for-duchenne-drug/428417/|url-status=live}}</ref>

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.<ref>{{cite web|url=https://www.england.nhs.uk/2016/07/drug-treatment/|title=NHS England successfully negotiates access to new drug treatment for children with duchenne muscular dystrophy|website=NHS England |date=7 July 2016 }}</ref>

In March 2017, PTC terminated development of ataluren for cystic fibrosis due to lack of efficacy in the phase III trials.<ref>{{cite news|title=Drug Company Ends Ataluren Program for CF Nonsense Mutations|url=https://www.cff.org/News/News-Archive/2017/Drug-Company-Ends-Ataluren-Program-for-CF-Nonsense-Mutations/|work=Cystic Fibrosis Foundation|date=3 March 2017}}</ref><ref>{{cite journal | vauthors = DeFrancesco L | title = Drug pipeline: 1Q17 | journal = Nature Biotechnology | volume = 35 | issue = 5 | page = 400 | date = May 2017 | pmid = 28486449 | doi = 10.1038/nbt.3874 | s2cid = 205284732 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Aslam AA, Sinha IP, Southern KW | title = Ataluren and similar compounds (specific therapies for premature termination codon class I mutations) for cystic fibrosis | journal = The Cochrane Database of Systematic Reviews | volume = 2023 | issue = 3 | article-number = CD012040 | date = March 2023 | pmid = 36866921 | pmc = 9983356 | doi = 10.1002/14651858.CD012040.pub3 }}</ref>

== Society and culture ==

=== Legal status === In June 2024, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency recommended not renewing the conditional marketing authorization for Translarna, a medicine for treating people with Duchenne muscular dystrophy.<ref>{{cite web | title=EMA recommends non-renewal of authorization of Duchenne muscular dystrophy medicine Translarna | website=European Medicines Agency (EMA) | date=15 September 2023 | url=https://www.ema.europa.eu/en/news/ema-recommends-non-renewal-authorisation-duchenne-muscular-dystrophy-medicine-translarna | access-date=29 June 2024}}</ref><ref>{{cite web | title=EMA recommends non-renewal of authorization of Duchenne muscular dystrophy medicine Translarna | website=European Medicines Agency (EMA) | date=28 June 2024 | url=https://www.ema.europa.eu/en/news/ema-recommends-non-renewal-authorisation-duchenne-muscular-dystrophy-medicine-translarna-0 | access-date=29 June 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref><ref>{{cite web | title=Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 24-27 June 2024 | website=European Medicines Agency (EMA) | date=28 June 2024 | url=https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-24-27-june-2024 | access-date=12 July 2024 | archive-date=12 July 2024 | archive-url=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 | url-status=live }}</ref><ref>{{cite web | title=Translarna: EMA re-confirms non-renewal of authorization of Duchenne muscular dystrophy medicine | website=European Medicines Agency (EMA) | date=18 October 2024 | url=https://www.ema.europa.eu/en/news/translarna-ema-re-confirms-non-renewal-authorisation-duchenne-muscular-dystrophy-medicine | access-date=19 October 2024}}</ref> In October 2024, the CHMP confirmed its recommendation to not renew the conditional marketing authorization for Translarna.<ref>{{cite web | title=Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 14-17 October 2024 | website=European Medicines Agency (EMA) | date=18 October 2024 | url=https://www.ema.europa.eu/en/news/meeting-highlights-committee-medicinal-products-human-use-chmp-14-17-october-2024 | access-date=21 October 2024}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

== References == {{reflist}}

{{Other drugs for disorders of the musculo-skeletal system}} {{Portal bar | Medicine}} {{Authority control}}

Category:Benzoic acids Category:Cystic fibrosis Category:Oxadiazoles Category:Orphan drugs Category:Muscle protectors Category:2-Fluorophenyl compounds