Ataluren

Last updated

Ataluren
Ataluren.svg
Ataluren ball-and-stick model.png
Clinical data
Trade names Translarna
Other namesPTC124
AHFS/Drugs.com International Drug Names
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • UK: POM (Prescription only) [1]
  • EU:Rx-only [2]
Identifiers
  • 3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.132.097 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H9FN2O3
Molar mass 284.246 g·mol−1
3D model (JSmol)
  • Fc3ccccc3c1nc(no1)c2cc(ccc2)C(=O)O
  • InChI=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) Yes check.svgY
  • Key:OOUGLTULBSNHNF-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)

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

Contents

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, [3] [4] [5] [6] [7] [8] 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. [9] [10]

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. [11] It seems to work particularly well for the stop codon 'UGA'. [4] [12]

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. [12] Studies in mice with the premature stop codon mutation for cystic fibrosis demonstrated increased CFTR protein production and function. [13] 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. [11]

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." [14]

Chemistry

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

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. [15] 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. [7] [5] [12] As with the results of many cell-based screens, the biological target of ataluren is not known. [4]

Phase I clinical trials started in 2004. [16]

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. [17]

In May 2014, ataluren received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) [18] and received market authorization from the European Commission to treat people with nonsense mutation Duchenne muscular dystrophy in August 2014; [2] a confirmatory phase III clinical trial was required. [19] 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]

Related Research Articles

<span class="mw-page-title-main">Muscular dystrophy</span> Genetic disorder

Muscular dystrophies (MD) are a genetically and clinically heterogeneous group of rare neuromuscular diseases that cause progressive weakness and breakdown of skeletal muscles over time. The disorders differ as to which muscles are primarily affected, the degree of weakness, how fast they worsen, and when symptoms begin. Some types are also associated with problems in other organs.

<span class="mw-page-title-main">Cystic fibrosis</span> Medical condition

Cystic fibrosis (CF) is a genetic disorder inherited in an autosomal recessive manner that impairs the normal clearance of mucus from the lungs, which facilitates the colonization and infection of the lungs by bacteria, notably Staphylococcus aureus. CF is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. The hallmark feature of CF is the accumulation of thick mucus in different organs. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. Other signs and symptoms may include sinus infections, poor growth, fatty stool, clubbing of the fingers and toes, and infertility in most males. Different people may have different degrees of symptoms.

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. Nonsense mutations are not always harmful; the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. As nonsense mutations leads to premature termination of polypeptide chains; they are also called chain termination mutations.

<span class="mw-page-title-main">Dystrophin</span> Rod-shaped cytoplasmic protein

Dystrophin is a rod-shaped cytoplasmic protein, and a vital part of a protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane. This complex is variously known as the costamere or the dystrophin-associated protein complex (DAPC). Many muscle proteins, such as α-dystrobrevin, syncoilin, synemin, sarcoglycan, dystroglycan, and sarcospan, colocalize with dystrophin at the costamere. It has a molecular weight of 427 kDa

<span class="mw-page-title-main">Duchenne muscular dystrophy</span> Type of muscular dystrophy

Duchenne muscular dystrophy (DMD) is a severe type of muscular dystrophy predominantly affecting boys. The onset of muscle weakness typically begins around age four, with rapid progression. Initially, muscle loss occurs in the thighs and pelvis, extending to the arms, which can lead to difficulties in standing up. By the age of 12, most individuals with Duchenne muscular dystrophy are unable to walk. Affected muscles may appear larger due to an increase in fat content, and scoliosis is common. Some individuals may experience intellectual disability, and females carrying a single copy of the mutated gene may show mild symptoms.

<span class="mw-page-title-main">Becker muscular dystrophy</span> Genetic muscle disorder

Becker muscular dystrophy (BMD) is an X-linked recessive inherited disorder characterized by slowly progressing muscle weakness of the legs and pelvis. It is a type of dystrophinopathy. The cause is mutations and deletions in any of the 79 exons encoding the large dystrophin protein, essential for maintaining the muscle fiber's cell membrane integrity. Becker muscular dystrophy is related to Duchenne muscular dystrophy in that both result from a mutation in the dystrophin gene, however the hallmark of Becker is milder in-frame deletions. and hence has a milder course, with patients maintaining ambulation till 50–60 years if detected early.

Antisense therapy is a form of treatment that uses antisense oligonucleotides (ASOs) to target messenger RNA (mRNA). ASOs are capable of altering mRNA expression through a variety of mechanisms, including ribonuclease H mediated decay of the pre-mRNA, direct steric blockage, and exon content modulation through splicing site binding on pre-mRNA. Several ASOs have been approved in the United States, the European Union, and elsewhere.

<span class="mw-page-title-main">Cystic fibrosis transmembrane conductance regulator</span> Mammalian protein found in humans

Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.

The dystrophin-associated protein complex, also known as the dystrophin-associated glycoprotein complex is a multiprotein complex that includes dystrophin and the dystrophin-associated proteins. It is one of the two protein complexes that make up the costamere in striated muscle cells. The other complex is the integrin-vinculin-talin complex.

<span class="mw-page-title-main">PTC Therapeutics</span> Pharmaceutical company

PTC Therapeutics is a US pharmaceutical company focused on the development of orally administered small molecule drugs and gene therapy which regulate gene expression by targeting post-transcriptional control (PTC) mechanisms in orphan diseases.

In molecular biology, exon skipping is a form of RNA splicing used to cause cells to “skip” over faulty or misaligned sections (exons) of genetic code, leading to a truncated but still functional protein despite the genetic mutation.

<span class="mw-page-title-main">Eteplirsen</span> Medication

Eteplirsen is a medication to treat, but not cure, some types of Duchenne muscular dystrophy (DMD), caused by a specific mutation. Eteplirsen only targets specific mutations and can be used to treat about 14% of DMD cases. Eteplirsen is a form of antisense therapy.

<span class="mw-page-title-main">Ezutromid</span> Chemical compound

Ezutromid is an orally administered small molecule utrophin modulator involved in a Phase 2 clinical trial produced by Summit Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). DMD is a fatal x-linked recessive disease affecting approximately 1 in 5000 males and is a designated orphan disease by the FDA and European Medicines Agency. Approximately 1/3 of the children obtain DMD as a result of spontaneous mutation in the dystrophin gene and have no family history of the disease. Dystrophin is a vital component of mature muscle function, and therefore DMD patients have multifarious forms of defunct or deficient dystrophin proteins that all manifest symptomatically as muscle necrosis and eventually organ failure. Ezutromid is theorized to maintain utrophin, a protein functionally and structurally similar to dystrophin that precedes and is replaced by dystrophin during development. Utrophin and dystrophin are reciprocally expressed, and are found in different locations in a mature muscle cell. However, in dystrophin-deficient patients, utrophin was found to be upregulated and is theorized to replace dystrophin in order to maintain muscle fibers. Ezutromid is projected to have the potential to treat all patients suffering with DMD as it maintains the production of utrophin to counteract the lack of dystrophin to retard muscle degeneration. Both the FDA and European Medicines Agency has given ezutromid an orphan drug designation. The FDA Office of Orphan Products and Development offers an Orphan Drug Designation program (ODD) that allows drugs aimed to treat diseases that affect less than 200,000 people in the U.S. monetary incentives such as a period of market exclusivity, tax incentives, and expedited approval processes.

H. Lee Sweeney is an American scientist who studies muscle.

Elexacaftor/tezacaftor/ivacaftor, sold under the brand names Trikafta and Kaftrio, is a fixed-dose combination medication used to treat cystic fibrosis. Elexacaftor/tezacaftor/ivacaftor is composed of a combination of ivacaftor, a chloride channel opener, and elexacaftor and tezacaftor, CFTR modulators.

Viltolarsen, sold under the brand name Viltepso, is a medication used for the treatment of Duchenne muscular dystrophy (DMD). Viltolarsen is a Morpholino antisense oligonucleotide.

Batsheva Kerem is an Israeli geneticist who was on the research team that identified and cloned the CFTR gene, which when mutated, is responsible for causing cystic fibrosis (CF). She later established the Israel National Center for CF Genetic Research. She discovered the most prevalent cystic fibrosis-causing mutations among the Israeli population, allowing for the establishment of nationwide genetic screening programs to identify carriers of these mutations and enabling prenatal diagnoses. She researches how some CF mutations prevent CFTR protein production by causing nonsense-mediated decay and abnormal mRNA splicing, and how therapies might be able to counteract those problems. She also studies the role of genetic instability in cancer. She is currently a professor at the Hebrew University.

Casimersen, sold under the brand name Amondys 45, is an antisense oligonucleotide medication used for the treatment of Duchenne muscular dystrophy (DMD) in people who have a confirmed mutation of the dystrophin gene that is amenable to exon 45 skipping. It is an antisense oligonucleotide of phosphorodiamidate morpholino oligomer (PMO). Duchenne muscular dystrophy is a rare disease that primarily affects boys. It is caused by low levels of a muscle protein called dystrophin. The lack of dystrophin causes progressive muscle weakness and premature death.

Delandistrogene moxeparvovec, sold under the brand name Elevidys, is a recombinant gene therapy used for the treatment of Duchenne muscular dystrophy. It is designed to deliver into the body a gene that leads to production of Elevidys micro-dystrophin that contains selected domains of the dystrophin protein present in normal muscle cells. It is an adeno-associated virus vector-based gene therapy that is given by injection into a vein.

Stephen Donald Wilton, also known as Steve Wilton, is an Australian molecular biologist and academic, serving as the Foundation Professor of Molecular Therapy at Murdoch University and adjunct professor at the University of Western Australia (UWA). He also fulfills dual roles as a Director at the Perron Institute for Neurological and Translational Science and deputy director at Murdoch's Centre for Molecular Medicine and Innovative Therapeutics (CMMIT).

References

  1. 1 2 3 4 5 "Translarna - Summary of Product Characteristics". UK Electronic Medicines Compendium. 24 April 2017. Archived from the original on 15 July 2017. Retrieved 18 June 2017.
  2. 1 2 "Translarna EPAR". European Medicines Agency (EMA). 17 September 2018. Archived from the original on 29 October 2020. Retrieved 29 September 2020.
  3. ↑ Karijolich J, Yu YT (August 2014). "Therapeutic suppression of premature termination codons: mechanisms and clinical considerations (review)". International Journal of Molecular Medicine. 34 (2): 355–362. doi:10.3892/ijmm.2014.1809. PMC   4094583 . PMID   24939317.
  4. 1 2 3 4 Pace A, Buscemi S, Piccionello AP, Pibiri I (2015). Scriven EF, Ramsden CA (eds.). 3. Recent Advances in the Chemistry of 1,2,4-Oxadiazoles. Advances in Heterocyclic Chemistry. Academic Press. p. 127. ISBN   978-0-12-802874-2.
  5. 1 2 Roberts RG (25 June 2013). "A read-through drug put through its paces". PLOS Biology. 11 (6): e1001458. doi: 10.1371/journal.pbio.1001458 . PMC   3692443 . PMID   23824301.
  6. ↑ Devitt L (25 June 2013). "Researchers question 'read-through' mechanism of muscular dystrophy drug ataluren : Spoonful of Medicine". Nature Medicine: Spoonful of Medicine. Archived from the original on 16 May 2017. Retrieved 18 June 2017.
  7. 1 2 "Press Release: Questions Raised About Process Used to Identify Experimental Drug for Genetic Disease". NIH via Drug Discovery & Development. 3 February 2009. Archived from the original on 7 October 2017. Retrieved 18 June 2017.
  8. ↑ Schmitz A, Famulok M (May 2007). "Chemical biology: ignore the nonsense". Nature. 447 (7140): 42–43. Bibcode:2007Natur.447...42S. doi: 10.1038/nature05715 . PMID   17450128. S2CID   29789135.
  9. ↑ Auld DS, Thorne N, Maguire WF, Inglese J (March 2009). "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. Bibcode:2009PNAS..106.3585A. doi: 10.1073/pnas.0813345106 . PMC   2638738 . PMID   19208811.
  10. ↑ Auld DS, Lovell S, Thorne N, Lea WA, Maloney DJ, Shen M, et al. (March 2010). "Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124" (PDF). Proceedings of the National Academy of Sciences of the United States of America. 107 (11): 4878–4883. Bibcode:2010PNAS..107.4878A. doi: 10.1073/pnas.0909141107 . PMC   2841876 . PMID   20194791. Archived (PDF) from the original on 23 August 2023. Retrieved 4 November 2018.
  11. 1 2 Roy B, Friesen WJ, Tomizawa Y, Leszyk JD, Zhuo J, Johnson B, et al. (November 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 (44): 12508–12513. Bibcode:2016PNAS..11312508R. doi: 10.1073/pnas.1605336113 . PMC   5098639 . PMID   27702906.
  12. 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. S2CID   4423529.
  13. ↑ 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): 2064–2069. Bibcode:2008PNAS..105.2064D. doi: 10.1073/pnas.0711795105 . PMC   2538881 . PMID   18272502.
  14. ↑ Haas M, Vlcek V, Balabanov P, Salmonson T, Bakchine S, Markey G, et al. (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. S2CID   41468577.
  15. ↑ "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. Archived from the original on 23 August 2023. Retrieved 18 June 2017.
  16. ↑ "PTC Therapeutics, Inc. Initiates Phase 2 Study Of PTC124 In Duchenne Muscular Dystrophy". BioSpace (Press release). 27 January 2006. Retrieved 22 August 2023.
  17. ↑ "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 (Press release). 3 March 2010. Retrieved 22 August 2023.
  18. ↑ "PTC Therapeutics Receives Positive Opinion from CHMP for Translarna (ataluren)". MarketWatch. Archived from the original on 30 May 2019. Retrieved 30 May 2019.
  19. 1 2 "PTC Therapeutics Announces Launch of Translarna (ataluren) in Germany". MarketWatch. 3 December 2014. Archived from the original on 27 December 2014. Retrieved 27 December 2014.
  20. ↑ Pagliarulo N (17 October 2016). "FDA snubs PTC appeal for Duchenne drug". BioPharma Dive. Archived from the original on 28 January 2017. Retrieved 18 June 2017.
  21. ↑ "NHS England successfully negotiates access to new drug treatment for children with duchenne muscular dystrophy". NHS England.
  22. ↑ "Drug Company Ends Ataluren Program for CF Nonsense Mutations". Cystic Fibrosis Foundation. 3 March 2017.
  23. ↑ DeFrancesco L (May 2017). "Drug pipeline: 1Q17". Nature Biotechnology. 35 (5): 400. doi: 10.1038/nbt.3874 . PMID   28486449. S2CID   205284732.
  24. ↑ Aslam AA, Sinha IP, Southern KW (March 2023). "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. doi:10.1002/14651858.CD012040.pub3. PMC   9983356 . PMID   36866921.
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