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PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF)

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ATALUREN

PTC 124

3-[5-(2-Fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid

 

 MF C15H9FN2O3
Molecular Weight 284.24
CAS Registry Number 775304-57-9

PTC Therapeutics Initiates Confirmatory Phase 3 Clinical Trial of Translarna™ (ataluren) in Patients with Nonsense Mutation Cystic Fibrosis (nmCF) – MarketWatch

SOUTH PLAINFIELD, N.J., June 30, 2014 /PRNewswire/ — PTC Therapeutics, Inc. /quotes/zigman/16944148/delayed/quotes/nls/ptct PTCT -0.01% today announced the initiation of a global confirmatory Phase 3 clinical trial of Translarna™ (ataluren), an investigational new drug, in patients with nonsense mutation cystic fibrosis (nmCF). Nonsense mutations within cystic fibrosis are categorized as Class I mutations, a severe form of CF that results in little or no production of the CFTR protein. The Phase 3 confirmatory trial is referred to as ACT CF (ataluren confirmatory trial in cystic fibrosis) and the primary endpoint is lung function as measured by relative change in percent predicted forced expiratory volume in one second, or FEV1.read at

http://www.marketwatch.com/story/ptc-therapeutics-initiates-confirmatory-phase-3-clinical-trial-of-translarna-ataluren-in-patients-with-nonsense-mutation-cystic-fibrosis-nmcf-2014-06-30?reflink=MW_news_stmp

 

Ataluren, formerly known as PTC124, is a small-molecular agent designed by PTC Therapeutics and sold under the trade nameTranslarna. It makes ribosomes less sensitive to premature stop codons (referred to as “read-through”). This may be beneficial in diseases such as Duchenne muscular dystrophy where the mRNA contains a mutation causing premature stop codons or nonsense codons. There is ongoing debate over whether Ataluren is truly a functional drug (inducing codon read-through), or if it is nonfunctional, and the result was a false-positive hit from a biochemical screen based on luciferase.[1]

Ataluren has been tested on healthy humans and humans carrying genetic disorders caused by nonsense mutations,[2][3] such as some people with cystic fibrosis and Duchenne muscular dystrophy. 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.[4] This failure resulted in the termination of a $100 million deal with Genzyme to pursue the drug. However, other phase 2 clinical trials were successful for cystic fibrosis in Israel, France and Belgium.[5] Multicountry phase 3 clinical trials are currently in progress for cystic fibrosis in Europe and the USA.[6]

In cystic fibrosis, early studies of ataluren show that it improves nasal potential difference.[7]

Ataluren appears to be most effective for the stop codon ‘UGA’.[2]

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).[8]

It is not that ataluren is a complex molecule. To judge from one of the patents, synthesis is straightforward starting from 2-cyanobenoic acid and 2-fluorobenzoyl chloride, both commercially available. The synthetic steps are methylation of 2-cyanobenoic acid (iodomethane), nitrile hydrolysis with hydroxylamine, esterification with the fluoro acid chloride using DIPEA, high-temperature dehydration to the oxadiazole and finally ester hydrolysis (NaOH).

 

 

References

  1. Derek (2013-09-18). “The Arguing Over PTC124 and Duchenne Muscular Dystrophy. In the Pipeline:”. Pipeline.corante.com. Retrieved 2013-11-28.
  2.  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 (May 2007). “PTC124 targets genetic disorders caused by nonsense mutations”. Nature 447 (7140): 87–91.doi:10.1038/nature05756PMID 17450125.
  3.  Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL (Apr 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): 430–444. doi:10.1177/0091270006297140PMID 17389552.
  4.  “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.
  5.  Wilschanski, M.; Miller, L. L.; Shoseyov, D.; Blau, H.; Rivlin, J.; Aviram, M.; Cohen, M.; Armoni, S.; Yaakov, Y.; Pugatsch, T.; Cohen-Cymberknoh, M.; Miller, N. L.; Reha, A.; Northcutt, V. J.; Hirawat, S.; Donnelly, K.; Elfring, G. L.; Ajayi, T.; Kerem, E. (2011). “Chronic ataluren (PTC124) treatment of nonsense mutation cystic fibrosis”. European Respiratory Journal 38 (1): 59–69. doi:10.1183/09031936.00120910PMID 21233271. edit Sermet-Gaudelus, I.; Boeck, K. D.; Casimir, G. J.; Vermeulen, F.; Leal, T.; Mogenet, A.; Roussel, D.; Fritsch, J.; Hanssens, L.; Hirawat, S.; Miller, N. L.; Constantine, S.; Reha, A.; Ajayi, T.; Elfring, G. L.; Miller, L. L. (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): 1262–1272.doi:10.1164/rccm.201001-0137OCPMID 20622033. edit
  6.  “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.
  7.  Wilschanski, M. (2013). “Novel therapeutic approaches for cystic fibrosis”. Discovery medicine 15 (81): 127–133. PMID 23449115. edit
  8.  http://www.marketwatch.com/story/ptc-therapeutics-receives-positive-opinion-from-chmp-for-translarna-ataluren-2014-05-23

External links

 

other sources

rINN: Ataluren
Other Names
PTC124®, 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid
Pharmacological Information
Pharmacology Images

Ataluren Molecule

Ataluren.png
Web information on Ataluren
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature

Orphan drug under investigation for treatment of genetic conditions where nonsense mutations result in premature termination of polypeptides. This drug, which is convenient to deliver orally, appears to allow ribosomal transcription ofRNA to continue past premature termination codon mutations with correct reading of the full normal transcript which then terminates at the proper stop codon. Problematically it has been postulated that assay artifact may have complicated evaluation of its efficacy which appears to be less than gentamicin.[1] Faults of this class in the transcription process are involved in several inherited diseases.

Some forms of cystic fibrosis and Duchenne muscular dystrophy are being targeted in the development stage of the drug.[2] Phase I and II trials are promising for cystic fibrosis.[3][4] In a mouse model of Duchenne muscular dystrophy, restoration of muscle function occurred.[5]

A potential issue is that there may be parts of the human genome whose optimal gene function through evolution has resulted from relatively recent in evolutionary terms insertion of a premature termination codon and so functional suboptimal transcripts of other proteins or functional RNAs might result.

References

  1.  Roberts RG. A read-through drug put through its paces. PLoS biology. 2013; 11(6):e1001458.(Link to article – subscription may be required.)
  2.  Hirawat S, Welch EM, Elfring GL, Northcutt VJ, Paushkin S, Hwang S, Leonard EM, Almstead NG, Ju W, Peltz SW, Miller LL. 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. 2007 Apr; 47(4):430-44.(Link to article– subscription may be required.)
  3.  Kerem E, Hirawat S, Armoni S, Yaakov Y, Shoseyov D, Cohen M, Nissim-Rafinia M, Blau H, Rivlin J, Aviram M, Elfring GL, Northcutt VJ, Miller LL, Kerem B, Wilschanski M. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet. 2008 Aug 30; 372(9640):719-27.(Link to article – subscription may be required.)
  4.  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. 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. 2010 Nov 15; 182(10):1262-72.(Link to article – subscription may be required.)
  5.  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. 2007 May 3; 447(7140):87-91.(Link to article – subscription may be required.)

old cut paste

A large-scale, multinational, phase 3 trial of the experimental drug ataluren has opened its first trial site, in Cincinnati, Ohio.

The trial is recruiting boys with Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by anonsense mutation —  also known as a premature stop codon — in the dystrophin gene. This type of mutation causes cells to stop synthesizing a protein before the process is complete, resulting in a short, nonfunctional protein. Nonsense mutations are believed to cause DMD or BMD in approximately 10 to 15 percent of boys with these disorders.

Ataluren — sometimes referred to as a stop codon read-through drug — has the potential to overcome the effects of a nonsense mutation and allow functional dystrophin — the muscle protein that’s missing in Duchenne MD and deficient in Becker MD — to be produced.

The orally delivered drug is being developed by PTC Therapeutics, a South Plainfield, N.J., biotechnology company, to whichMDA gave a $1.5 million grant in 2005.

PTC124 has been developed by PTC Therapeutics.


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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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