Phase 2a Study of Ataluren-Mediated Dystrophin Production in Patients with Nonsense Mutation Duchenne Muscular Dystrophy

Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, lead...

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Published inPloS one Vol. 8; no. 12; p. e81302
Main Authors Finkel, Richard S., Flanigan, Kevin M., Wong, Brenda, Bönnemann, Carsten, Sampson, Jacinda, Sweeney, H. Lee, Reha, Allen, Northcutt, Valerie J., Elfring, Gary, Barth, Jay, Peltz, Stuart W.
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 11.12.2013
Public Library of Science (PLoS)
Subjects
Analysis
Biopsy
Child
Clinical trials
Codon, Nonsense - genetics
Codons
Drug dosages
Drug therapy
Duchenne muscular dystrophy
Duchenne's muscular dystrophy
Dystrophin
Dystrophin - metabolism
Dystrophy
Genetic aspects
Hospitals
Humans
Kinases
Male
Medicine
mRNA
Muscles
Muscular dystrophy
Muscular Dystrophy, Duchenne - drug therapy
Muscular Dystrophy, Duchenne - metabolism
Mutation
Nonsense mutation
Oxadiazoles - therapeutic use
Proteins
Qualitative analysis
Quantitative analysis
Rodents
Spectrin
Stop codon
Utrophin
New York
Ohio
United States > US
New Jersey
Utah
Pennsylvania
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Summary:Approximately 13% of boys with Duchenne muscular dystrophy (DMD) have a nonsense mutation in the dystrophin gene, resulting in a premature stop codon in the corresponding mRNA and failure to generate a functional protein. Ataluren (PTC124) enables ribosomal readthrough of premature stop codons, leading to production of full-length, functional proteins. This Phase 2a open-label, sequential dose-ranging trial recruited 38 boys with nonsense mutation DMD. The first cohort (n = 6) received ataluren three times per day at morning, midday, and evening doses of 4, 4, and 8 mg/kg; the second cohort (n = 20) was dosed at 10, 10, 20 mg/kg; and the third cohort (n = 12) was dosed at 20, 20, 40 mg/kg. Treatment duration was 28 days. Change in full-length dystrophin expression, as assessed by immunostaining in pre- and post-treatment muscle biopsy specimens, was the primary endpoint. Twenty three of 38 (61%) subjects demonstrated increases in post-treatment dystrophin expression in a quantitative analysis assessing the ratio of dystrophin/spectrin. A qualitative analysis also showed positive changes in dystrophin expression. Expression was not associated with nonsense mutation type or exon location. Ataluren trough plasma concentrations active in the mdx mouse model were consistently achieved at the mid- and high- dose levels in participants. Ataluren was generally well tolerated. Ataluren showed activity and safety in this short-term study, supporting evaluation of ataluren 10, 10, 20 mg/kg and 20, 20, 40 mg/kg in a Phase 2b, double-blind, long-term study in nonsense mutation DMD. ClinicalTrials.gov NCT00264888.
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Conceived and designed the experiments: RSF KMF BW CB VJN GE SWP. Performed the experiments: RSF KMF BW CB HLS JS. Analyzed the data: RSF KMF BW CB VJN GE SWP AR JB HLS. Contributed reagents/materials/analysis tools: CB HLS. Wrote the paper: RSF KMF BW CB VJN GE SWP AR JB. Performed analysis and interpretation of in vitro dystrophin expression data: HLS. Performed analysis and interpretation of in vivo dystrophin expression data: CB.
Competing Interests: AR, VJN, GE, JB, and SWP are employees of PTC Therapeutics, Inc. and hold financial interests in the company. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. The following authors work on this study resulted in institutional compensation as a grant awarded to PTC Therapeutics: BW, KMF, RSF, HLS, CB, and JS, PTC employee authors and the PTC Study Group. BW was compensated for travel to meetings for the study. BW and KMF received a consulting fee or honorarium associated with this study. CB’s institution, the Children’s Hospital of Philadelphia, received a consulting fee or honorarium for laboratory supplies and technician time. Regarding financial activities conducted outside of the study presented in this manuscript, the following authors have received compensation for consultancy, or grant for their institution: KMF, RSF, HLS, and JS. HLS also received from various entities, compensation not associated with the submitted work for board membership, royalties, various travel accommodations and meeting expenses. All other authors do not have a relationship with a commercial entity that has an interest in the subject of this manuscript other than the study sponsor.
Current address: National Institute of Neurological Disorders and Stroke/NIH Porter Neuroscience Research Center, Bethesda, Maryland, United States of America
Current address: Nationwide Children’s Hospital, Columbus, Ohio, United States of America
Current address: Columbia University, New York, New York, United States of America
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0081302