Ataluren treatment of patients with nonsense mutation dystrophinopathy

• Type of Material: Article
• Authors: Stephanie Wechsler, Emory University; Katharine Bushby, University of Newcastle upon Tyne; Richard Finkel, Children's Hospital of Philadelphia; Brenda Wong, Cincinnati Children's Hospital Medical Center; Richard Barohn, University of Kansas Medical Center; Craig Campbell, Western University; Giacomo P. Comi, Università degli Studi di Milano; Anne M. Connolly, Washington University in St. Louis; John W. Day, University of Minnesota Twin Cities; Kevin M. Flanigan, Ohio State University; Nathalie Goemans, University Hospital Leuven; Kristii J. Jones, Sydney Children's Hospital; Eugenio Mercuri, Università Cattolica Sacro Cuore; Ros Quinlivan, University College London; James B. Renfroe, Northwest Florida Clinical Research Group; Barry Russman, Oregon Health & Science University; Monique M. Ryan, Murdoch Children's Research Institute; Mar Tulinius, Göteborgs Universitet; Thomas Voit, Sorbonne Universite
• Language: English
• Date: 2014-10-01
• Publisher: Wiley: 12 months
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Wiley Periodicals, Inc..
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/mus.24332
• Title of Journal or Parent Work: Muscle and Nerve
• ISSN: 0148-639X
• Volume: 50
• Issue: 4
• Start Page: 477
• End Page: 487
• Grant/Funding Information: The study in Newcastle was supported by the staff of the MRC Translational Centre for neuromuscular diseases, especially Mr. Geoffrey Bell, the Muscular Dystrophy Campaign, and the TREAT-NMD network.; The Newcastle team acknowledges the support of the National Institute for Health Research through the Newcastle Clinical Research Facility and across the UK by means of the support for the Medicines for Children Research Network.; We gratefully acknowledge the support of the Clinical Translational Research Center at the Children's Hospital of Philadelphia (UL1-RR-024134).; Steven Moore was partially supported by the Iowa Wellstone MDCRC NS053672.; This study was sponsored by PTC Therapeutics, funded in part by a grant from the FDA Office of Orphan Products.
• Keywords: Muscular Dystrophy, Duchenne; Walking; Child, Preschool; Adolescent; International Cooperation; Male; orphan; Humans; nonsense mutation; genetic; Double-Blind Method; Dose-Response Relationship, Drug; Codon, Nonsense; pediatric; Prospective Studies; Dystrophin; Time Factors; Oxadiazoles; Child; Outcome Assessment, Health Care; Duchenne muscular dystrophy
• Research Categories: Biology, Neuroscience; Biology, Genetics

Abstract

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. Methods: Randomized, double-blind, placebo-controlled study; males ≥5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. Conclusions: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need.