Ataluren treatment of patients with nonsense mutation dystrophinopathy

Authors

Katharine Bushby, University of Newcastle upon Tyne, Faculty of Medical Sciences
Richard Finkel, The Children's Hospital of Philadelphia
Brenda Wong, Cincinnati Children's Hospital Medical Center
Richard Barohn, University of Kansas Medical Center
Craig Campbell, Western UniversityFollow
Giacomo P. Comi, Università degli Studi di Milano
Anne M. Connolly, Washington University School of Medicine in St. Louis
John W. Day, University of Minnesota Twin Cities

Document Type

Article

Publication Date

10-1-2014

Journal

Muscle and Nerve

Volume

50

Issue

4

First Page

477

Last Page

487

URL with Digital Object Identifier

10.1002/mus.24332

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.