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Duchenne muscular dystrophy (DMD) is a rare, X-linked disorder that causes severe, progressive muscle loss and early death. In ∼13% of patients, the disease is caused by a nonsense mutation (nm) in the gene for dystrophin. Ataluren is an orally delivered, investigational drug designed to promote ribosomal readthrough of premature stop codons in mRNA, leading to production of full-length, functional protein. A confirmatory Phase 3, multicenter, randomized, double-blind, placebo-controlled study has been designed to assess the efficacy and safety of ataluren 10, 10, 20mg/kg tid in patients with nmDMD. The study design reflects lessons learned from prior studies and targets a study population to best demonstrate the treatment effect over 48weeks. Key study entry criteria require that patients are male with a nonsense mutation in the dystrophin gene, between the ages of 7 and 16years, receiving a stable dose of corticosteroids, able to walk ⩾150m during the screening 6-min walk test (6MWT), and have a screening 6MWT below the protocol-specified threshold for %-predicted 6MWD. These criteria were selected based on the results of a retrospective subgroup analysis of patients in the Phase 2b trial of ataluren in nmDMD meeting these criteria, in which the difference between the 10, 10, 20mg/kg dose of ataluren (n =30) vs placebo (n =31) in mean change in 6MWD over 48weeks was ∼50m. In the planned study, 220 patients will be randomized in a 1:1 ratio to either placebo or ataluren. The primary outcome measure is the 6MWT. Secondary measures include: timed function tests, quality of life, North Star Ambulatory Assessment, patient/parent-reported activities of daily living, safety, compliance to study drug, and ataluren exposure of ataluren in blood. This study will be the largest clinical trial of an investigational drug in DMD and is designed to confirm the treatment effect of ataluren seen in the Phase 2b ataluren trial. [Copyright &y& Elsevier]

Duchenne muscular dystrophy (DMD) subjects >5years with nonsense mutations were followed for 48weeks in a multicenter, randomized, double-blind, placebo-controlled trial of ataluren. Placebo arm data (N =57) provide insight into the natural history of the 6-min walk test (6MWT) and other endpoints. Eligibility criteria included nonsense-mediated severe dystrophinopathy, males⩾5years, and ambulatory (defined as ability to walk >75m on the 6MWT). A total of 57 males (70% of whom were treated with glucocorticoids) were randomized to orally receive placebo treatment and followed for 48weeks. Evaluations performed every 6weeks included the 6-min walk distance (6MWD), timed function tests (TFTs), and quantitative strength using hand-held myometry. Natural history (placebo treated) data on 57 males over 48eeks showed decline in mean scores and mean change scores from baseline in 6MWD, increase in time to climb 4 stairs and time to run/walk 10m, and increase in EEI. Quantitative strength remained fairly stable over 48weeks. Baseline age (⩾7years), 6MWD, and selected TFT performance, are strong predictors of decline in ambulation (Δ 6MWD) and time to 10% worsening in 6MWD. Baseline 6MWD was also predictive of weeks to loss of ambulation. A baseline 6MWD of <350m was associated with greater functional decline and loss of ambulation was only seen in those with baseline 6MWD <325m. Only 1/42 (2.3%) of subjects able to stand from supine lost ambulation. A 30m change from mean 6MWD places patients at a level of ambulatory function where they will experience increased risk of disease progression and loss of ambulation. Findings confirm the clinical meaningfulness of the 6MWD—the most accepted primary clinical endpoint in ambulatory DMD trials. [Copyright &y& Elsevier]

Introduction: An international clinical trial enrolled 174 ambulatory males ⩾5years old with nonsense mutation Duchenne muscular dystrophy (DMD). Pre-treatment data provide insight into reliability, concurrent validity, and minimal clinically important differences (MCID) of the 6-min walk test (6MWT), and other endpoints. Methods: Eligibility criteria included nonsense-mediated severe dystrophinopathy, males ⩾5years, and ambulatory (defined as ability to walk >75m on the 6MWT). A total of 174 patients, 70% of whom were treated with corticosteroids, were randomized into three treatment groups for the PTC124-GD-007 Ataluren clinical trial and evaluated initially at screening and baseline visits. The 6min walk distance (6MWD) was defined as primary endpoint and other secondary and exploratory endpoints included timed function tests ¨C TFTs (time to stand from supine, time to climb 4 stairs, time to run/walk 10m, and methods during TFTs), quantitative strength by hand-held myometry (knee extensors, knee flexors, elbow extensors, and elbow flexors), the PedsQL physical functioning scale, and energy expenditure index determined by heart rate measurement during the 6-min walk test. Results: The 6MWT proved feasible and reliable in a multicenter context. Concurrent validity with other endpoints was excellent. The MCID for 6MWD was 28.5 and 31.7m based on two statistical distribution methods. Discussion: The ratio of MCID to baseline mean is lower for 6MWD than for other endpoints demonstrating the sensitivity of this endpoint. The 6MWD showed an MCID of approximately 30m – similar to the magnitude of change observed in previous registration trials focused on other clinical populations. The 6MWD is a reliable, valid and clinically meaningful primary endpoint and an optimal primary endpoint for DMD clinical trials that are therapeutically focused on preservation of ambulatory functioning and slowing disease progression. [Copyright &y& Elsevier]