S1 Development of a confirmatory phase 3, multicentre, randomized, double-blind, placebo-controlled study of ataluren in patients with nonsense mutation Duchenne muscular dystrophy

Abstract

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, 20 mg/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 48 weeks. Key study entry criteria require that patients are male with a nonsense mutation in the dystrophin gene, between the ages of 7 and 16 years, receiving a stable dose of corticosteroids, able to walk ⩾150 m 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, 20 mg/kg dose of ataluren ( n = 30) vs placebo ( n = 31) in mean change in 6MWD over 48 weeks was ∼50 m. 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.