Design of a Confirmatory Phase 3, Multicenter, Randomized, Double Blind, Placebo-Controlled Study (ACT DMD) of Ataluren in Patients with Nonsense Mutation Duchenne Muscular Dystrophy

Aim: Approximately 13% of Duchenne muscular dystrophy (DMD) is caused by nonsense mutation (nm) in the dystrophin gene. Nonsense mutations in DNA correspond to premature stop codons in mRNA. Ataluren an oral drug designed to promote ribosomal read through of premature stop codons, enabling production of full length, and functional protein. Currently ongoing is a Phase 3, randomized, double-blind, placebo-controlled study (ACT DMD) designed to confirm the efficacy and safety of ataluren 40 mg/kg/d in boys with nmDMD, initially demonstrated in a Phase 2b study. The design of ACT DMD reflects lessons learned from previous study and evolving understanding of the natural history of DMD. The study design targets an enriched study population of patients in the ambulatory decline phase of DMD to efficiently demonstrate disease stabilization over 48 weeks.

Methods: Key entry criteria included the following: male, nonsense mutation in the dystrophin gene,7 to 16 years of age, stable dose of corticosteroids, and screening 6-minute walk distance (6MWD) up to 150 m but < 80% predicted. Study enrollment is completed; 230 patients have been randomized in a 1:1 ratio to placebo or ataluren. The primary end point is change in 6MWD over 48 weeks. Secondary efficacy measures the following: timed function tests, QoL, North Star Ambulatory Assessment, patient/parent-reported disease-related symptoms, and activities of daily living.

Results: A previous Phase 2b trial in nmDMD demonstrated a clinical benefit at the 40mg/kg/d dose in the overall study population. On the basis of the natural history data, a subgroup of patients in the ambulatory decline phase of DMD was retrospectively identified. In this subgroup, the definition of which reflects the key entry criteria for ACT DMD, the difference between ataluren 40 mg/kg/d (n = 32) versus placebo (n = 31) in mean change in 6MWD over 48 weeks was 49.9 m (p = 0.0096).

Conclusion: ACT DMD is designed to confirm the treatment effect of ataluren seen in the Phase 2b ataluren trial. The study is fully enrolled and represents one of the largest trials conducted in DMD. Treatment is ongoing, with top line results anticipated by 4Q2015.

Keywords: nonsense mutation, Duchenne muscular dystrophy, confirmatory Phase 3 study, Ataluren.