R. Spiegel

T.P.5

A Phase 2b, double-blind, placebo-controlled study of ataluren, an investigational drug, assessed change in 6-minute walk distance (6MWD) over 48 weeks in ambulatory males ⩾5 yrs old with nonsense mutation Duchenne muscular dystrophy (nmDMD) and showed evidence of clinical benefit for ataluren 40 mg/kg/day vs placebo. Based on emergent natural history data, 6MWD, timed function tests, and other measures of physical function were analyzed in subgroups of patients who, at baseline, were at high risk of ambulatory decline. An ambulatory decline phase subgroup was retrospectively defined as: ⩾7 to ⩽16 years old, ⩾150 m 6MWD but ⩽80%-predicted 6MWD at baseline, and on a stable dose of corticosteroids. A subgroup of patients with baseline 6MWD

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

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, 20xa0mg/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 48xa0weeks. Key study entry criteria require that patients are male with a nonsense mutation in the dystrophin gene, between the ages of 7 and 16xa0years, receiving a stable dose of corticosteroids, able to walk ⩾150xa0m 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, 20xa0mg/kg dose of ataluren ( n xa0=xa030) vs placebo ( n xa0=xa031) in mean change in 6MWD over 48xa0weeks was ∼50xa0m. 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.

G.P.106

Ataluren is an oral, investigational drug designed to promote ribosomal readthrough of premature stop codons in mRNA, leading to production of full-length, functional protein. In a Phase 2b, 48-week study in nonsense mutation Duchenne muscular dystrophy (nmDMD), ataluren 40xa0mg/kg/day was associated with slowing of ambulatory decline (measured by 6-min walk distance [6MWD]) vs placebo. Positive trends were also seen in timed function tests of stair-climbing, stair-descending, and walking/running 10xa0m. Treatment differences vs placebo were larger in an ambulatory decline phase subgroup (7–16xa0yrs old, on corticosteroids, baseline 6MWD iÝ150xa0m but %-predicted 6MWD iU80%). Internal consistency and robustness of physical function outcomes were evaluated by statistical methods. Endpoint analyses were repeated 1000 times (Monte Carlo simulation), each time with 10% of patients in each arm excluded at random. Separately, endpoint analyses were performed after excluding one or more extreme results (best/worst exclusion) from each arm. These methods were applied to the overall study population and ambulatory decline phase subgroup. Monte Carlo simulation demonstrated that treatment differences in model-estimated mean change in 6MWD of ∼xa030xa0m in the overall study population and ∼45xa0m in the ambulatory decline phase subgroup, favoring ataluren vs placebo, were not driven by a small number of patients. Best/worst exclusion analysis confirmed these treatment differences were not distorted by outliers. Timed function test outcomes were consistent with 6MWD findings. Ambulatory decline in patients with nmDMD could potentially be delayed or stabilized with disease-modifying treatment. These analyses document the internal consistency and give evidence of robustness of the Phase 2b efficacy data for ataluren in nmDMD, confirming observations of relative stabilization of ambulatory measures of disease progression over 48xa0weeks with ataluren.