G.P.106: Internal consistency and robustness of clinical efficacy data from the phase 2b study of ataluren (PTC124®) in nonsense mutation Duchenne muscular dystrophy

Abstract

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 40 mg/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 10 m. Treatment differences vs placebo were larger in an ambulatory decline phase subgroup (7–16 yrs old, on corticosteroids, baseline 6MWD ¡Ý150 m but %-predicted 6MWD ¡Ü80%). 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 ∼ 30 m in the overall study population and ∼45 m 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 48 weeks with ataluren. 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 40 mg/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 10 m. Treatment differences vs placebo were larger in an ambulatory decline phase subgroup (7–16 yrs old, on corticosteroids, baseline 6MWD ¡Ý150 m but %-predicted 6MWD ¡Ü80%). 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 ∼ 30 m in the overall study population and ∼45 m 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 48 weeks with ataluren.