Ataluren Confirmatory Trial in DMD: Effect of Ataluren on Activities of Daily Living in Nonsense Mutation Duchenne Muscular Dystrophy (P5.002)

Objective: Evaluate the effect of ataluren on ambulatory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD). Change in activities of daily living (ADL) was investigated as a secondary endpoint. Background: Ataluren is the first drug to target the underlying cause of nmDMD, by promoting readthrough of a premature stop codon to produce full-length functional dystrophin. Methods: ACT DMD was a randomized (1:1), double-blind, placebo-controlled Phase 3 study that evaluated ataluren 40 mg/kg/day, administered over 3 doses, vs placebo over 48 weeks. Inclusion/exclusion criteria were designed to enrich for a population with the greatest opportunity to detect a clinical benefit over a 48-week study, while being inclusive enough to enroll an appropriate number of subjects over a feasible time period for an orphan disease. Participants were males 7-16 years of age with a screening six-minute walk distance (6MWD) ≥150m and ≤80[percnt]-predicted. Patients or parents/caregivers reported changes from baseline in physical functioning, general energy level, cognition/school function, emotional/social functioning, and sleep, rated on a Likert scale from 1 (much worse) to 5 (much better), using a DMD-specific survey developed for this study. Results: 230 patients were randomized to ataluren (n=115) or placebo (n=115). Changes in ADL/disease symptoms trended in favor of ataluren versus placebo across all physical functioning categories, including lower- and upper-extremity muscle function. At Week 48, more ataluren- than placebo-treated patients reported improvement (22.2[percnt] vs 16.1[percnt], respectively) or lack of progression (55.6[percnt] vs 50.9[percnt]) in walking and fewer ataluren-treated patients reported worsening in walking (22.2[percnt] vs 33.0[percnt]). These effects did not reach statistical significance. The same pattern of changes (with smaller group differences) was observed for stair-climbing and upper extremity activities of self-care. Conclusions: Results indicate a positive clinical effect of ataluren on ADL in boys with nmDMD, expanding the benefit beyond ambulation. Supported By: PTC Therapeutics Inc. Disclosure: Dr. Quinlivan has received royalty payments from Oxford University Press. Dr. Luo has received personal compensation for activities with PTC Therapeutics as an employee. Dr. Elfring has received personal compensation for activities with PTC Therapeutics as an employee. Dr. Kroger has received personal compensation for activities with PTC Therapeutics, Inc. as an employee. Dr. Riebling has received personal compensation for activities with PTC Therapeutics, Inc. Dr. Ong has received personal compensation for activities with a pharmaceutical company as an employee. Dr. Spiegel has received personal compensation from PTC Therapeutics. Dr. Peltz has nothing to disclose. Dr. Kirschner has received research support from ISIS Pharmaceuticals, Biogen, PTC Therapeutics, Eli Lilly and Company, BioMarin, and Novartis.