P.11.19 Phase 2b, dose-ranging study of ataluren (PTC124®) innonsense mutation Duchenne muscular dystrophy – results of a post hoc analysis of change in %-predicted 6-min walk distance

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 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. An international, multicenter, randomized, double-blind, placebo-controlled trial (Study 007) enrolled ambulatory males ⩾5 years with nonsense mutation DMD. Patients received tid 20, 20, 40 mg/kg ataluren; 10, 10, 20 mg/kg ataluren; or placebo orally for 48 weeks. The primary endpoint was absolute change in 6-min walk distance (6MWD) over 48 weeks. The study enrolled 174 subjects (median [range] age = 8 [5–20] years, median [range] height = 123 [99–173] cm) at 37 sites in 11 countries. A post hoc analysis was performed to convert absolute 6MWD data to %-predicted 6MWD using a previously published age and height-based equation to adjust for maturational differences. Median [range] baseline %-predicted 6MWD = 63[12–96]%. Mean decline in %-predicted 6MWD at Week 48 of 7.6% was observed for placebo, vs 2.7% for ataluren 10, 10, 20 mg/kg, resulting in a difference of 4.9% (nominal p -value = 0.0273). Mean decline for ataluren 20, 20, 40 mg/kg was no different from placebo (7.7%), for a difference of 0.1% from placebo. Conversion of absolute 6MWD data to %-predicted 6MWD assists in the interpretation of disease-related progressive loss of function against the background of normal growth and development. Analysis of Study 007 using %-predicted 6MWD data adjusts for maturational influences and supports the treatment difference between ataluren 10, 10, 20 mg/kg and placebo seen in the primary analysis of 6MWD in meters.