Résumé :
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Subsets of patients with a large number of genetic disorders have disease due to a premature stop (nonsense) mutation in the coding sequence of a protein. Ataluren is an investigational drug designed to overcome the deleterious effects of nonsense mutations.Cultured myotubes from patients in a Phase 2a clinical trial in nmDBMD designed to evaluate ataluren exposure and safety showed dose-dependent dystrophin expression in 100% of cases. Instead of being sigmoidal, the dose-response curve displayed a peak read-through at ~10?g/ml, with decreasing read-through at higher drug concentrations.In a Phase 2b randomized, double-blind, placebo-controlled trial (Study 007) in nmDBMD, low-dose ataluren (10, 10, 20 mg/kg TID, N=57) demonstrated a 29.7-m better mean change in 6MWD from baseline to Week 48 versus placebo. No difference was observed between high-dose ataluren (20, 20, 40 mg/kg TID, N=60)) and placebo (N=57). Study 007 and Study 007e (extension of Study 007 evaluating open-label high-dose) measured ataluren trough plasma concentration, 6MWD, and timed function tests. The high-dose treated subjects within each study were grouped by mean trough concentration (_10.0 ?g/mL [low-concentration] and >10.0 ?g/mL [high-concentration]); 10.0 ?g/mL was chosen as the cut-off value, consistent with nonclinical target plasma concentration (2 to 10 ?g/mL) and because nearly all low-dose subjects in Study 007 had mean trough concentration _10.0 ?g/mL. Changes from baseline to Week 48 (Study 007) and from baseline to Week 12 (Study 007e) in 6MWD and timed function tests were determined for each concentration group. High-dose treated subjects in Studies 007 and 007e with low-concentrations experienced less mean decline in 6MWD (N=22, N=66; -11m, -5m) than high-concentration subjects (N=37, N=73; -60m, -17m). The high-dose treated subjects with low-concentrations had generally better outcomes in the time to ascend 4 stairs, descend 4 stairs, run 10m, and stand from supine than high-concentration subjects. In Study 007e, subjects who had been treated with placebo in Study 007, low-concentration subjects experienced less mean decline in 6MWD (n=21, -2 m) than high-concentration subjects (n=26, -12m). Study Support: PTC Therapeutics, Inc; Genzyme Corporation, Inc; FDA Office of Orphan Drug Products.
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