This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. PTC124 is a novel, orally bioavailable, small-molecule compound that promotes ribosomal readthrough of messenger ribonucleic acid (mRNA) containing a premature stop codon (also referred to as a nonsense mutation). The drug has the potential to overcome the genetic defect in subjects with nonsense mutations as the basis for Duchenne muscular dystrophy (DMD) and other genetic disorders. Development of PTC124 offers a unique strategy for the treatment of DMD, coupling testing for a specific type of genetic defect with a small-molecule remedy that has the potential to safely correct the phenotypic expression of that genetic defect by restoring the production of the missing protein. This protocol describes a Phase 2a, multi-site, open-label, dose-ranging, efficacy, safety, and pharmacokinetic (PK) study in 24 subjects with nonsense-mutation-mediated DMD who are greater than 5 years of age. This study will be conducted as part of an overall development program aimed at obtaining regulatory approval of PTC124 as treatment for subjects with DMD resulting from a nonsense mutation in the dystrophin gene. It is intended that 6 subjects will be enrolled to receive 28 days of treatment with PTC124, given 3 times per day (TID) at a dose of 4-, 4-, and 8-mg/kg. Once these subjects have completed 28 days of treatment and the data for these subjects have been reviewed by the Data Monitoring Committee (DMC) for the study, it is intended that 18 additional subjects will be enrolled to receive 28 days of treatment with PTC124, given TID at a dose of 10-, 10-, and 20-mg/kg. The planned doses in this study are within the dose range that was safe and tolerable in the preceding Phase 1 multiple-dose trial in healthy volunteers. The total duration of PTC124 treatment, 28 days, is supported by the results of toxicology studies of 28 days duration in rats and dogs, and safety data derived from the 14-day Phase 1 multiple-dose trial in healthy volunteers.
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