A PHASE 2 STUDY OF PTC124 FOR CYSTIC FIBROSIS

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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. This is a Phase 2a, multi-site, open-label, dose-ranging, efficacy, safety, and pharmacokinetic (PK) study in 18 patients with nonsense-mutation-mediated CF who are ?18 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 patients with CF resulting from a nonsense mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Patients with nonsense-mutation-mediated CF will receive sequential, escalating dose levels ofPTC124 (given 3 times per day [TID] at doses of 4-, 4-, and 8-mg/kg in Cycle 1, and 10-, 10-, and 20-mg/kg in Cycle 2) in 2 repeated 28-day cycles comprising 14 days on therapy and 14 days off therapy. The total duration of TC124 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. The primary objective of this study is to document pharmacodynamic activity as determined by changes in the nasal transepithelial potential difference (TEPD) with a dosing regimen that can be safely administered. The protocol will assess other measures of pharmacological activity, evaluate drug compliance, and evaluate PTC124 safety and PK in CF patients. Based on thecharacterization of PTC124 from this study, clinical development of the drug for use in patients with CF will continue in a registration-directed clinical trials program.