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). Development of PTC124 offers a unique strategy for the treatment of cystic fibrosis (CF), 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 the genetic defect by restoring the production of the missing protein. This protocol 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 or older. 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. In this study, patients will receive sequential, escalating dose levels of PTC124 (given 3 times per day 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 planned doses in this study are within the dose range that was safe and tolerable in the preceding Phase I multiple-dose trial in healthy volunteers. The primary objective of the study is to determine whether PTC124 safely provides pharmacological activity as evaluated by transepithelial potential difference (TEPD) assessment of chloride secretion. The protocol will assess other measures of pharmacological activity, evaluate drug compliance, and evaluate PTC124 safety and PK in CF patients. Based on the characterization 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. This study will be conducted at 4 or more centers that are member institutions of the Cystic Fibrosis Therapeutics Development Network. Enrollment is planed to occur over 8 months, with follow-up and analysis to be completed within 4 to 6 months. The study will enroll up to 24 subjects to have 18 subjects complete the protocol, with 6 subjects expected at this site.
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