PTC

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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. PTC124 is a small-molecule compound that promotes ribosomal read-through of messenger ribonucleic acid containing a premature stop codon referred to as a nonsense mutation. The drug has the potential to overcome the genetic defect in patients with nonsense mutations as the basis for cystic fibrosis and other genetic disorders. This Phase 2a-multisite, open-label, dose-ranging, efficacy, safety, and PK study will be performed in 18 patients with nonsense-mutation-mediated CF who are 18 years old or older. 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. The drug will be given in 2 repeated 28-day cycles comprising 14 days on therapy and 14 days off therapy. Development of PTC124 offers a unique strategy for the treatment of cystic fibrosis, 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. The primary objective of this study is to document pharmacodynarnic 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, evaluated drug compliance, and evaluated PTC124 safety and PK in patients with CF.