PTC124 is an oral compound that promotes ribosomal readthrough of mRNA containing a premature stop codon. The drug has the potential to overcome the genetic defect in patients with nonsense mutations as the basis for cystic fibrosis (CF). This application describes a Phase 2, dose-ranging, efficacy, safety, and pharmacokinetic (PK) study that will be conducted as part of an overall development program aimed at obtaining regulatory approval of PTC124 as treatment of patients with CF resulting from a nonsense mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The program hypothesis underlying this study is that daily oral dosing of PTC124 to maintain target plasma concentrations will safely modify disease-specific pharmacodynamic markers in patients with nonsense-mutation-mediated CE. The trial will be conducted in patients >12 years of age. Patients will receive sequentially escalating doses of PTC124 in 3 repeated 4- week cycles comprising 2 weeks on and 2 weeks off therapy. The dose range will be encompassed within the dose range that proved tolerable in the preceding Phase 1 multiple-dose trial. Thereafter, the Phase 2 study patients will receive further continuous treatment for 3 months at the highest individually tolerated dose. The total duration of PTC124 treatment will be approximately 4.5 months in each patient. The primary objective will be to determine a dosing regimen that safely achieves pharmacodynamic activity as determined by the pharmacodynamic endpoint of nasal TEPD. Pharmacological activity will also be assessed by sweat chloride testing, evaluation of immunofluorescence for CFTR protein in nasal epithelium, determination of density of P. aeruginosa in sputum, and measurement of markers of inflammation (interleukin-8, neutrophils) in sputum. In addition, patients will undergo pulmonary function testing, safety assessments, and evaluations for PTC124 PK.
