PTC124 is an orally bioavailable, small-molecule drug that may promote ribosomal read through of messenger ribonucleic acid (mRNA) containing a nonsense mutation (premature stop codon). Preclinical testing in a nonsense-mutation-mediated animal model of CF may indicate that PTC124 induces production of full-length, functional cystic fibrosis transmembrane conductance regulator (CFTR) protein that is appropriately localized to the epithelial cell surface and restores CFTR-mediated chloride channel activity. Phase 2a studies in 68 patients (ages 6-57 years) with nonsense-mutation-mediated CF receiving oral PTC124 for periods of 14 days through 12 weeks may indicate that oral PTC124 is generally well-tolerated, may generate production of apically localized epithelial CFTR protein that results in improvements in CFTR-mediated transepithelial chloride transport, and may be associated with salutary effects on CF related cough and trends toward improvement in pulmonary function. This application describes a Phase 3, international, multicenter, randomized, double-blind, placebo-controlled, efficacy and safety study. Eligible patients include 208 patients with nonsense-mutation-mediated CF who are at least 6 years of age and have a forced expiratory volume in 1 second (FEV1) between 40% and 90% of predicted. They will be randomized in a 1 to 1 ratio to receive 10-, 10-, 20-milligrams PTC124/kilogram, or placebo 3 times per day at morning, midday, and evening doses. Subjects will continue on blinded treatment for 48 weeks. The sample size provides at least 0.90 power to detect a change of at least 6% in the percent-predicted FEV1, the primary outcome measure. Secondary and tertiary efficacy measures will include assessments of patient functioning, pharmacodynamic evaluations, and determinations of PTC124 safety and exposure. CF is a disabling and life-threatening condition with high unmet medical needs. Development of PTC124 may comprise a novel therapeutic approach to the treatment of genetic disorders, coupling identification of patients with a specific type of genetic defect and application of a small-molecule, orally delivered, systemic therapy that has the potential to safely correct the phenotypic expression of that genetic defect. In addition to offering the potential for a major therapeutic advance by addressing the underlying cause of the disease, PTC124 development may provide the opportunity to systematically validate the concept of nonsense mutation suppression in a formal, registration-directed clinical development program. Building on Phase 2a studies that have generated information on the pharmacodynamic effects of PTC124, this study will evaluate PTC124 treatment effects on FEV1, supported by other functional and pharmacodynamic measures. The intent is to document improvements that would be a direct reflection of therapeutic clinical benefit to patients with CF.
Cystic fibrosis (CF), a rare and severe orphan genetic disorder, is caused by a genetic defect. No treatments to correct this genetic defect are available. In previous studies in animals and humans, PTC124 has shown the potential to treat the underlying cause of CF in a subset of patients whose disease is caused by a specific type of genetic abnormality called a nonsense mutation. The goal of the planned clinical trial is to evaluate the efficacy and safety of PTC124. The intent is to generate adequate data to support FDA approval of PTC124, thereby addressing a major unmet medical need.
