PTC124 is a novel, orally bioavailable, small-molecule drug that promotes ribosomal readthrough of mRNA containing a nonsense mutation (premature stop codon). Preclinical testing in the mdx mouse has documented that PTC124 induces production of full-length functional dystrophin protein in muscle, decreasing eccentric contraction injury and reducing muscle-derived creatine kinase (CK) in the serum. A previous Phase 2a study, supported by the Office of Orphan Product Development (OOPD), enrolled 38 boys with Duchenne/Becker muscular dystrophy (DMD/BMD) to receive 28 days of PTC124 treatment. The study demonstrated PTC124-related increases in in vitro and in vivo dystrophin expression and statistically significant reductions in serum concentrations of muscle-derived CK. This OOPD grant application describes a Phase 2b, international, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, efficacy and safety study. Eligible patients will include approximately 165 boys with DMD/BMD who are greater than or equal to 5 years of age and are ambulatory. They will be randomized in a 1:1:1 ratio to receive 20-, 20-, 40-mg/kg of PTC124 or 10-, 10-, 20-mg/kg of PTC124 or placebo 3 times per day at morning, midday, and evening doses. The planned enrollment period is 12 months but is likely to extend to 24 months. Subjects will continue on blinded treatment for 48 weeks. The sample size provides =0.85 power to detect a 10% (30-meter) improvement in the 6-minute walk distance, the primary outcome measure. Secondary and tertiary efficacy measures will include assessments of patient functioning, pharmacodynamic evaluations, and determinations of PTC124 safety and exposure. DMD/BMD is a disabling and life-threatening condition with high unmet medical need. Development of PTC124 comprises 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 provides the opportunity to systematically validate the concept of nonsense mutation suppression in a formal registration-directed clinical development program. Building on an OOPD-supported Phase 2a study that has generated information on the pharmacodynamic effects of PTC124, this Phase 2b study will evaluate PTC124 treatment effects on ambulation, supported by other functional and pharmacodynamic measures. The intent is to document improvements that would be a direct reflection of therapeutic clinical benefit to boys with DMD/BMD and to yield evidence that supports registration of PTC124 as the first FDA-approved treatment for this serious orphan disease.
There are no FDA-approved treatments for Duchenne/Becker muscular dystrophy (DMD/BMD), a rare and severe orphan genetic disorder. In previous studies in animals and humans, PTC124 has shown the potential to treat the underlying cause of DMD/BMD in a subset of patients whose disease is caused by a specific type of genetic defect. 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.