PHASE 2 STUDY OF PTC124 AS AN ORAL TREATMENT FOR NONSEN*

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DESCRIPTION (provided by applicant): PTC124 is a novel, orally bioavailable, small-molecule compound that promotes ribosomal readthrough of mRNA containing a nonsense mutation (premature stop codon). Preclinical testing in the nonsense- mutation-mediated mdx mouse model of DMD indicates that PTC124 can induce production of full-length functional dystrophin protein that improves strength, decreases eccentric contraction injury to muscle, and reduces serum creatine kinase levels. Toxicology evaluations and Phase 1 clinical studies of PTCI24 in healthy volunteers are now complete. This Orphan Products Development grant application describes a Phase 2, dose-ranging, efficacy, safety, and PK study that will be conducted as part of an overall development program aimed at obtaining regulatory approval of PTC 124 in DMD. 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 DMD (as determined by dystrophin gene sequencing). The trial will be conducted in patients =5 years of age. Initially 6 patients will receive a low dose of PTC124 given 3 times per day (TID) for 28 days. Thereafter 18 patients will be enrolled to receive a higher dose of PTC124 TID for 28 days. Based on PK modeling of the Phase 1 clinical data, the dose levels are projected to achieve plasma concentrations that proved active in the mdx mouse model. The primary objective of the Phase 2 study will be to determine a dosing regimen that safely achieves pharmacodynamic activity as determined by induction of dystrophin production when comparing pre- and post-treatment biopsies of the extensor digitorum brevis muscle. Pharmacological activity will also be assessed by measurement of muscle strength, evaluation of timed muscle function tests, and collection of serial serum creatine kinase levels. In addition, patients will undergo compliance and safety assessments, and evaluations for PTC124 PK. Development of PTC124 offer a unique approach to overcoming the genetic defect in a subset of patients with DMD, a debilitating and life-threatening orphan disease of high unmet medical need.