Safety, Tolerability, and Pharmacokinetics of PTC124, a Nonaminoglycoside Nonsense Mutation Suppressor, Following Single‐ and Multiple‐Dose Administration to Healthy Male and Female Adult Volunteers

Abstract

Nonsense (premature stop codon) mutations are causative in 5% to 15% of patients with monogenetic inherited disorders. PTC124, a 284-Dalton 1,2,4-oxadiazole, promotes ribosomal readthrough of premature stop codons in mRNA and offers therapeutic potential for multiple genetic diseases. The authors conducted 2 phase I studies of PTC124 in 62 healthy adult volunteers. The initial, single-dose study evaluated doses of 3 to 200 mg/kg and assessed fed-fasting status on pharmacokinetics following a dose of 50 mg/kg. The subsequent multiple-dose study evaluated doses from 10 to 50 mg/kg/dose twice per day (bid) for up to 14 days. PTC124 administered orally as a liquid suspension was palatable and well tolerated through single doses of 100 mg/kg. At 150 and 200 mg/kg, PTC124 induced mild headache, dizziness, and gastrointestinal events. With repeated doses through 50 mg/kg/dose bid, reversible transaminase elevations <2 times the upper limit of normal were sometimes observed. Immunoblot analyses of peripheral blood mononuclear cell extracts revealed no protein elongation due to nonspecific ribosomal readthrough of normal stop codons. PTC124 plasma concentrations exceeding the 2- to 10-microg/mL values associated with activity in preclinical genetic disease models were safely achieved. No sex-related differences in pharmacokinetics were seen. No drug accumulation with repeated dosing was apparent. Diurnal variation was observed, with greater PTC124 exposures after evening doses. PTC124 excretion in the urine was <2%. PTC124 pharmacokinetics were described by a 1-compartment model. Collectively, the data support initiation of phase II studies of PTC124 in patients with nonsense mutation-mediated cystic fibrosis and Duchenne muscular dystrophy.

Ataluren stimulates ribosomal selection of near-cognate tRNAs to promote nonsense suppression

“…Ataluren has been shown to exhibit a favorable safety profile (27), and we speculate that at least two aspects of its activity support this attribute. First, as discussed above, ataluren stimulates PTC insertion of a set of near-cognate tRNAs that closely resemble those inserted endogenously at much lower levels.…”

“…Thus, G418 treatment yielded a pattern and frequency of amino acid insertion that differed significantly from endogenous readthrough, with the greatest difference at the UAG PTC, followed by UGA, and then UAA. Comparisons to endogenous readthrough indicated that G418 altered PTC decoding in both yeast and human cells and in part may reflect G418's interference with the decoding process (1,27). This was found to be true for another aminoglycoside readthrough effector, gentamicin, in both yeast (21) and human cells (SI Appendix, Table S4).…”

Targeting a genetic defect: cystic fibrosis transmembrane conductance regulator modulators in cystic fibrosis

“…The agent is available in an easy-to-use formulation and is currently undergoing clinical trials. Initial clinical studies in healthy adults did not raise any safety concerns and analysis of subjects' peripheral blood mononuclear cells showed no aberrant elongation of CFTR protein [44]. This could have occurred due to nonspecific ribosomal read-through of normal stop codons.…”

Approaching a New Age in Duchenne Muscular Dystrophy Treatment

“…51 PTC124 was well-tolerated in phase 1 healthy volunteers. 52 A phase 2A trial of PTC124 is currently evaluating muscle dystrophin expression and a randomized, controlled, 48-week treatment phase 2B trial in DMD and Becker muscular dystrophy with nonsense mutations has begun, which will use total distance during a 6-minute walk test as a primary outcome measure (NCT00592553, clinicaltrials.gov).…”