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Worldwide, approximately 10% of patients with cystic fibrosis have premature stop codons in the mRNA for the CFTR gene. These result in phenotypically severe variants of cystic fibrosis. PTC124 is a small molecule available as an oral preparation which allows the ribosome to selectively ignore these mutations and hence produce the functioning protein.
This prospective phase II trial recruited 23 adults with cystic fibrosis, all of whom had at least one nonsense mutation. The patients were given PTC124 orally in two cycles of 28 days. In the first cycle, 16 mg/kg was administered daily in three divided doses for 14 days followed by 14 days without treatment. In the second cycle, the same patients received an increased dose of 40 mg/kg.
Across both cycles, statistical significance was achieved in the three primary outcome goals using nasal potential measurement. There were increases in total chloride transport, in the proportion who developed normal chloride transport and in the proportion of patients who responded to treatment predefined as a change in potential difference of −5 mV or more. No drug-related serious adverse events were recorded.
The results were less impressive in the second cycle. The authors attribute this to a possible decrease in sensitivity of nasal potential difference with repeated testing, but did not consider other causes such as a tolerability effect with PTC124 or a dose saturation below 40 mg/kg. The numbers are small and judgement should be reserved until phase III trials are undertaken; however, these results are promising and may herald a trend towards individually tailored genetic treatment for specific mutations in cystic fibrosis.
▸ Kerem E, Hirawat S, Armoni S, et al. Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial. Lancet 2008;372:719–27.