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Title: PTC124 Bypasses Genetic Defect, Improves Cell Membrane Function in Cystic Fibrosis
URL: http://www.pslgroup.com/dg/22984E.htm
Doctor's Guide
August 20, 2008

NEW YORK -- August 20, 2008 -- PTC124 can bypass the genetic defect in the protein-making machinery of patients and improve the functioning of cell membranes that is normally hampered by cystic fibrosis, according to results from a phase 2 trial published early online and in an upcoming edition of The Lancet.

Eitan Kerem, MD, Hadassah Hebrew University Hospital, Jerusalem, Israel, and colleagues conducted a study in 23 patients receiving PTC124 in 2 cycles. In each cycle the patients received 3 doses of PTC124 per day for 14 days, followed by 14 days without treatment.

In the first cycle, the patients received a lower dose than the second. The efficacy of the drug was measured by calculating improvements in chloride ion transport through the cell membranes, by measuring tiny voltage changes across the nasal epithelial cells.

Voltage changes were measured in 23 patients in the first cycle and 21 patients in the second. Mean total chloride ion transport increased in the first cycle, with a change of -7.1 mV, and also in the second cycle but by a lesser amount, -3.7 mV.

A response in total chloride transport, defined as a change of -5.0 mV or more, was recorded in 16 of 23 patients in the first cycle and 8 of 21 in the second cycle. Chloride ion transport entered the normal range for 13 of 23 patients in the first cycle and 9 of 21 in the second cycle.

As well as these voltage changes, use of PTC124 was associated with small increases in lung respiratory function and bodyweight in most patients, as well as a reduction in numbers of neutrophils. Some patients also reported decreases in lung-related symptoms such as cough.

Only 2 patients given PTC124 had constipation without intestinal obstruction, and 4 had mild dysuria.

"This trial exemplifies the concept of personalised medicine: integrating selection of patients with a specific genetic defect, use of a treatment designed to overcome that defect in gene expression, and direct assessment of protein function within disease-affected tissues," wrote the authors.

"... The further development of PTC124 could offer a practical means to address the underlying cause of disease in patients with nonsense mutations as the basis for cystic fibrosis."


SOURCE: The Lancet

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