New cystic fibrosis drug found to be promising

New cystic fibrosis drug found to be promising

Researchers in Israel have found that a new drug for cystic fibrosis, PTC124, is able to bypass the genetic defect in the protein-making machinery of patients and improve the functioning of weakened cell membranes. The results in published in an upcoming edition of The Lancet.

Dr Eitan Kerem (Hadassah Hebrew University Hospital, Jerusalem, Israel) and colleagues note that 10% of patients worldwide and over 50% in Israel have cystic fibrosis that is due to premature "stop" signals (nonsense mutations) in genes responsible for the cystic fibrosis transmembrane conductance regulator (CFTR). It is the CFTR that creates the protein channels crossing the cell membrane that permit chloride ion transport. The premature signals are defects that result in dehydration of the mucus encompassing the body's epithelial cells (cells that line the cavities and surfaces of structures throughout the body), and the outcome is chronic inflammation, respiratory problems, repeated infections, and usually death at an early age.

The new drug, PTC124, was created to allow the CFTR pathway to function normally by allowing the protein-making machinery to avoid or bypass the premature stop signals. In the phase II trial described here, researchers studied 23 patients who received PTC124 in two cycles. Each cycle consisted of three PTC124 doses per day for two weeks followed by two weeks without treatment. The dose in the first cycle was lower than the dose in the second. The researchers measured drug efficacy by measuring tiny voltage changes across the nasal epithelial cells, informing improvements in chloride ion transport through the cell membranes.

Twenty-three patients received voltage-change measurements in the first cycle and 21 were available in the second cycle. In the first cycle, the average total chloride ion transport increased (noted by a -7.1mV change), and in the second cycle there was a lesser increase (noted by a -3.7mV change). In 16 of 23 patients after the first cycle, there was a response in total chloride transport (a change of -5.0mV or more); 8 of 21 responded to the second cycle. Thirteen of 23 patients in the first cycle achieved the normal range of chloride ion transport, and 9 of 21 in the second cycle did as well. Accompanying the voltage changes, PTC124 use was linked to small increases in lung respiratory function and bodyweight in most patients. In addition, the drug was associated with a reduction in immune system cells that respond to inflammation called neutrophils. Other side-effects included decreases in lung-related symptoms (such as cough), constipation without intestinal obstruction (2 patients), and mild dysuria or painful urination (4 patients).

"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...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," conclude the authors.

An accompanying comment

Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial

Eitan Kerem, Samit Hirawat, Shoshana Armoni, Yasmin Yaakov, David Shoseyov, Michael Cohen, Malka Nissim-Rafinia, Hannah Blau, Joseph Rivlin, Micha Aviram, Gary L Elfring, Valerie J Northcutt, Langdon L Miller, Batsheva Kerem, Michael Wilschanski

The Lancet.


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