Experimental Cystic Fibrosis Drug Shown Safe in Clinical Trial

Mutations of the CFTR gene affect functioning of the chloride ion channels in these cell membranes, leading to cystic fibrosis. All disease-causing mutations in the CFTR gene prevent the channel from functioning properly, leading to a blockage of the movement of salt and water into and out of cells. Because of this blockage, cells that line the passageways of the lungs, pancreas, and other organs produce abnormally thick, sticky mucus. This mucus obstructs the airways and glands, causing the characteristic signs and symptoms of cystic fibrosis. While thin mucus can be removed by cilia, thick mucus cannot be removed by cilia, thus trapping bacteria that give rise to chronic infections.

VX-770 is a drug being tested by Vertex Pharmaceuticals (Cambridge, MA, USA) in individuals with cystic fibrosis who have at least one copy of the G551D mutation. The drug is thought to target the defect caused by the CFTR gene and restore the ability of its protein product to open up chloride channels, allowing salt to flow in and out of the cells properly. Unlike gene therapy, VX-770 does not replace the defective gene. Rather, if successful, VX-770 would repair the problem caused by the mutation in the existing gene.

The paper published in the November 18, 2010, issue of the New England Journal of Medicine (NEJM) described a study in which 39 adults with cystic fibrosis and at least one G551D-CFTR allele received oral VX-770 every 12 hours at a dose of 25 mg, 75 mg, or 150 mg or placebo for 14 days (in part 1 of the study) or VX-770 every 12 hours at a dose of 150 mg or 250 mg or placebo for 28 days (in part 2 of the study).

Results showed that the patients who took VX-770 for 28 days showed improvements in several key indicators of cystic fibrosis, including lung function, nasal potential difference measurements, and sweat chloride levels. Six severe adverse events occurred in two subjects (diffuse macular rash in one subject and five incidents of elevated blood and urine glucose levels in one subject with diabetes). All severe adverse events resolved without the discontinuation of VX-770.

"Patients with CF have a defective protein in chloride channels in lung cells that, in effect, causes a door to shut too tightly, ultimately leading to severe infections in the lung” said contributing author Dr. Steven M. Rowe, assistant professor of medicine at the University of Alabama (Birmingham, USA), one of 16 study sites nationwide for this VX-770 trial. "The data suggest that the drug seems to improve the function of the protein, so that the door opens and closes more properly.”

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Vertex Pharmaceuticals
University of Alabama