Ivacaftor Cystic Fibrosis Drug Improves Lung Dysfunction Due to Mutated Gene

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Out of the 30,000 people in the United States with Cystic Fibrosis, about 4 to 5% have a genetic mutation known as G551D-CFTR, the second most common mutation among patients with the devastating lung disease. Ivacaftor, an experimental drug developed by Vertex Pharmaceuticals and formerly known as VX-770, is associated with improving lung function in those patients with the G551D mutation, as finds results from a new study published in the New England Journal of Medicine.

Cystic fibrosis is an inherited chronic disease that causes the body to produce an unusually thick, sticky mucus that clogs the lungs and digestive system. This can lead to life-threatening lung infections and an obstruction of pancreatic enzymes that would normally help the body break down and absorb food. There are about 1,000 new cases of CF diagnosed each year and the predicted median age of survival is in the late 30’s.

Ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) protein modulator. This protein was pinpointed as a cause of cystic fibrosis in 1989 because it plays a role in the absorption and secretion of salt and water in various tissues, including the lung, sweat glands, pancreas, and gastrointestinal tract. Ivacaftor increases the time that activated CFTR channels at the cell surface remain open thus being better able to transport salt in and out of the cells.

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In a study first reported here in February 2011, those who took the experimental drug showed a marked improvement in lung function at 24 weeks. A significant 10.6 percentage point improvement in forced expiratory volume in one second (FEV1) was seen specifically in those patients with the G551D-CFTR mutation. The drug was also associated with greater reductions in pulmonary exacerbations and respiratory symptoms, reports lead investigator Bonnie Ramsey MD of Seattle Children’s Hospital.

Another positive of the Ivacaftor treatment is weight gain, as patients with CF often have difficulty gaining and maintaining weight. Those patients on the experimental drug gained about 2.7kg (almost 6 pounds) more on average than those on a placebo. Dr. Ramsey suspects the drug’s activity in the gastrointestinal epithelia contributes to an improved absorption of nutrients.

“This is the first treatment to successfully target the source of the problem,” Dr. Ramsey added. It is a “great victory in the war against genetic diseases,” adds Pamela Davis MD PhD of Case Western Reserve University who writes an accompanying editorial for NEJM.

Longer-term effects are being monitored in an ongoing, open-label follow-up trial. "It is too early to tell whether the drug will improve lifespan," Ramsey said. "We do know that FEV1 is associated with lifespan, so patients who have higher FEV1 over time tend to have a longer lifespan."

Source references:
Ramsey BW, et al "A CFTR potentiator in patients with cystic fibrosis and the G551D mutation" N Engl J Med 2011; 365(18): 1663-1672.
Davis PB "Therapy for cystic fibrosis -- the end of the beginning?" N Engl J Med 2011; 365(18): 1734-1735.

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