UW News

February 23, 2011

Trial shows drug to correct abnormal protein improves lung function in cystic fibrosis patients

UW Health Sciences/UW Medicine

Listen to the Feb. 23 Vertex conference call

A drug to correct the function of the abnormal protein in some forms of cystic fibrosis has been shown to improve lung function in clinical trials. Dr. Bonnie Ramsey, UW professor of pediatrics and a physician at Seattle Childrens, was one of the lead investigators on the trial.

Cystic fibrosis is a life-shortening genetic disorder characterized by thick, sticky mucus that leads to chronic lung infections, progressive lung damage and abnormally low body weight. It affects about 30,000 Americans and 70,000 people worldwide. People with the disease have a median age of survival of about 37 years.

The gene for cystic fibrosis was discovered in 1989. Various mutations in this gene result in defective or missing Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein. This protein regulates the flow of charged particles, such as chloride ions, across cell membranes.

It took more than two decades to determine ways a certain genetic mutation might disrupt normal transmembrane functions and to design drugs to try to fix particular disruptions at the molecular level.

The results of the STRIVE study, a phase 3 trial, were released Feb. 23 by Vertex Pharmaceuticals, Inc. The trial tested VX-770, a medication taken by mouth, which targets a mutation in the cystic fibrosis (CF) gene known as G551D. This mutation accounts for about 4 percent of cystic fibrosis cases.

In patients with this mutation, CFTR proteins are present on the cell surface but dont work correctly. The drug VX-770 aims to increase the function of these defective proteins by improving their ability to transport ions across the cell surface.

Current approved treatments for cystic fibrosis include two inhaled antibiotics and a drug that loosens mucus. As yet, no approved treatment approaches the underlying problem directly by gating the flow of chloride ions into and out of the cell.

The STRIVE study evaluated VX-770 cystic fibrosis patients age 12 and older who had at least one copy of the G551D mutation. The study enrolled 161 patients. Enrollees receiving the experimental drug continued to receive standard cystic fibrosis therapy, as did those receiving the placebo. The enrollees swallowed a single 150 mg tablet or placebo pill twice daily.

Lung function tests showed significant improvements in patients receiving VX-770 compared to those taking a placebo. After 24 weeks, those who received VX-770 gained 10.6 percent on the lung function test. The improvement was sustained at 10.5 percent through 48 weeks in the study.

Compared to those receiving the placebo, patients receiving VX-770 were 55 percent less likely to experience worsening of lung disease requiring antibiotic treatment, reported having fewer respiratory symptoms like coughing and wheezing, and on average gained seven pounds. Patients on VX-700 also showed a reduction in the amount of salt in their sweat.

A high sweat chloride is a diagnostic hallmark of cystic fibrosis. Its a marker of the CFTR protein dysfunction in the sweat ducts and reflects the underlying molecular problem responsible for the disease.

Adverse events that were 5 percent greater among those treated with VX-770 compared to placebo were headache, upper respiratory tract infections, nasal congestion, rash, dizziness, and bacteria in the sputum. The most commonly reported serious adverse effects during the study included exacerbation of lung disease (13 percent in the VX-770 group compared to 33 percent in the placebo group) and bloody cough (1 percent compared to 5 percent in the placebo group).

Vertex also reported results from the Phase 2 DISCOVER study, which was primarily designed to provide additional safety data for VX-770. DISCOVER enrolled 140 patients who had two copies of the F508del mutation in the CF gene. This mutation prevents the CFTR protein from moving to its proper location on the surface of the cell. The majority of people with cystic fibrosis have at least one copy of this mutation.

Adverse effects reported more frequently in the treatment group than in the placebo group were cough, nausea, rash, and skin inflammation. None of these events were serious and none led to stopping use of VX-770.

A third study, ENVISION, is under way to evaluated VX-770 in children 6 to 11 years old who have at least one copy of the G551D mutation. Data from this study is expected in mid-2011.

Information for this article came from a press release from Vertex and its Feb. 23 webcast on the results.