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New Drug Combo Treats Cause of Most Common Form of Cystic Fibrosis

Medication reduces pulmonary exacerbations by nearly 40%

A new combination of medications can successfully treat the underlying cause of cystic fibrosis for patients age 12 and older with the most common form of the life-threatening genetic disease, according to results from two phase 3 clinical trials published in the New England Journal of Medicine (NEJM).

The international trial, which studied more than 1,000 cystic fibrosis (CF) patients age 12 and older with two copies of the F508del gene mutation, showed that a combination of the drugs Kalydeco (ivacaftor) and lumacaftor, an experimental drug that has not yet been approved by the Food and Drug Administration, successfully treated the defective CF protein and improved lung function. The drug combination would be marketed as Orkambi (Vertex Pharmaceuticals).

The F508del gene mutation is found in more than half of the CF population. Approximately 8,500 people in the U.S., and 22,000 people in North America, Europe, and Australia, age 12 and older with CF carry this gene mutation.

In the studies, 1,108 patients underwent randomization and received the study drug. The mean baseline forced expiratory volume in one second (FEV1) was 61% of the predicted value. In both studies, there were significant improvements in the absolute change from baseline in the percentage of predicted FEV1 at week 24 in both lumacaftor/ivacaftor dose groups (lumacaftor 600 mg once daily or 400 mg every 12 hours in combination with ivacaftor 250 mg every 12 hours).

The difference between active treatment and placebo in the mean absolute improvement in the percentage of predicted FEV1 ranged from 2.6 to 4.0% percentage points, corresponding to a mean relative treatment difference of 4.3% to 6.7%. Pooled analyses showed that the rate of pulmonary exacerbations (the leading cause of death in CF patients) was 30% to 39% lower in the lumacaftor/ivacaftor groups than in the placebo group. The rate of events leading to hospitalization or the use of intravenous antibiotics was lower in the lumacaftor/ivacaftor groups as well.

The incidence of adverse events was generally similar in the lumacaftor/ivacaftor and placebo groups. The rate of discontinuation due to an adverse event was 4.2% among patients who received lumacaftor/ivacaftor versus 1.6% among those who received placebo.

“Being able to treat not just the symptoms, but the underlying cause of cystic fibrosis by targeting this specific gene mutation, is a major game changer because it is by far the most common in patients with this disease,” said Bonnie Ramsey, MD, Director of the Center for Clinical and Translational Research at Seattle Children’s Research Institute, Professor of Pediatrics at the University of Washington, and one of four lead authors of the NEJM article. “Previously, we found that Kalydeco treated just 4% of cystic fibrosis patients, but this new combination treats the defective CF protein for a much greater number of patients.”

The drugs work together to address the defective gene mutation by allowing the proteins within the cell to fold properly, reach the cell surface and then work as a salt channel.

Sources: Seattle Children’s Hospital; May 17, 2015; NEJM; May 17, 2015

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