Novel Drug Combo Improves Function of Cystic Fibrosis Protein

A novel two-drug combination has the potential to target and restore a defective protein underlying cystic fibrosis (CF), according to two phase III clinical trials conducted at 187 medical centers around the world, including Johns Hopkins.

The drug ivacaftor, in combination with an experimental medication called lumacaftor, led to modest improvements in lung function, but significant reductions in hospitalizations and antibiotics needed for lung infections. These results were published May 17 in the New England Journal of Medicine. The drug combination is intended for people 12 and up who have two copies of the most common CF mutation, called F508del.

“This is something the CF community has wanted to do for years, ever since the discovery of the gene causing CF in 1989,” says senior study author Michael P. Boyle, M.D., associate professor of medicine at Johns Hopkins and vice president of therapeutics development at the Cystic Fibrosis Foundation. “It is not a cure, but it is the first treatment to target the underlying cause of the most common form of CF. Ongoing trials already are underway, testing even stronger versions of these medications.”

Normally, a protein called CFTR controls the salt and water balance in cells lining the lungs. In patients with CF, CFTR is defective, resulting in mucous buildup in the lungs and lung infections. Ivacaftor has been found to restore CFTR function, but only in a small subgroup of 4 percent of patients with CF in whom the protein sits on the cell surface. Lumacaftor helps bring the protein to the cell surface in the most common type of CF, where ivacaftor can help restore it.

In clinical trials called TRAFFIC and TRANSPORT, 1,108 patients with CF were randomly assigned to receive lumacaftor at either 600 milligrams a day or 400 milligrams twice a day, with ivacaftor 250 milligrams twice a day, or placebo, for six months. “After six months, there was a clear benefit” in those taking the active drug, Boyle says.

Across both studies, FEV1, a measure of lung function, improved by an average of 2.6 to 4 percentage points among participants taking the active drug. Considered a modest improvement, this was observed as early as day 15 and continued throughout the study. Patients receiving the active drug also had a 30 to 39 percent reduction in the rate of lung exacerbations, which is considered statistically significant, as well as a statistically significant 61 percent decrease in the number of exacerbations requiring hospitalizations and 56 percent decrease in exacerbations requiring intravenous antibiotics. Some patients were also able to gain weight and had a significantly improved body mass index.

Serious adverse events were reported in up to 23 percent of participants taking the active drug, most often infective pulmonary exacerbation, but were less frequent than those taking placebo. The majority of adverse events reported were mild to moderate and included shortness of breath and chest tightness.

The drugs’ manufacturer, Vertex Pharmaceuticals, submitted a New Drug Application for approval of the combination therapy to the Food and Drug Administration last November. A decision is expected this summer, Boyle says.

Study coauthors were from 16 institutions in America, Europe and Australia: the University of Queensland in Australia; Queens University of Belfast in the U.K.; Seattle Children’s Hospital; University of Washington School of Medicine; Azienda Ospedaliera Universitaria Integrata in Italy; University of Milan in Italy; Royal Brompton and Harefield NHS Foundation Trust and Imperial College London in the U.K.; University Hospital Gasthuisberg in Belgium; Medical University of South Carolina; Case Western Reserve University; Rainbow Babies and Children’s Hospital; Northwestern University Feinberg School of Medicine; Nationwide Children’s Hospital; The Ohio State University; St. Vincent’s University Hospital in Ireland; University College Dublin School of Medicine in Ireland; Hôpital Robert Debré, Université Paris; The Hospital for Sick Children, University of Toronto; University of Alabama at Birmingham; and Vertex Pharmaceuticals Inc.

The work was funded locally by the Johns Hopkins Institute for Clinical and Translational Research. Boyle has served as a consultant for and received grant funding from Vertex Pharmaceuticals, manufacturer of the medications. This relationship has been managed by Johns Hopkins in accordance with its conflict of interest policies.