New drug combination therapy for cystic fibrosis shows promise

Newswise — BIRMINGHAM, Ala. – A two-drug combination therapy for cystic fibrosis is effective in improving lung function in patients with certain mutations in the CFTR gene responsible for the disease. In findings published in the New England Journal of Medicine and presented today at the North American Cystic Fibrosis Conference in Indianapolis on the EXPAND study, researchers from the University of Alabama at Birmingham report that the combination of tezacaftor and ivacaftor improved lung function by nearly 7 percent compared to placebo in a certain subset of patients. The combination therapy produced a nearly 2 percent improvement over ivacaftor alone.

“Ivacaftor, known by the trade name Kalydeco and developed by Vertex Pharmaceuticals, was the first medication to treat the underlying cause of CF,” said Steven Rowe, M.D., director of the Gregory Fleming James Cystic Fibrosis Center, professor in the Division of Pulmonary, Allergy and Critical Medicine at UAB, and principal investigator of the study. “Tezacaftor, also developed by Vertex, has a different method of action than ivacaftor so that the drugs complement each other — for the first time, using both drugs in combination, we have shown an effective combination for this important group of patients with CF.”

Cystic fibrosis is caused by any one of several defects in the CFTR protein, which regulates fluid flow within cells and affects the components of lung mucus, digestive fluids and sweat. In a healthy cell, salt and fluid pass through the CFTR ion channel to the cell surface. Proteins must assume a very particular shape in order to form a normal ion channel pore, a process called protein folding.

The UAB study looked at 248 CF patients with one copy of the F508del mutation and a second mutation referred to as a residual function mutation. F508del causes the CFTR protein to be misfolded, preventing its passage through the ion channel to the cell’s surface. The residual function mutation decreases CFTR function at the surface of cells, essentially reducing the ability of salt and fluid to exit the cell. 

Ivacaftor, known as a potentiator, helps to open the ion channel. Tezacaftor has been shown to improve CFTR folding. The combination of the two improves overall lung function by restoring proper operation of the CFTR ion channel, allowing normal salt and fluid to pass through.

A second study presented at the North American CF conference from the University of Colorado reports on similar efficacy of the tezacaftor/ivacaftor combination in patients with two copies of the F508del mutation, about half of all people with CF. 

“Ivacaftor on its own improves symptoms in about 7 percent of patients with CF,” Rowe said. “The patient population in our study represents another 7 to 9 percent of patients, and the University of Colorado study represents about 50 percent. That still leaves a subset of patients without a good therapy for CF; but we are extremely excited about the next generation of medications currently under development, which could constitute a triple-combination therapy approach.”

Rowe says there are four next-generation medications that have begun clinical trials. Each of the four will be tested in combination with tezacaftor/ivacaftor. Several others are close behind.

“We anticipate that one or more of these next-generation drugs could prove effective when used in conjunction with the tezacaftor/ivacaftor combination,” Rowe said. “That triple combination therapy should provide a useful, beneficial therapy for another 30 to 40 percent of patients with CF, and further improve treatment options for many others.”     

Rowe says the triple combination therapy should also provide enhanced benefit to patients who respond to the new double combination therapy, in addition to reaching a new subset of patients.  

“I’ve been working in the field of cystic fibrosis for over 15 years, and the development of ivacaftor is the biggest medication breakthrough for this disease,” Rowe said. “The current discoveries are the next big step, as these lay the foundation for the triple drug regimens, which should prove to be truly significant in improving life span and overall quality of life for up to 90 percent of patients with CF.”

Rowe holds the Nancy R. and Eugene C. Gwaltney Family Endowed Chair in Medical Research at UAB. Funding for the study was provided by Vertex Pharmaceuticals and the Cystic Fibrosis Foundation.

About UAB

Known for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham is the state of Alabama’s largest employer and an internationally renowned research university and academic medical center; its professional schools and specialty patient-care programs are consistently ranked among the nation’s top 50. UAB’s Center for Clinical and Translational Science is advancing innovative discoveries for better health as a two-time recipient of the prestigious Center for Translational Science Award. Find more information at and

EDITOR’S NOTE: The University of Alabama at Birmingham is a separate, independent institution from the University of Alabama, which is located in Tuscaloosa. Please use University of Alabama at Birmingham on first reference and UAB on subsequent references.