Ten years ago, people with cystic fibrosis (CF) celebrated when the FDA approved ivacaftor, the first drug designed to target the defective protein that causes the disease. CF is an inherited disorder that inflicts severe damage to the lungs, digestive system and other organs in the body. Since then, several additional drugs that use a similar mechanism have been approved by the FDA for CF.
These drugs share a similar mechanism called CFTR modulators, which stands for cystic fibrosis transmembrane conductance regulator. These CFTR modulators have made a huge difference for people with CF, improving their lung function, digestive symptoms, quality of life--and extending life expectancy. Prior to their approval, the only treatments available for CF focused on alleviating symptoms, not treating the underlying cause of the disease.
Jordana Hoppe, MD, with patient
Jordana Hoppe, MD, assistant professor at the University of Colorado School of Medicine, is the lead author of a new study in the Journal of Cystic Fibrosis. “I wanted to better understand the biology of CFTR modulation,” said Hoppe, who is a pediatric pulmonologist at Children’s Hospital Colorado.
Her research evaluated inflammation and growth-related proteins in blood samples from 64 children and adults with CF before starting ivacaftor treatment--and then one and six months after treatment. In a second group of 30 people with CF, researchers looked at over 1,300 proteins in blood collected before treatment and six months after starting ivacaftor.
The study showed three key findings related to changes in protein levels after six months of ivacaftor treatment. (Because all CFTR modulators include ivacaftor as the backbone, the results of this study are relevant for all modulators being taken by people with CF.)
Markers of inflammation in the blood are reduced following ivacaftor treatment. This is essential as most of the lung damage of CF is due to inflammation.
Ivacaftor led to increases in a growth factor that may have implications for improved height in children with CF, especially if started at younger ages.
A discovery approach (proteomic platform) to evaluate changes in the protein profile in blood identified nine proteins that changed significantly as a result of treatment. These proteins lend insight into the impact of ivacaftor in other parts of the body, outside of the lungs.
“We know that treatment with ivacaftor has led to beneficial effects on lung function, exacerbation frequency and quality of life," Hoppe says. “However, prior to this publication, very little was known about its impact on inflammation and effects outside of the lungs. In this study, we investigated the systemic effects of CFTR restoration, by examining changes in measures of inflammation and growth in the blood.”
The Colorado Clinical and Translational Sciences Institute’s (CCTSI) resources and expertise were critical to the operation of the study. CCTSI’s Clinical Translational Research Center’s pediatric core laboratory measured the markers of inflammation and growth in the blood. And the CCTSI’s specialized research nurses conducted the study visits at Children’s Hospital Colorado.
The results of the analysis performed in the Clinical Translational Research Center’s pediatric core laboratory suggest that levels of inflammation in the blood are reduced after 6 months of ivacaftor treatment. Changes in markers of inflammation were associated with changes in lung function.
“This study was also using a discovery-based approach to look at what other biologic pathways and organ systems are involved with this treatment,” says Scott Sagel, MD, professor of pediatrics.
“The study applied a novel proteomic platform to look more broadly at how protein profiles in the circulation changed with this CF therapy,” says Sagel who is also a pediatric pulmonologist at Children’s Colorado and director of The Mike McMorris Cystic Fibrosis Research and Care Center.
The analysis evaluated 1,300 different proteins and identified nine that changed significantly as a result of ivacaftor treatment. Some of these proteins are made in or have effects in the pancreas and the brain and central nervous system. Other proteins are involved in fat digestion and how cells are organized. Changes in several proteins were associated with improvements in lung function, weight and sweat chloride measurements.
Hoppe says, “The results can help us know how a medication may impact someone, especially if we anticipate they will take it for a long period of time. And it can help us understand potential side effects of the treatment.”
These findings may lead to more research to answer how inflammation is decreased or how other organs in the body work following ivacaftor treatment.
Going forward, Hoppe says, “We want to know whether similar changes in inflammation, digestion and growth are seen with the triple combination CFTR modulators. We also want to learn what changes in proteins in the bloodstream are seen in children under six years of age who are treated with CFTR modulators.”