Which Patients With Cystic Fibrosis Will Respond Best to Lumacaftor/Ivacaftor?

Columbus, OH – July 2018

Cystic fibrosis is an inherited disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. New therapeutics called CFTR modulators are now in clinical use, with many others under development.

The combination of the CFTR modulators lumacaftor and ivacaftor is FDA approved for cystic fibrosis patients with a specific genetic mutation, but its effectiveness varies among patients.

In a new study in the journal Pediatric Pulmonology, physicians and researchers from Nationwide Children’s Hospital used metabolomics to identify biochemical markers associated with taking lumacaftor/ivacaftor. They characterized metabolic changes in 20 patients pre- and post-lumacaftor/ivacaftor treatment to identify critical pathways altered by CFTR modulation as well as potential biomarkers of therapeutic response.

The researchers found 188 metabolites that were differentially regulated in patients before and after taking the drug combination, mostly in lipid and amino acid metabolic pathways. In particular, bile acids, phospholipids, and bacteria-associated metabolites were affected by drug initiation. Importantly, changes in lipid and amino acid metabolic pathways were associated with clinical responders to lumacaftor/ivacaftor, suggesting that targeted metabolomics might one day provide useful biomarkers of CFTR modulator responses.

“There is potential to use this in coordination with clinical outcomes as a biomarker of response or with other pre-therapy testing to see which patients would be the best candidates for certain medications,” says Benjamin Kopp, MD, MPH, a member of the Section of Pulmonary Medicine at Nationwide Children’s and the study’s first author.

Dr. Kopp, who is also assistant professor of pediatrics at The Ohio State University College of Medicine, says integrating metabolomics information into clinical use could happen in the next several years.

Metabolomic information could also provide a framework with which to evaluate new CFTR modulators. Dr. Kopp says there are combinations of three drugs that are in clinical trials right now that appear to be even more effective than existing drugs. It will be useful to compare the metabolic alterations associated with this and any other future drugs or drug combinations to those associated with lumacaftor/ivacaftor.

The results of this study will direct future studies from Dr. Kopp and colleagues as well as inform the work of other research groups.

“We will follow up on the most significant metabolites individually,” says Dr. Kopp. “We want to know if they target new pathways that have not yet been identified or if they have other therapeutic uses that we can investigate.”

Another line of research Dr. Kopp is pursuing is how the observed metabolic changes integrate with changes in gene expression. He says that gene expression profiles from the same patients might provide further insights into how metabolic pathways in clinical responders are altered.

Dr. Kopp believes the metabolomics approach is a powerful one that could result in a lot of useful information.

“It helps highlight specific areas within cystic fibrosis that are dysregulated and potentially identifies novel compounds that can help drive new areas of research,” he says.


Kopp, BT, McCulloch, S, Shrestha, CL, Zhang, S, Sarzynski, L, Woodley, FW, and Hayes, Jr., D. Metabolomic responses to lumacaftor/ivacaftor in cystic fibrosis. Pediatric Pulmonology 2018 May; 53(5):583-591.