Cystic Fibrosis: Triple therapy particularly effective in early childhood

Cystic fibrosis is an incurable genetic disorder. Since 2020, there has been a treatment that addresses the underlying cause, known as triple therapy, which is now also approved for children as young as two years old. In their study, researchers at Charité – Universitätsmedizin Berlin showed that this therapy is particularly effective in early childhood: The molecular mucosal channels, which do not function or function poorly in cystic fibrosis, reached nearly normal functional levels in children between the ages of two and eleven following treatment. The researchers view the results as a case for starting treatment early. The study was published in the journal European Respiratory Journal.

People with cystic fibrosis struggle with thick mucus in their lungs, frequent respiratory infections, and problems with the pancreas, liver, and intestines. “The reason for this is that, due to a genetic defect, certain molecular structures within the mucous membranes – known as CFTR channels, which regulate water and salt balance there—do not function at all or function inadequately,” explains Dr. Simon Gräber, head of the Junior Research Group “Precision Medicine in Cystic Fibrosis” at Charité’s Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine. "Until a few years ago, life expectancy for those affected was significantly reduced. Thanks to the triple therapy, which has been available since 2020, both life expectancy and quality of life for patients have improved dramatically." Since 2022, the therapy – a combination of the three active ingredients elexacaftor, tezacaftor, and ivacaftor – has been approved for children ages six and older, and since 2023, for children ages two and older.

First indication in the sweat test

Studies in adolescents and adults have shown that triple therapy is able to restore CFTR channel function to about 50 percent. To date, however, there have been no direct measurements of CFTR channel function in children. Clinical studies, however, showed that the combination drug led to greater improvements in children in the so-called sweat test than was the case in older patients. The sweat test is a common procedure used in the diagnosis of cystic fibrosis, in which the salt concentration in sweat is measured. A high salt content indicates that the channels are not functioning properly. “With our study, we wanted to investigate this finding and examine, at the functional level, the extent to which the triple therapy restores CFTR channels in children, and whether this effect is more pronounced than in adults,” says Prof. Marcus Mall, director of the Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine at Charité.

Functional impairment in children has been nearly completely corrected

Under the leadership of Charité, 26 children with cystic fibrosis, aged 2 to 11, who had at least one of the most common disease-causing genetic defects (the F508del mutation) were examined. Before the start of treatment and again after four months, lung function was measured, a sweat test was performed, and nutritional parameters were assessed. In addition, small samples of the intestinal mucosa were collected using a painless procedure. The researchers transferred these to a culture medium and conducted current measurements to investigate the function of the CFTR channels in the mucosa.

"A functional CFTR channel transports negatively charged chloride ions. We can detect and quantify this transport by measuring the current," explains Simon Gräber. "The result was astounding: The triple therapy restored CFTR channel function to 90 or even 100 percent." "We really hadn't expected that the children treated with the triple therapy would have values close to normal—that is, values similar to those of children without cystic fibrosis," adds Marcus Mall. “Such positive findings regarding the functional efficacy of triple therapy in children are truly remarkable and offer hope.”

The younger, the more effective

The researchers compared the data collected in the study with the results of a previous study they had conducted using the same methodology among adolescents and adults. "In comparison, the restoration of CFTR function was significantly more pronounced in younger children than in adolescents and adults. We were able to identify a clear correlation with age here: the younger the person, the more effective it is," says Simon Gräber. "If early treatment in childhood can prevent disease progression and the associated irreversible tissue changes and functional impairments – especially in the lungs – in the future, that would be wonderful."

The results of this study are consistent with those of a previous study in which the research team led by Marcus Mall was already able to show that children benefit greatly from triple therapy, as both their lung function and changes in their lung tissue improved. “With our latest study, we now provide a mechanistic explanation – based on the functional improvement of the CFTR channel – for why starting treatment early is particularly promising,” says Marcus Mall.

In further studies, the Charité team plans to use single-cell analyses to zoom in on mucosal cells and investigate how the triple therapy works at the molecular level. If the triple therapy is approved in the future for children as young as 1 year old, the researchers want to investigate whether starting treatment even earlier might be even more effective at preventing disease-related changes.

Reference:

Jasmin Berger, Yin Yu, Elexacaftor/tezacaftor/ivacaftor improves CFTR function to near-normal levels in children with cystic fibrosis, European Respiratory Journal, https://doi.org/10.1183/13993003.00422-2026