Observational study shows: Triple therapy sustainably reduces systemic inflammation in cystic fibrosis

New analyses from the multicenter observational study MODULATE-CF (NCT04732910) provide robust long-term data for the first time on the effects of the triple therapy elexacaftor/tezacaftor/ivacaftor (ETI) on systemic inflammation in people with cystic fibrosis (CF). The study, published in the European Respiratory Journal, involved researchers from all five sites of the German Center for Lung Research (DZL) as well as the associated partner Charité – Universitätsmedizin Berlin. It builds on previous findings that had primarily described short-term effects. The analyses are based on biomaterials and clinical data from a CF cohort comprising 198 participants aged six years and older, providing a particularly robust data set.

While earlier studies demonstrated that ETI improves lung function and reduces symptom burden, data on the long-term course of inflammatory activity had so far been lacking. The present study closes this gap by following children, adolescents, and adults for up to 24 months after therapy initiation. A marked reduction in key inflammatory markers in the blood—including C-reactive protein (CRP), neutrophil granulocytes, and various cytokines—was already evident after three months, and this effect was sustained in large parts of the cohort over two years. Inflammatory marker levels declined to approximately 40–80% of baseline values within three months. At the same time, lung function improved significantly and remained stable, with close associations observed between clinical improvements and reductions in inflammatory markers.

“It is particularly noteworthy that this study was conducted in a real-world care setting,” says Dr. Olga Halle, human biologist at the DZL site BREATH. “It confirms that the positive effects of triple therapy are not limited to the controlled conditions of clinical trials but are also evident in patients’ everyday clinical care.” She adds: “This new evidence complements previous reports that mainly emphasized the superiority of triple therapy over older dual combinations in terms of clinical and functional parameters by addressing the important aspect of systemic inflammation.” The available data now allow a much more precise characterization of the effects of ETI: the therapy not only acts symptomatically and improves mucus clearance, but also appears to influence fundamental biological processes of the disease—particularly chronic inflammation, which plays a central role in long-term tissue damage. After no more than 24 months, nearly all inflammatory markers examined corresponded on average to the levels of a healthy reference group.

At the same time, the study shows that despite substantial improvements, a degree of residual inflammation persists in many individuals. Some markers remained above healthy levels in certain participants even after 24 months, suggesting ongoing or recurrent residual inflammation. Notably, children aged 6 to 11 years already exhibited lower inflammatory activity prior to therapy initiation compared with adolescents and adults.

These findings open up new research questions, including the clinical relevance of residual inflammatory activity and the potential role of add-on therapies to further slow long-term disease progression. For the DZL, the study therefore underscores not only the importance of precise long-term observations, but also the need to further develop future therapeutic strategies. The data suggest that complementary anti-inflammatory or anti-infective approaches could be valuable in further reducing remaining inflammatory activity.

“With this study, we demonstrate for the first time in routine clinical care that triple therapy not only relieves the burden on the lungs, but also sustainably reduces systemic inflammation—an important step toward understanding the biological benefits of this treatment,” says senior author and DZL scientist Prof. Anna Maria Dittrich from the Clinic for Pediatric Pulmonology, Allergology and Neonatology at Hannover Medical School, DZL site BREATH.

The results represent a significant advance in CF research and highlight the potential of systematic, cross-site collaboration within the DZL. They also provide a solid scientific basis for assessing how sustainably ETI can influence disease progression—particularly in young patients, whose long-term prognosis depends strongly on early control of inflammation.

Source: BREATH

Original publication:
Halle O. et al. Longitudinal real-world effects of elexacaftor/tezacaftor/ivacaftor on systemic inflammation in cystic fibrosis. European Respiratory Journal 2025; 66(6): 2500150. DOI: 10.1183/13993003.00150-2025