Observational study shows significant decline in systemic inflammation levels after treatment with ETI medication.
In cystic fibrosis, a genetic defect leads to a gradual deterioration in lung function. Triple therapy helps in the long term. Copyright: Adobe Stock
Cystic fibrosis (CF) is the most common inherited metabolic disease in Europe. More than 8,000 sufferers live in Germany. Every year, around 150 to 200 children are born with the incurable disease. The cause is a defect in the gene for the CFTR transport channel. This disrupts the salt and water balance in the body and leads to thick mucus that can block various organs - including the lungs. This leads to repeated infections, inflammation and a gradual deterioration in lung function. Until 2020, the lung disease in CF was treated exclusively symptomatically with mucolytic inhalations and antibiotics. Since then, however, there has been a drug that combines the active ingredients elexacaftor, tezacaftor and ivacaftor (ETI), known as CFTR modulators.
The triple therapy improves the function of the transport channel and helps to reduce the formation of thick mucus. Now, researchers led by Prof. Dr. Anna-Maria Dittrich, senior physician at the Clinical Department of Paediatric Pneumology, Allergology and Neonatology at Hannover Medical School (MHH), in cooperation with the German Center for Lung Research (DZL) and Charité Universitätsmedizin Berlin, have investigated the long-term effects of ETI treatment. The multicenter observational study MODULATE-CF shows that the inflammation levels in those treated fell to around 40 to 80 percent of the initial values after just three months. At the same time, the lung function values improved significantly and sustainably. The results have been published in the "European Respiratory Journal".
Study under real conditions
Well over 2,000 mutations of the CFTR gene are known. However, the same mutation is present in 85 to 90 percent of all patients with cystic fibrosis in Germany. This is where the triple drug comes in. Previous studies have already shown that ETI improves lung function and alleviates symptoms. Until now, however, there has been a lack of data on how inflammatory activity develops over longer periods of time. The current study is based on biomaterials and clinical data from a CF cohort of the German Center for Lung Research, "MODULATE-CF", with a total of 198 participants from the age of six, which provides a particularly robust data basis. A significant reduction in central inflammatory markers in the blood was observed after just three months. This effect was maintained in many participants for two years. "It is particularly remarkable that the study was conducted in the context of real medical care," emphasizes Dr. Olga Halle, human biologist at the Children's Hospital and scientist at the DZL site BREATH Hannover. "It confirms that the positive effects of triple therapy not only occur under the previously selected, controlled conditions of clinical studies, but can also be shown in the everyday lives of patients," says the co-first author.
Better assessment of disease progression
Previous reports have already shown that triple therapy is superior to the older dual modulator combinations with the active substances lumacaftor and ivacaftor, for example in terms of improved lung function. With the data now available, the effect of ETI can be described much more precisely: it not only improves the removal of mucus from the lungs, but apparently also influences fundamental biological processes of the disease - in particular chronic inflammation, which plays a central role in long-term tissue damage. "With this study, we are showing for the first time in everyday care that triple therapy not only relieves the lungs, but also reduces systemic inflammation in the long term - an important step towards understanding the biological benefits of this treatment," says Professor Dittrich.
The results also provide a solid scientific basis for assessing how sustainably ETI can influence the course of the disease. This is particularly important for young patients, whose long-term prognosis depends heavily on controlling the inflammation at an early stage. Nevertheless, despite significant improvements, some residual inflammation persisted in many patients in the study. The work therefore underlines not only the importance of precise long-term monitoring, but also the need to further develop future treatment strategies. "The data suggest that complementary anti-inflammatory or anti-infective approaches could be valuable to further reduce residual inflammatory activity," the pediatric pulmonologist concludes.
The original paper "Longitudinal real-world effects of elexacaftor/tezacaftor/ivacaftor on systemic inflammation in cystic fibrosis" can be found here.
Text: Kirsten Pötzke