Cystic fibrosis: Triple therapy shows long-term efficacy and safety

Good news for cystic fibrosis patients: the interim analysis of the first long-term study shows that the therapy with the three cystic fibrosis transmembrane conductance regulators (CFTR) elexacaftor, tezacaftor and ivacaftor is effective, safe and well tolerated in the long run. Over a period of nearly three years, it was examined how the treatment affected the patients.

The study showed that the lung function as well as the breathing and nutritional status of those cystic fibrosis patients improved who took the combination of the three CFTR modulators over a period of almost three years.  In addition, the treatment proved to be safe and well tolerated, and deteriorations of lung function, so-called exacerbations, occurred less frequently.

“The results of this first long-term study of the triple therapy are of great importance for all cystic fibrosis patients”, says Prof. Dr. Matthias Griese, one of the principal investigators from the University of Munich and a researcher at the German Center for Lung Research (DZL). “Since they will probably take these modulators or similar medications for the rest of their lives. Long-term, scientifically sound safety and efficacy studies are therefore essential, in order to assess the benefit of the treatment for these patients.” Alongside Prof. Griese, the DZL researchers PD Dr. Felix Ringshausen from Hannover Medical School and Prof. Marcus Mall from the Charité were also involved in the study.

Modulators balance out mutations
In mucoviscidosis, also known as cystic fibrosis (CF), the gene for an ion channel called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is altered. Normally, the channel transports chloride ions out of the cell. In cystic fibrosis, this is either not at all possible or only to a limited extent. Thus, more water remains in the cells and the cell surfaces dry up. As a result, viscous mucus forms, which clogs the airways of the lung and inner organs, such as the intestine. A further indicator of the disorder is an increased salt concentration in sweat.

There are over 2,000 different genetic changes, thus mutations, of the CFTR channel. The CFTR modulators allow certain mutations in cystic fibrosis patients to be treated, including the frequent F508del CFTR mutation. Of those patients examined in this study, 107 carried this mutation on both CFTR gene copies, and 399 only on one.

The effectiveness and safety of the triple combination have already been determined in two clinical trials with cystic fibrosis patients. The results presented now are an interim analysis after 144 weeks of the 192-week extension study. Ten centres in Australia, Europe and North America took part in the international study. 

Lung function improves constantly
Previous studies have shown that the lung function in people with cystic fibrosis, being treated with one modulator (ivacaftor) or two modulators (tezacaftor/ivacaftor), deteriorates at a slower rate than in people not treated with CFTR modulators. “Here we were able to observe for the first time that the lung function over 144 weeks tended to increase”, says Griese. “Even if this effect was not statistically significant, this is a strong signal for the influence of this therapy. In order to stop the progressive deterioration, it is crucial not to reduce the previously established therapeutic efforts of the basic treatment of cystic fibrosis.”

The researchers also observed that the Body Mass Index (BMI) rose rapidly during the first 24 weeks of the triple therapy and after 144 weeks was within the normal range. This indicates that the combination of the three CFTR modulators generally leads to a rapid improvement in nutritional status, which will then in time be maintained.

In summary, it can be said that the triple therapy was, up to week 144 of the extension study, generally safe and well tolerated. The clinically significant improvement in measuring the lung function, respiratory symptoms, CFTR function, frequency of reduced lung function and nutritional status, as reported in both approval studies, also continued in this longer period of analysis. These results confirm the favourable safety profile and the long-term, disease-modifying clinical use of the therapy with the three CFTR modulators.


Original publication
Daines CL, Tullis E, Costa S, et al. Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in People With Cystic Fibrosis and at Least One F508del Allele: 144-Week Interim Results From a 192-Week Open-label Extension Study [published online ahead of print, 2023 Nov 9]. Eur Respir J. 2023;2202029. doi:10.1183/13993003.02029-2022


Text: German Center of Lung Research (DZL )

Photo: F. Ringshausen

PD Dr Felix C. Ringshausen, senior physician at the Department of Respiratory Medicine and Infectiology at Hannover Medical School, DZL-PI at site BREATH and co-author of the study