Good news for cystic fibrosis patients: The interim analysis of the first long-term study shows that the therapy with the three CFTR modulators Elexacaftor, Tezacaftor, and Ivacaftor is effective, safe, and well-tolerated in the long run. Over a period of nearly three years, the study investigated how the treatment affected the patients.
The study found that both lung function and respiratory and nutritional status of cystic fibrosis patients improved when taking the combination of the three CFTR modulators over the course of nearly three years. Additionally, the treatment proved to be safe and well-tolerated, with fewer exacerbations of lung function deterioration occurring.
"The results of this first long-term study on triple therapy are of great importance for all cystic fibrosis patients," says Prof. Dr. Matthias Griese, one of the study leaders from the University Hospital Munich and researcher at the German Center for Lung Research (DZL). "Because they are likely to take these modulators or similar medications for the rest of their lives. Long-term, scientifically based studies on safety and efficacy are therefore indispensable to assess the benefit of treatment for these patients." In addition to Griese, DZL scientists Prof. Marcus Mall from Charité - Universitätsmedizin Berlin and PD Dr. Felix Ringshausen from Hannover Medical School were also involved in the study.
In cystic fibrosis, also known as 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, it may not do this at all or only to a limited extent. This results in more water remaining in the cells and the cell surfaces drying out. As a result, a thick mucus forms, which clogs the airways of the lungs and internal organs such as the intestine. Another characteristic of the disease is an elevated salt content in the sweat.
There are over 2,000 different genetic alterations, or mutations, of the CFTR channel. CFTR modulators allow for the treatment of specific mutations in cystic fibrosis patients, including the common F508del CFTR mutation. Of the patients examined, 107 carried this mutation on both CFTR gene copies, while 399 had it only on one CFTR gene copy.
The effectiveness and safety of the triple combination have already been established in two approval studies in cystic fibrosis patients. The results presented now are an interim analysis after 144 weeks of the 192-week extension study. Ten centers in Australia, Europe, and North America participated in the international study. All participants had previously participated in one of the approval studies.
Previous studies have shown that lung function in people with cystic fibrosis treated with a modulator (Ivacaftor) or two modulators (Tezacaftor/Ivacaftor) deteriorates more slowly than in people who do not take CFTR modulators. "Here, for the first time, we were able to observe that lung function increased over 144 weeks," says Griese. "Although this effect was not statistically significant, it is a strong signal for the influence of this therapy. Crucial to halting progressive deterioration is not to relent in the established therapy efforts of basic cystic fibrosis treatment."
The researchers also observed that the Body Mass Index (BMI) increased rapidly during the first 24 weeks of triple therapy and was within the normal range after 144 weeks. This suggests that the combination of the three CFTR modulators generally leads to a rapid improvement in nutritional status, which is then maintained over time.
In summary, it can be said that triple therapy was generally safe and well-tolerated up to week 144 of the extension study. The clinically significant improvements in lung function measurement, respiratory symptoms, CFTR function, frequency of lung deteriorations, and nutritional status reported in the two approval studies remained consistent during this longer-term analysis period. These results confirm the favorable safety profile and long-term disease-modifying clinical benefit of therapy with the three CFTR modulators.
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
