Advances in the treatment of cystic fibrosis: CFTR modulators

Abstract

Cystic fibrosis is a severe genetic disease caused by variants in the CFTR gene. Although it is a multisystem disease, respiratory involvement is the main cause of morbidity and mortality. Cystic fibrosis transmembrane conductance regulator modulator (CFTRm) therapies have advanced the treatment of this disease by improving function of this protein. Ivacaftor, the first CFTRm, has been found to significantly improve lung function and quality of life in patients with certain gating variants. However, only a small percentage of patients in Spain are eligible for this treatment. Combinations of correctors and potentiators, such as lumacaftor-ivacaftor or tezacaftor-ivacaftor, have been developed for treatment of patients with the most frequent variant (F508del), although with limited benefits. Triple therapy with elexacaftor-tezacaftor-ivacaftor has been found to significantly improve respiratory, gastrointestinal and nutritional outcomes as well as quality of life, thus changing the management of CF in eligible patients. The impact of triple therapy is also reflected in an increase in life expectancy and a decrease in mortality and lung transplantation. As regards hepatic and pancreatic involvement, while CFTR modulators have exhibited promising effects, further research is required. The use of CFTR modulators has also shifted nutritional status trends in patients with CF, reducing the risk of undernutrition but increasing the risk of obesity. The use of these drugs for treatment of less frequent variants and for potential antenatal treatment is currently being investigated. Despite these advances, there is still a subset of patients who are ineligible for treatment with modulators or highly effective therapy.