CFTR Modulators in People with Cystic Fibrosis: Real-World Evidence in France

Abstract

Cystic fibrosis (CF) is a rare genetic multisystemic disease, the manifestations of which are due to mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein and can lead to respiratory insufficiency and premature death. CFTR modulators, which were developed in the past decade, partially restore CFTR protein function. Their clinical efficacy has been demonstrated in phase 3 clinical trials, particularly in terms of lung function and pulmonary exacerbations, nutritional status, and quality of life in people with gating mutations (ivacaftor), homozygous for the F508del mutation (lumacaftor/ivacaftor and tezacaftor/ivacaftor), and in those with at least one F508del mutation (elexacaftor/tezacaftor/ivacaftor). However, many questions remain regarding their long-term safety and effectiveness, particularly in patients with advanced lung disease, liver disease, renal insufficiency, or problematic bacterial colonization. The impact of CFTR modulators on other important outcomes such as concurrent treatments, lung transplantation, chest imaging, or pregnancies also warrants further investigation. The French CF Reference Network includes 47 CF centers that contribute patient data to the comprehensive French CF Registry and have conducted nationwide real-world studies on CFTR modulators. This review seeks to summarize the results of these real-world studies and examine their findings against those of randomized control trials.

Keywords: CFTR modulators; cystic fibrosis; elexacaftor; ivacaftor; real-world studies; tezacaftor.

Figure 1

Classification of CFTR mutations. CFTR protein is located at the apical surface of epithelial cells, where it acts as a bicarbonate and chloride (Cl⁻) channel. Mutations in the CFTR gene are classified as severe (Classes I, II, and III), resulting in absent or minimal CFTR function, and mild (Classes IV, V, VI), usually with residual CFTR function.

Figure 2

Proportion of the French CF population aged 12 years and older eligible for CFTR modulator therapy in 2011, 2015, and 2021 [20]. In 2011, only 3% of people with CF (pwCF) were eligible to receive a CFTR modulator (ivacaftor). In 2015, with lumacaftor–ivacaftor, half of the patient population became eligible, with 5% eligible for ivacaftor (at least one gating mutation) and 45% for lumacaftor–ivacaftor combination therapy (homozygous for the F508del mutation). By 2021, 82% were eligible for elexacaftor/tezacaftor/ivacaftor (at least one F508del mutation). There are still 10–15% of pwCF who have no access to CFTR modulator therapy. IVA: ivacaftor; LUM: lumacaftor; ELX: elexacaftor; TEZ: tezacaftor.

Figure 3

The French Cystic Fibrosis Reference Network.Upper insert: greater Paris area. Bottom left insert: La Réunion island.