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.

Real-world disparities and ethical considerations with access to CFTR modulator drugs: Mind the gap!

“…In terms of beneficence, there is compelling real-world evidence of substantial benefits of CFTRm therapy in pwCF and responsive CFTR mutations, with reported improvements in lung function and nutrition, reduced pulmonary exacerbation rates as well as the potential to alter the trajectory of CF disease, and low mortality rates in the long term ( Benden and Schwarz, 2021 ; Balfour-Lynn and King, 2022 ; Gifford et al, 2022 ; Keogh et al, 2022 ; Regard et al, 2022 ; Sawicki et al, 2015 ; Heijerman et al, 2019 ; Volkova et al, 2020 ; Carnovale et al, 2022 ). There is therefore clearly a conflict between the utilitarian approach to distributive justice and the principle of beneficence based on social or moral obligation ( Gericke et al, 2005 ).…”

“…Beyond clinical trials, real-world data on outcomes in pwCF on ivacaftor, the first CFTRm licensed more than a decade ago, provide compelling evidence over time of improved outcomes in nutrition, pulmonary exacerbations, and lung function. Furthermore, risk for mortality and lung transplantation are also significantly reduced ( Balfour-Lynn and King, 2022 ; Gifford et al, 2022 ; Regard et al, 2022 ). Although long-term, real-world data are lacking for ETI, similar outcomes are reported and projected for pwCF receiving ETI, including those with advanced lung disease ( Benden and Schwarz, 2021 ; Balfour-Lynn and King, 2022 ; Gifford et al, 2022 ; Keogh et al, 2022 ; Regard et al, 2022 ; McCoy et al, 2023 ).…”

“…Furthermore, risk for mortality and lung transplantation are also significantly reduced ( Balfour-Lynn and King, 2022 ; Gifford et al, 2022 ; Regard et al, 2022 ). Although long-term, real-world data are lacking for ETI, similar outcomes are reported and projected for pwCF receiving ETI, including those with advanced lung disease ( Benden and Schwarz, 2021 ; Balfour-Lynn and King, 2022 ; Gifford et al, 2022 ; Keogh et al, 2022 ; Regard et al, 2022 ; McCoy et al, 2023 ). The outlook and long-term prognosis, including survival, of pwCF has without doubt substantially improved for those eligible for CFTRm and have access to these drugs, especially if initiated at a younger age when end-organ disease is not established yet.…”

Using the genome to correct the ion transport defect in cystic fibrosis

“…Significant success was recently achieved with the approval of a highly effective modulator therapy drug rescuing F508del‐CFTR, which in clinical trials evidenced lung function improvement of ∼14% in individuals with either one or two copies of the F508del mutation (Heijerman et al., 2019; Middleton et al., 2019). Notwithstanding, there is high heterogeneity in clinical benefit, with some individuals having negligible (<5%) improvement in lung function, others with major adverse effects (weight gain, depression), and, importantly, overall CF symptoms are still present, albeit significantly attenuated (Barry & Taylor‐Cousar, 2021; Gramegna et al., 2020; Regard et al., 2022). For this reason and because the genes that are targeted by these novel drugs remain unknown, there is still considerable scope for improvement of therapeutic effectiveness through the investigation of the mechanisms of disease in a global way through ‘omics’, i.e.…”

Clinical Advances in Cystic Fibrosis

“…Since 2012, new promising therapeutic tools have been introduced, and these include small molecules targeting either the CFTR or the cascade of events downstream from CFTR dysfunction. So-called CFTR modulators have been developed in order to potentiate, correct, stabilize or amplify CFTR functionality [ 11 ]. To date, there are four CFTR modulator drugs approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA), but they are used in clinical practice only for specific genotypes and, as a consequence, for a small CF sub-population [ 9 ].…”