Off-label treatment with Elexacaftor/Tezacaftor/Ivacaftor in people with cystic fibrosis: real-world evidence from the German CF registry

Background Elexacaftor/tezacaftor/ivacaftor (ETI) have been introduced as causal therapy for people with cystic fibrosis (pwCF) carrying at least one F508del allele. The real-world effect of ETI in pwCF without any F508del allele is limited. Methods In this observational cohort study, data from the German CF Registry for pwCF who received off-label ETI for up to 365 days were used to study effects on lung function, nutritional status, and sweat chloride concentrations (SCC). Results 616 pwCF (mean age, 28.8±13.9 years) were registered with ETI treatment within a compassionate use (n=509; at least one F508del allele present) or off-label use (carrying non- F508del mutations likely to respond to ETI (n=81) or not (n=26)). After one year, mean percent predicted forced expiratory volume in 1 s increased by 10.3±11.0 ( p <0.0001) and 9.0±10.7 percentage points ( p <0.0001) compared to baseline in the at least one F508del and non- F508del predicted responsive group, and remained stable in the non- F508del predicted non-responsive group (p=0.31). Body mass index percentile increased in the at least one F508del and non- F508del predicted responsive group (11.4±15.2, p <0.0001; 5.0±12.3, p <0.05) and remained stable in the non-responsive group (p=0.14). Mean SCC after 3 months decreased by 43.9±24.6 mmol·l −1 ( p <0.0001) and 34.4±22.9 mmol·l −1 ( p <0.0001) in the at least one F508del and non- F508del predicted responsive group and increased in the non-responsive group (14.8±9.5 mmol·l −1 ; p <0.05). Conclusion Real-world data align with the results of randomized clinical trials for pwCF carrying at least one F508del allele. Clinical improvements in pwCF with a range of cystic fibrosis transmembrane conductance regulator mutations treated off-label with ETI provide compelling support for the recent ETI label extension in Europe.