Successful Therapy over 12 Months of People with Cystic Fibrosis with Rare Non-phe508del Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Mutations with Elexacaftor/Tezacaftor/Ivacaftor (ETI)

Abstract

Background: Elexacaftor/Tezacaftor/Ivacaftor (ETI) is a CFTR modulator therapy approved for people with cystic fibrosis (pwCF) who have at least one phe508del mutation. However, its approval in the European Union (EU) for pwCF with non-phe508del mutations is lacking, because data on treatment response in this subgroup are scarce. Methods: This retrospective observational study evaluated six pwCF (ages 6 to 66) with responsive CFTR mutations (M1101K, R347P, 2789+5G>A, G551D) undergoing off-label ETI therapy. Evaluations were conducted at 0, 3, 6, 9, and 12 months, assessing lung function (FEV₁), sweat chloride levels, body mass index (BMI), quality of life, medication satisfaction, ear, nose and throat (ENT) symptoms, and physical activity. A control group of four pwCF with classic symptoms and no ETI treatment was included. Results: FEV₁ improved significantly after 3 and 6 months (p < 0.05) and stabilized by 12 months. Sweat chloride levels decreased significantly, with four pwCF achieving levels <60 mmol/L. Improvements in the upper and lower airway symptoms, medication satisfaction, and increased BMI were noted. Conclusions: ETI demonstrates high efficacy in this small group of pwCF with rare CFTR mutations, offering a treatment option that warrants further monitoring and evaluation.

Keywords: cystic fibrosis; elexacaftor/tezacaftor/ivacaftor; non-phe508del CFTR mutations; off-label use; rare CFTR mutations.

Figure 1

Significant decrease in sweat chloride concentration in people with CF undergoing ETI therapy. Sweat chloride results are shown as individual values (mmol/l) and box-whisker plots with medians, interquartile range, minima, and maxima. Sweat chloride of pwCF (n = 6) is documented immediately before and 1–3 months on ETI therapy compared to sweat chloride of the pwCF control group without ETI (n = 4) at birth and in 2023. Using the Wilcoxon matched-pairs signed rank-test significant values were assessed at p < 0.05. Abbreviations: * = p < 0.05; ETI= Elexacaftor/Tezacaftor/Ivacaftor; CF= cystic fibrosis; pwCF = people with CF.

Figure 2

Improvement in FEV₁ of people with CF on ETI therapy. FEV₁ of pwCF (n = 6) immediately before and 3/6/9/12 months on ETI therapy compared to the FEV₁ of the pwCF control group without ETI (n = 4). Significant values with p < 0.05 were evaluated using the Friedman test. (A) FEV₁ z-score values are shown as medians with minima and maxima. (B) Predicted FEV₁ values are shown as percentage different from baseline (month 0, immediately before starting ETI therapy). Differences are outlined as individual single values, medians with minima and maxima. Abbreviations: * = p < 0.05; ETI = Elexacaftor/Tezacaftor/Ivacaftor; CF = cystic fibrosis; FEV₁ = forced expiratory volume in 1 s; pwCF = people with CF.

Figure 3

BMI of adult pwCF undergoing ETI therapy. BMI values are presented as individual values and whisker plots with medians and interquartile ranges. BMI values of adult pwCF (n = 5) are shown directly before and after 6–8 months on ETI therapy in comparison to the control group of pwCF without ETI (n = 3). Abbreviations: ETI = Elexacaftor/Tezacaftor/Ivacaftor; BMI = Body-Mass-Index; pwCF = people with CF.

Figure 4

PwCF on ETI therapy report significant improvement in respiratory symptoms compared to baseline. CFQ-R RD results (%) of pwCF (n = 6) immediately before and 6–8 months after initiation of ETI therapy compared to the control group (n = 4) are presented as individual values and box-whisker plots with medians, interquartile range, minima and maxima. Changes after 6–8 months were evaluated using the Wilcoxon matched-pairs signed rank-test, differences to the control group by using the Wilcoxon–Mann–Whitney test. Significant values were assessed at p < 0.05. Abbreviations: * = p < 0.05, ** = p < 0.005; ETI = Elexacaftor/Tezacaftor/Ivacaftor; CFQ-R RD = Cystic Fibrosis Quality of Life Respiratory Domain; pwCF = people with CF.

Figure 5

Significant decrease in ENT symptoms of pwCF undergoing ETI therapy compared to baseline. SNOT-22 scores of pwCF (n = 6) are shown immediately before and 6–8 months after the start of ETI therapy compared to the control group (n = 4), presented as individual values and box-whisker plots with medians, interquartile ranges, minima and maxima. Significant reduction in ENT symptoms at 6–8 months on ETI was evaluated using the comparison to the control group using the Wilcoxon–Mann–Whitney test. Significant values were defined by p < 0.05. Abbreviations: * = p < 0.05; ETI = Elexacaftor/Tezacaftor/Ivacaftor; ENT = ear, nose and throat; SNOT-22 = Sino-Nasal Outcome Test-22; pwCF = people with CF.

Figure 6

Significant improvement in physical performance of pwCF after 6–8 months on ETI therapy compared to baseline. Shown are the walking minutes pwCF could complete immediately before and 6–8 months after initiation of ETI therapy (n = 6) compared to the control group (n = 4). The number of minutes is presented as individual values and box-whisker plots with medians, interquartile ranges, minima, and maxima. Significant values were defined by p < 0.05 by using the Wilcoxon matched-pairs signed rank-test. Abbreviations: * = p < 0.05; ETI= Elexacaftor/Tezacaftor/Ivacaftor; pwCF = people with CF.