The effectiveness of CFTR modulators in people with CF and rare mutations: A real‐world study

Cystic fibrosis (CF) is an autosomal recessive disease, caused by reduced function of the cystic fibrosis transmembrane conductance regulator (CFTR) protein. CFTR modulators (CFTRm) directly target this defect, first becoming commercially available for people with CF (pwCF) and gating mutations in 2012. The efficacy of CFTRm for the majority of pwCF is well established, with studies of elexacaftor/tezacaftor/ivacaftor (ETI) showing improvements in the percentage of predicted forced expiratory volume in 1 s (ppFEV1) of at least 10.0% if at least one copy of the common F508del mutation is present.1 Benefits have also been demonstrated in pwCF with the R117H mutation on ivacaftor and residual function mutations (with F508del) on tezacaftor/ivacaftor (TI).2, 3 Despite these advances, for ∼10% with rare (nonF508del/gating/R117H) mutations the clinical effectiveness of CFTRm is unknown. Studies using the rectal organoid model have demonstrated in vitro responses of rare mutations to TI but so far there has been very limited evidence of the clinical translation of these findings.4 Other in vitro models using Fisher rat thyroid cells to assess CFTR function also suggest many of these mutations may respond to CFTRm and therefore access has been made available in some countries. Thus, we conducted this retrospective observational single-center study to investigate the clinical benefits of TI and ETI in pwCF with rare mutations not currently licenced by the European Medicines Agency, but where access has been approved via our national extended access programme.5 All adult patients with nonF508del/gating/R117H mutations commenced on TI or ETI between 2018 and 2021 were included. Data were collected retrospectively from patient records, including patient characteristics, genotype, sputum microbiology, and pre-CFTRm sweat chloride (SwCl). Baseline body mass index (BMI) and spirometry were recorded 3 months before CFTRm initiation during a period of clinical stability. Spirometry was collected at approximately 1, 3, and 6 months after CFTRm initiation, with BMI and SwCl, collected up to 12 months after. Annualized intravenous (IV) antibiotic days were collected from the 12 months prior and 6 months post initiation. Changes pre- and post-CFTRm initiation in ppFEV1 were analyzed using a mixed effects model (assuming the time points of measurement were independent), while SwCl, BMI, and IV antibiotic days were analyzed by Wilcoxon signed rank test, with the treatment difference reported as Hodges-Lehmann estimate. The data were collected as part of standard clinical care so formal ethical approval was not sought. Eighteen and nine pwCF were commenced on TI and ETI, respectively. One patient in the TI group developed a rash within 4 weeks of initiation so the drug was permanently discontinued and they were excluded from the analysis. The mean (SD) age was 45.0 (13.0) and 37.0 (15.1) years in the TI and ETI groups, respectively. In the TI group, six (35%) were male, eight (47%) had pancreatic insufficiency, and nine (53%) were chronically infected with Pseudomonas aeruginosa. In the ETI group, three (33%) were male, three (33%) had pancreatic insufficiency, and seven (78%) were chronically infected with P. aeruginosa. There was a total of 25 different CFTR mutations across the two groups (Table 1). The three most common mutations covered by the extended access program in the TI group were 3849+10kbC>T (prevalence 20.6%), 2789+5G>A (14.7%), and D1152H (5.9%). In the ETI group, they were G85E (16.7%) and I502T (16.7%). The third most common mutation in the ETI group was of equal prevalence amongst five different rare mutations. Three of the patients in the ETI group were previously on a different CFTRm. Pre-ETI SwCl and spirometry for these patients were collected on their previous CFTRm. c.2657+5G>A/ 2789+5G>A c.2657+5G>A/ 2789+5G-A c.3717+1219C>T/ 3849+10kbC>T c.1367T>C/ Val456Ala There was a significant increase in ppFEV1 after initiation of the CFTRm in both the TI and ETI groups (Figure 1A). In the TI group, the mean (95% confidence intervals, CIs) ppFEV1 increased from baseline by 4.39 (1.05–7.73; p = .01) at 1 month and remained stable for 6 months. Over the duration of the study, for every unit change in time (week), the ppFEV1 increased by 0.13 (0.01–0.26; p = .04). In the ETI group, the mean ppFEV1 increased by 9.26 (4.81–13.71; p < .001) at 1 month and remained stable to 6 months. For every week, the ppFEV1 increased by 0.29 (0.08–0.49; p = .005). For patients with paired SwCl values pre-/post-CFTRm, there was a significant decrease in both groups (Figure 1B,C), with a mean (95% CI) treatment effect of 17.6 (1.5–33.8) mmol/L (p = .022) in the TI group (n = 7) and 36.5 (6–54.5) mmol/L (p = .018) in the ETI group (n = 7). In the TI group, there was a significant improvement in median (interquartile range) BMI, from 23 (21.7, 26.5) to 24 (22.1, 27.7; p = .002). Annualized IV antibiotic requirements reduced from a median of 8 (0, 14) days/year to 0 (0, 0) days/year, p = .036. In the ETI group, BMI pre-/post treatment initiation was 21.5 (19.5, 25.0) and 21.3 (20.0, 27.6) and annualized IV antibiotic requirements were 14 (14, 24) days/year and 0 (0, 0) days/year, but neither were statistically significant. In the TI group, one patient temporarily ceased the medication due to deranged liver function while also receiving non-tuberculous mycobacteria treatment. In the ETI group, one patient temporarily stopped due to deranged liver function. One patient temporarily held ETI after initiation due to a rash. The results from this retrospective study support in vitro data by showing TI and ETI are associated with significant improvements in both FEV1 and SwCl in patients with nonF508del/gating/R117H mutations. In addition, there were significant improvements in BMI and annualized IV antibiotic use in the TI group. The nonsignificant trends in BMI and IV antibiotic usage in the ETI group were likely affected by the small sample size. In addition, three of the nine patients in this group were already established on TI before commencing ETI, which may have reduced the effect. In both groups, the drugs were well tolerated with no new safety concerns identified. Although this was an adult study, it also has important implications for children with rare mutations, as the benefits of CFTRm are highly likely to extend to all age groups, as already demonstrated by pediatric studies of more common genotypes.6 This study is one of the first to show the potentially important clinical benefits of CFTRm in pwCF with a wide range of rare mutations. As interpretation is limited by its retrospective design and relatively small numbers, there is now an urgent need to complete prospective multicenter studies to confirm these results so the benefit of CFTRm can be extended to even more pwCF. Sofia Hanger: Data curation; formal analysis; writing—original draft; methodology. Imogen Felton: Writing—review and editing. Emem-Fong Ukor: Writing—review and editing. Elaine Bowman: Data curation. Clare Caldwell: Data curation. Winston Banya: Formal analysis. Susan Madge: Writing—review and editing. Andrew L. Jones: Writing—review and editing. Nicholas J. Simmonds: Supervision; conceptualization; writing—review and editing; methodology. Nicholas J. Simmonds has received consulting fees for advisory boards from Vertex, Chiesi, Gilead, and Menarini. He has also received honoraria for speaker services from Vertex, Gilead, and Chiesi. A. Jones has received honoraria for speaker services from Vertex. The remaining authors declare no conflict of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.