Elexacaftor/tezacaftor/ivacaftor in children aged 6-11 years with cystic fibrosis, at least one F508DEL allele, and advanced lung disease: A 24-week observational study

To The Editor, It has been shown that elexacaftor/tezacaftor/ivacaftor (ETI) cystic fibrosis transmembrane conductance regulator (CFTR) modulatory treatment is safe and efficacious in cystic fibrosis (CF) patients aged >12 years with at least one F508del CFTR allele.1, 2 However, the clinical consequences of CF often appear in early childhood and require aggressive symptomatic treatment with the aim of preserving lung function and maintaining adequate nutrition and growth.3 Unfortunately, some children still develop severe lung disease despite intensive care in specialized CF centers: the Italian CF Registry showed that about 1% of 674 children aged 6–11 years had <40% of predicted forced expiratory volume in the first second (FEV1) in 2020 (personal communication). Such cases are extremely difficult to manage and, when conventional treatment fails, the only alternative is lung transplantation. However, pediatric lung transplantations are often unavailable because of the scarcity of specialized centers, and the patients are at high risk of dying while they are still on the waiting list.4 It has been shown that ivacaftor, lumacaftor, and tezacaftor (used singly or in combination) are safe and efficacious in children aged 6–11 years.5 Furthermore, the results of a 24-week, Phase-III open-label trial of ETI have shown that the treatment was as safe and effective in CF patients aged 6–11 years with at least one F508del allele as in adults and adolescents.6 However, as is usual in clinical trials, this study excluded patients with severe pulmonary impairment (defined as an FEV1 of <40% of the predicted value). In 2021, Vertex Pharmaceuticals established an Italian managed access program (MAP) to allow severely affected CF patients aged 6–11 years with at least one F508del allele to receive ETI treatment before its reimbursed marketing authorization. The aim of this study was to evaluate the effectiveness and safety of a 24-week ETI treatment in a cohort of children with CF aged 6–11 years with severe lung disease. Our retrospective observational study involved nine patients enrolled in the MAP attending five CF centers between February and August 2021. The MAP inclusion criteria were homozygosity for F508del (F/F) or heterozygosity for F508del and one qualifying minimal function (MF) allele,6 an age of 6–11 years, and a highest predicted FEV1 of <40% in the preceding 60 days. The treatment was administered orally to all of the patients on the basis of their body weight.6 The primary objective was to measure the improvement in lung function in terms of the absolute change in the percentage of predicted (pp)FEV1 between the start of treatment and Week 24. The secondary endpoints were the absolute change in forced vital capacity (ppFVC), and in forced expiratory flow between 25% and 75% of FVC (ppFEF25–75), nutritional improvement, sweat chloride concentration (SCC), the quality of life, and the use of antibiotics. Detailed information concerning the study methods and a statistical plan is available in the Supporting Information. Nine patients (three males, 33.3%) had a median age of 9.75 years (range 6.42–11.33). Four (44.4%) were homozygous for F508del, and five (55.6%) were compound heterozygous for F508del and one MF mutation. All of the patients had pancreatic insufficiency. None had CF-related diabetes or underwent tube feeding; none were undergoing long-term oxygen treatment or noninvasive ventilation; none were on the lung transplantation waiting list; and none had previously received CFTR modulators. Details concerning their other characteristics are available in the Supporting Information: Table S1. Mean (SD) ppFEV1 was 31.30 (4.65) at baseline, 42.51 (6.98) after 4 weeks' treatment, 47.17 (6.46) after 12 weeks, and 53.67 (12.67) after 24 weeks. The mean absolute increase in ppFEV1 was 11.21 (95% confidence interval [CI] 7.39–15.03; p < 0.001) after 4 weeks' treatment, 15.87 (11.43–20.31; p < 0.001) after 12 weeks, and 22.4 (15.22–29.52; p < 0.001) after 24 weeks (Figure 1). The trends of ppFVC and ppFEF25–75 were similar (Table 1). The mean (SD) BMI for age z-score at baseline was −0.72 (1.00), but it progressively increased to −0.16 (0.74) over the 24-week treatment period (p < 0.05). The mean absolute change was 0.60 (95% CI 0.33–0.87; p < 0.001). The weight and height for age z-score also progressively increased (Table 1). The mean (SD) SCC significantly decreased from a baseline value of 102.72 (15.65) to 36.0 (11.12) mmol/L after 4 weeks' treatment (p < 0.00001), 29.0 (8.8) mmol/L after 12 weeks, and 23.8 (7.1) mmol/L after 24 weeks. The mean absolute change from baseline was −68.17 mmol/L (95% CI −81.54 to −54.79; p < 0.001) after 4 weeks, and −79.2 (−92.67 to −65.64; p < 0.001) after 24 weeks (Table 1). All of the patients had an SCC of <60 mmol/L after 24 weeks of treatment, and 67% had an SCC of <30 mmol/L. The cystic fibrosis questionnaire-revised (CFQ-R) respiratory domain score improved rapidly and in a sustained manner throughout the 24 weeks of treatment: the median baseline score of 25 (range 16.6–75) significantly increased to 83.3 (66.6–91.6) after 4 weeks (p < 0.001), and 100 (100–100) after 24 weeks (p < 0.001). During the 24 weeks before starting ETI, nine patients had required 17 hospitalizations. ETI treatment led to an 80% lower rate of antibiotic treatment over the 24 weeks of the study, and no hospitalization was reported. Eight patients (88.9%) remained free of antimicrobial use during the study period, and only one (11.1%) needed monthly 14-day oral antibiotic treatment. None of the children experienced any treatment-related adverse events, and there were no relevant abnormalities in the findings of clinical laboratory tests (serum chemistry, hematology, coagulation studies, liver function tests, and urinalysis), vital signs, or physical examinations (skin rash, arterial hypertension, and headache). No deaths occurred during the study period, and there were no study drug interruptions or discontinuations. ETI treatment improved lung function and nutrition, decreased SCC, greatly reduced the need for antibiotics, and improved the quality of life of CF patients aged 6–11 years with severe lung disease and at least one F508del CFTR allele. Although the children involved in this study had lower mean baseline ppFEV1 (38.96) and median CFQ-R respiratory domain scores (25 points) than those in the Phase III trial of their peers (respectively 88.8 and 80),6 the treatment was associated with an equally rapid and sustained improvement in lung function, and a greater mean absolute increase in ppFEV1 after 24 weeks of treatment (22.4, 95% CI 15.22–29.52 vs. 10.2, 95% CI 7.9–12.6). The improvement in ppFEV1 was accompanied by a rapid and sustained improvement in the CFQ-R respiratory domain score, which increased to the maximum of 100 in all cases. These findings underline the possibility of recovering some lung function and thus improving the well-being of children with CF. The study population also showed improvements in all of the growth and nutritional parameters during the 24 weeks of ETI treatment. The mean increase in the BMI z-score was higher than that observed in the Phase III trial (0.60 vs. 0.37) and, given the extraordinary decrease in the number of infections, catch-up growth could be expected. These findings confirm that CFTR modulatory treatment has beneficial effects on nutrition and overall growth in patients of all ages regardless of the severity of their pulmonary disease,1, 2, 6 and may therefore require a lifelong change in the approach to nutritional advice. The improvement in SCC was similar to that observed in the Phase III trial.6 Changes in SCC provide a direct indicator of systemic CFTR function, as has been shown by parallel measurements of CFTR function in the epithelia of CF patients with one or two F508del alleles.7 The marked decrease in the need for antibiotics presumably played a major role in the observed improvements. Our patients were characterized by a higher rate of hospitalizations and recurrent infections in the 24 weeks preceding the start of ETI treatment, but the striking results of the 24-week MAP included no reported hospitalization and the fact that 88.9% of the children did not require any antibiotic courses. The treatment was safe and well tolerated, and there was no need for any treatment interruptions or discontinuations. It is obviously necessary to collect safety data over a longer time and in larger groups of children, but the safety profile of ETI in CF patients aged 6–11 years has so far been consistent with its known profile in those aged >12 years.1, 2, 6 The most important limitations of this study are its retrospective design, the very small number of patients, and the lack of a control group. We have tried to limit the effects of these by adopting a descriptive rather than an analytical approach, and by making within-group comparisons. Further limitations are the lack of microbiological data and imaging findings. The findings of this study of a selected subgroup of children aged 6–11 years with at least one F508del CFTR allele and advanced CF-related lung disease further support early treatment with ETI. The recovery of lung function and improvement in growth dynamics raise the hope that such early treatment can avert serious long-term complications. However, longer observation times and more real-world and disease registry data are required to confirm the safety and effectiveness of the new and highly efficient CFTR modulators in children with CF. Donatello Salvatore: conceptualizaIon (lead); formal analysis (equal); methodology (equal); writing—original draft (lead); writing—review & editing (lead). Giuseppe Cimino: formal analysis (equal); writing—review & editing (equal). Patrizia Troiani: data curation (equal); investigation (equal); writing—review & editing (supporting). Elisabetta Bignamini: formal analysis (equal); writing—original draft (equal); writing—review & editing (equal). Irene Esposito: data curation (equal); investigation (equal); writing—review & editing (supporting). Giuseppina Leone: datacuration (equal); investigation (equal); writing—review & editing (supporting). Maurizio Zanda: writing—review & ediIng (supporting). Daniela Manunza: investigation (equal); writing—review & editing (supporting). Angela Pepe: data curation (equal); investigation (equal); writing—review & editing (supporting). The authors thank Professor Kevin Richard Smart for language help. Lega Italiana Fibrosi Cistica—Basilicata odv supported this study. This study did not receive any external funding. Donatello Salvatore has been the principal investigator in several clinical trials conducted by Vertex Pharmaceuticals and for which his institution has received funding; he has received fees for participation in advisory boards, satellite symposia, or specific projects. Elisabetta Bignamini has been the principal investigator in clinical trials conducted by Vertex Pharmaceuticals and for which her institution has received funding. Irene Esposito has received a fee for participation in a workshop conducted by Vertex Pharmaceuticals. The remaining authors declare no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.