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Background: New CFTR Modulator triple therapy Elexacaftor-Ivacaftor-Tezacaftor (ETI) prove efficacy in pulmonary outcomes. However, its impact on nasal sinus symptoms in children has not been specifically studied. The aim of this study is to evaluate the impact of this therapy on nasal sinus symptomatology in children aged 6-12 years., Methods: A prospective, single-center cohort study was conducted over a 12-month follow-up period in children aged 6-12 years at the initiation of ETI therapy. The primary outcome was evolution of the SN-5 score, a validated pediatric questionnaire measuring quality of life related to nasal sinus symptoms. A decrease of 0.5 points is considered clinically significant. Secondary outcomes included changes in clinical examination findings (obstructive turbinate hypertrophy, polyps, presence of pus in the middle meatus, and externalized mucocele), quality of life measured by the Visual Analog Scale (VAS), and number of antibiotic courses during the study period., Results: Twenty-six patients were included between March and September 2023, with no lost to follow-up. The initial mean SN-5 score was 2.88 (95% CI {1.91; 3.85}). After 1 year, the mean SN-5 score was significantly lower (1.41, 95% CI {1.00; 1.88}, Delta = 1.47, p < 0.001). The VAS related to symptoms also improved (Delta = 1.7, p < 0.001), and the number of antibiotic courses decreased (25 vs. 69, p < 0.001). A trend toward improvement in clinical examination parameters was observed., Conclusion: ETI therapy appears to significantly improve nasal sinus symptoms in children aged 6-12 years, as evidenced by improved quality-of-life scales and reduced antibiotic use., (© 2025 The Author(s). Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background: Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response., Methods: The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France's 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses., Findings: The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV 1 (ppFEV 1 ) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV 1 was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor., Interpretation: In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population., Funding: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR., Competing Interests: Declaration of interests P-RB declares consulting fees from AstraZeneca, Chiesi, GSK, Insmed, MSD, Sanofi, Vertex, Viatris, and Zambon, outside of the submitted work. IS-G declares grants and consulting fees from Vertex, outside of the submitted work. ID declares support for attending meetings from Mylan and Zambon. CA declares consulting fees from Vertex and Viatris and support for attending meetings from SOS Oxygène, Viatris, and Zambon. DG declares support for attending meetings from Zambon. MM-E declares fees for report testimony from Vertex. MM declares consulting fees from Vertex. BD declares fees for participation on a data safety and monitoring board from Vertex. CR reports grants from Vaincre la Mucoviscidose and unpaid participation on the leadership of the French newborn screening programme and the French Rare Diseases Network. CM declares consulting fees from AstraZeneca, Boehringer Ingelheim, Chiesi, and GSK, and support for attending meetings from Boehringer Ingelheim and Chiesi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: A major breakthrough in cystic fibrosis (CF) therapy was achievedAQ1 with CFTR modulators. The lumacaftor/ivacaftor combination is indicated for the treatment of CF in pediatric patients above 6 years old. Pharmacokinetic (PK) studies of lumacaftor/ivacaftor in these vulnerable pediatric populations are AQ2crucial to optimize treatment protocols., Objectives and Methods: The objectives of this study were to describe the population PK (PPK) of lumacaftor and ivacaftor in children with CF, and to identify factors associated with interindividual variability. The association between drug exposure and clinical response was also investigated., Results: A total of 75 children were included in this PPK study, with 191 concentrations available for each compound and known metabolites (lumacaftor, ivacaftor, ivacaftor-M1, and ivacaftor-M6). PPK analysis was performed using Monolix software. A large interindividual variability was observed. The main sources of interpatient variability identified were patient bodyweight and hepatic function (aspartate aminotransferase). Forced expiratory volume in the first second (FEV1) was statistically associated with the level of exposure to ivacaftor after 48 weeks of treatment., Conclusions: This study is the first analysis of lumacaftor/ivacaftor PPK in children with CF. These data suggest that dose adjustment is required after identifying variability factors to optimize efficacy. The use of therapeutic drug monitoring as a basis for dose adjustment in children with CF may be useful., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Lung clearance index (LCI) is a biomarker of ventilation inhomogeneity. Data are scarce on its usefulness in daily practice for monitoring the effects of treatments in older children and adults with CF. In this French observational study of lumacaftor-ivacaftor, 63 of 845 patients (7.5%) had available LCI performed at baseline and at six (M6; n=34) or 12 months (M12; n=46) after lumacaftor-ivacaftor initiation. At inclusion, median [IQR] age was 16 years [13-17], ppFEV 1 was 72.8 [59.6-80.7], and LCI was 12.3 [10.3-15.0]. At both M6 and M12, no statistically significant LCI increases of 0.13 units or 1.34% (95% CI: -4.85-7.53) and 0.6 units or 6.66% (95% CI: -0.03-13.5) were observed. Discordant results between LCI and ppFEV 1 were observed in one-third of the patients. In daily practice, LCI monitoring in adolescents and young adults with moderate lung disease gives results that are more heterogenous than those reported in children with milder disease., (Copyright © 2021 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Background: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV 1 ) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV 1 ., Methods: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV 1 <40 or ppFEV 1 ≥90 in comparison with those with ppFEV 1 [40-90[. Analysis of data collected during a real world study, which included all patients aged ≥12 years who started LUMA-IVA in 2016 across all 47 French CF centers., Results: 827 patients were classified into 3 subgroups according to ppFEV 1 at treatment initiation (ppFEV 1 <40, n = 121; ppFEV 1 [40-90[, n = 609; ppFEV 1 ≥90, n = 97). Treatment discontinuation rate was higher in ppFEV 1 <40 patients (28.9%) than in those with ppFEV 1 [40-90[(16.4%) or ppFEV 1 ≥90 (17.5%). In patients with uninterrupted treatment, significant increase in ppFEV 1 occurred in the ppFEV 1 [40-90[subgroup (+2.9%, P<0.001), and in those ppFEV 1 <40 (+0.5%, P = 0.03) but not in those with ppFEV 1 ≥90 (P = 0.46). Compared with the year prior to initiation, the number of days of intravenous antibiotics were reduced in all subgroups, although 72% of patients with ppFEV 1 <40 still experienced at least one exacerbation/year under LUMA-IVA. Comparable increase in body mass index was seen in the three subgroups., Conclusion: Phe508del homozygous CF patients benefit from LUMA-IVA at all levels of baseline lung function , but the characteristics and magnitude of the response vary depending on ppFEV 1 at baseline., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest related to the work submitted for publication., (Copyright © 2020. Published by Elsevier B.V.)

Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation. Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting. Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations. Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV 1 (ppFEV 1 ) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV 1 (+3.67%), an increase in body mass index (+0.73 kg/m 2 ), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV 1 , without improvement in body mass index or decrease in intravenous antibiotic courses. Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.

The combination of lumacaftor and ivacaftor (LUM/IVA) has been reported to induce a mean acute absolute drop of -4.1% predicted forced expiratory volume in 1s (FEV 1 ) after a unique administration in healthy subjects. The aim of the present study was to assess acute FEV 1 changes after the first dose of LUM/IVA in CF patients. A total of 32 pediatric patients were included. Respiratory manifestations occurred in only 3 patients (9.4%), but FEV 1 consistently decreased (-10.4±4.6%, range: -1.5; -21.8%). FEV 1 only partially resumed after salbutamol inhalation. Patients with previously known significant reversible airway obstruction and low FEV 1 were more at risk of FEV 1 decrease., (Copyright © 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)