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Background: Inhibition of the epithelial sodium channel (ENaC) in cystic fibrosis (CF) airways provides a mutation-agnostic approach that could improve mucociliary clearance in all CF patients. BI 1265162 is an ENaC inhibitor with demonstrated pre-clinical efficacy and safety already demonstrated in humans., Objective: We present results from BALANCE-CF TM 1, a phase II, placebo-controlled, randomised, double-blind study of four dose levels of BI 1265162 versus placebo for 4 weeks on top of standard of care in adults and adolescents with CF., Results: Initially, 28 randomised subjects (BI 1265162 200 µg twice daily n=14, placebo twice daily n=14) were assessed at an interim futility analysis. Compared with placebo, numerical changes of -0.8% (95% CI -6.6 to 4.9%) in percentage predicted forced expiratory volume in 1s (ppFEV 1 ) and +2.1 units (95% CI -2.4 to 6.5 units) in lung clearance index (LCI) were observed in the active group, meeting a pre-defined stopping rule; accordingly, the study was terminated. Recruitment had continued during the interim analysis and pending results; 24 patients were added across three dose levels and placebo. The final results including these patients (+1.5% ppFEV 1 , 200 µg twice-daily dose versus placebo) were not supportive of relevant clinical effect. Furthermore, LCI change was not supportive, although interpretation was limited due to insufficient traces meeting quality criteria. A 9.4-point improvement in the Cystic Fibrosis Questionnaire - Revised Respiratory Domain was observed in the 200 µg twice daily dose group versus placebo. BI 1265162 up to 200 µg twice daily was safe and well-tolerated. Pharmacokinetics were similar to those in healthy volunteers., Conclusion: BI 1265162 was safe, but did not demonstrate a potential for clinical benefit. Development has been terminated., Competing Interests: Conflict of interest: C.H. Goss reports grants from the Cystic Fibrosis Foundation, the European Commission and NIH (NHLBI, NIDDK and NCRR), during the conduct of the study; personal fees for grant review board work from Gilead Sciences, personal fees for data monitoring committee work from Novartis, grants from the NIH and FDA, non-financial support (reimbursement for travel and meeting attendance) and other (serving as trial lead with site contract) from Boehringer Ingelheim, personal fees for lectures from Vertex Pharmaceuticals, outside the submitted work. Conflict of interest: I. Fajac reports grants and personal fees for consultancy from Boehringer, during the conduct of the study; grants and personal fees for consultancy from Proteostasis Therapeutics and Vertex Pharmaceuticals, personal fees for consultancy from Kither Biotech, outside the submitted work. Conflict of interest: R. Jain reports grants and personal fees for consultancy from Vertex Pharmaceuticals, grants from the CF Foundation, Sound Pharma, Armata Pharmaceuticals, Corbus Pharmaceuticals and Genetech, grants and personal fees for advisory board work from Boehringer Ingelheim, outside the submitted work. Conflict of interest: W. Seibold is an employee of Boehringer Ingelheim. Conflict of interest: A. Gupta is an employee of Boehringer Ingelheim. Conflict of interest: M-C. Hsu is a former employee of Boehringer Ingelheim (China) and current employee of Shanghai Junshi Biosciences Co Ltd. Conflict of interest: S. Sutharsan reports personal fees for advisory board work from Vertex Pharmaceuticals, personal fees for lectures from Novartis, outside the submitted work. Conflict of interest: J.C. Davies reports other (advisory board and clinical trial lead) from Algipharma AS, Bayer AG, Galapagos NV and Proteostasis Therapeutics, Inc., other (advisory board) from Boehringer Ingelheim Pharma GmbH & Co. KG, Nivalis Therapeutics, Inc., Raptor Pharmaceuticals, Inc., Enterprise, Novartis, ProQR Therapeutics III BV, Pulmocide and Flatley, other (advisory board and trial design assistance) from ImevaX GmbH and ProQR Therapeutics III BV, other (advisory board and national co-ordinator/global co-investigator) from Vertex Pharmaceuticals (Europe) Limited, grants from the CF Trust, other (educational activities) from Teva, outside the submitted work. Conflict of interest: M.A. Mall reports grants, personal fees for advisory board work and non-financial support (travel expenses) from Boehringer Ingelheim, during the conduct of the study; personal fees for advisory board work, consultancy and lectures from Boehringer Ingelheim, personal fees for advisory board work and consultancy from Arrowhead Pharmaceuticals, Santhera, Enterprise Therapeutics, Antabio and Kither Biotech, grants and personal fees for advisory board work, consultancy and lectures from Vertex Pharmaceuticals, personal fees for consultancy from Galapagos and Sterna Biologicals, personal fees for lectures from Celtaxys, outside the submitted work., (Copyright ©The authors 2022.)

We aimed to characterise lymphoid neogenesis in bronchiectasis and cystic fibrosis (CF) lungs and to examine the role of bacterial infection.Lymphoid aggregates were examined using immunohistochemical staining and morphometric analysis in surgical lung sections obtained from nonsmokers and patients with bronchiectasis or CF. Sterile, Pseudomonas aeruginosa - or Staphylococcus aureus -coated agarose beads were instilled intratracheally in mice. Kinetics of lymphoid neogenesis and chemokine expression were examined over 14 days.Lymphoid aggregates were scarce in human lungs of nonsmokers, but numerous peribronchial lymphoid aggregates containing B-lymphocytes, T-lymphocytes, germinal centres and high endothelial venules were found in bronchiectasis and CF. Mouse lungs contained no lymphoid aggregate at baseline. During persistent P. aeruginosa or S. aureus airway infection peribronchial lymphoid neogenesis occurred. At day 14 after instillation, lymphoid aggregates expressed markers of tertiary lymphoid organs and the chemokines CXCL12 and CXCL13. The airway epithelium was an important site of CXCL12, CXCL13 and interleukin-17A expression, which began at day 1 after instillation.Peribronchial tertiary lymphoid organs are present in bronchiectasis and in CF, and persistent bacterial infection triggered peribronchial lymphoid neogenesis in mice. Peribronchial localisation of tertiary lymphoid organs and epithelial expression of chemokines suggest roles for airway epithelium in lymphoid neogenesis., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

Progressive cystic fibrosis (CF) lung disease is the main cause of mortality in CF patients. CF lung disease starts in early childhood. With current standards of care, respiratory function remains largely normal in children and more sensitive outcome measures are needed to monitor early CF lung disease. Chest CT is currently the most sensitive imaging modality to monitor pulmonary structural changes in children and adolescents with CF. To quantify structural lung disease reliably among multiple centres, standardisation of chest CT protocols is needed. SCIFI CF (Standardised Chest Imaging Framework for Interventions and Personalised Medicine in CF) was founded to characterise chest CT image quality and radiation doses among 16 participating European CF centres in 10 different countries. We aimed to optimise CT protocols in children and adolescents among several CF centres. A large variety was found in CT protocols, image quality and radiation dose usage among the centres. However, the performance of all CT scanners was found to be very similar, when taking spatial resolution and radiation dose into account. We conclude that multicentre standardisation of chest CT in children and adolescents with CF can be achieved for future clinical trials., (Copyright ©ERS 2016.)

Peribronchial angiogenesis may occur in cystic fibrosis and vascular endothelial growth factor (VEGF)-A regulates angiogenesis in airways. Peribronchial vascularity and VEGF-A expression were examined using immunocytochemistry and morphometric analysis in lung sections obtained in 10 cystic fibrosis patients at transplantation versus 10 control nonsmokers, and in two strains of Cftr-deficient mice versus wild-type littermates. Airway epithelial NCI-H292 cells and primary cultures of noncystic fibrosis human airway epithelial cells were treated with cystic fibrosis transmembrane conductance regulator (CFTR) inhibitors (CFTR-inh(172) or PPQ-102) or transfected with a CFTR small interfering (si)RNA with or without a selective epidermal growth factor receptor tyrosine kinase inhibitor. Concentrations of VEGF-A and phosphorylated epidermal growth factor receptor were measured by ELISA. Peribronchial vascularity was increased in cystic fibrosis patients, but not in Cftr-deficient mice. VEGF-A immunostaining was localised to airway epithelium and was increased in cystic fibrosis patients and in Cftr-deficient mice. In cultured airway epithelial cells, treatment with CFTR inhibitors or transfection with CFTR siRNA induced a twofold increase in VEGF-A production. CFTR inhibitors triggered epidermal growth factor receptor phosphorylation that was required for VEGF-A synthesis. Cystic fibrosis airways at transplantation showed increased peribronchial vascularity and epithelial VEGF-A expression. CFTR dysfunction triggered epithelial synthesis of VEGF-A, which may contribute to vascular remodelling.

In patients with cystic fibrosis, cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers, such as sweat chloride concentration and/or nasal potential difference, are used as end-points of efficacy in phase-III clinical trials with the disease modifying drugs ivacaftor (VX-770), VX809 and ataluren. The aim of this project was to review the literature on reliability, validity and responsiveness of nasal potential difference, sweat chloride and intestinal current measurement in patients with cystic fibrosis. Data on clinimetric properties were collected for each biomarker and reviewed by an international team of experts. Data on reliability, validity and responsiveness were tabulated. In addition, narrative answers to four key questions were discussed and agreed by the team of experts. The data collected demonstrated the reliability, validity and responsiveness of nasal potential difference. Fewer data were found on reliability of sweat chloride concentration; however, validity and responsiveness were demonstrated. Validity was demonstrated for intestinal current measurement, but further information is required on reliability and responsiveness. For all three end-points, normal values were collected and further research requirements were proposed. This body of work adds useful information to support the promotion of CFTR biomarkers to surrogate end-points and to guide further research in the area.