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AbstractIntroduction Vaccination hesitancy is an important barrier to vaccination among IBD patients. The development of adverse events is the main concern reported. The purpose of this monocentric study was to assess SARS-CoV-2 vaccination safety in IBD patients by evaluating the postvaccination flare risk and incidence of overall adverse events.Methods Surveys were handed out on three consecutive months to each patient presenting at the Crohn-Colitis Centre, where they documented their vaccination status and any side effects experienced after vaccination.Dates of flares occurring in 2021 were recorded from their electronic medical records. Baseline and IBD characteristics and flare incidence were compared between the vaccinated and unvaccinated patients, and among the vaccinated population before and after their vaccination doses. The characteristics of patients who developed side effects and of those who did not were compared.Results We enrolled 396 IBD patients, of whom 91% were vaccinated. The proportion of patients who experienced flares was statistically not different between the vaccinated and the unvaccinated population (1.8 vs 2.6 flares per 100 person-months (p = 0.28)). Among vaccinated patients, there was no difference across the prevaccination, 1 month post any vaccination, and more than 1 month after any vaccination periods, and between the Spikevax and Cominarty subgroups. Overall, 46% of patients reported vaccination side effects, mostly mild flu-like symptoms.Conclusion SARS-CoV-2 vaccination with mRNA vaccines seems safe, with mostly mild side effects. The IBD flare risk is not increased in the month following any vaccination.

Background: Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx., Methods: In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of pulmonary oedema., Results: After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups., Conclusions: Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model., Trial Registration: The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408)., Competing Interests: Declaration of competing interest KH, MK, and TL are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. WS and AG are employees of Boehringer Ingelheim International. JMH has received grants to his institution for clinical trial conduct and personal fees for consultancy from Boehringer Ingelheim Pharma GmbH & Co. KG. CG, JVC, PB, and MM have nothing to declare., (Copyright © 2023. Published by Elsevier Ltd.)

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.)

Background: Inhibition of the epithelial sodium channel (ENaC) represents a mutation-agnostic therapeutic approach to restore airway surface liquid hydration and mucociliary clearance in patients with cystic fibrosis. BI 1265162 is an inhaled ENaC inhibitor with demonstrated preclinical efficacy., Methods: Three phase I trials of BI 1265162 in healthy male subjects are presented: NCT03349723 (single-rising-dose trial evaluating safety, tolerability and pharmacokinetics (PK)); NCT03576144 (multiple-rising-dose trial evaluating safety, tolerability and PK); and NCT03907280 (absolute bioavailability trial)., Results: BI 1265162 single doses ≤1200 µg and multiple doses of 600 µg were well tolerated. Adverse events were balanced across treatment groups, were of mainly mild or moderate intensity and resolved by trial-end. One subject discontinued from trial medication on day 7 (asymptomatic hyperkalaemia adverse event; recovered day 8). One subject experienced a serious adverse event (neuropathia vestibularis) leading to hospitalisation and missed one of the four dosing periods. Both events were not considered to be drug-related and subjects recovered. BI 1265162 displayed dose-proportional, time-independent PK; maximum accumulation was 1.6-fold; calculated effective elimination half-life was 3.6-8.7 h over the dose ranges tested. Renal excretion was not a major drug elimination route. Oral and inhaled dosing (±activated oral charcoal) absolute bioavailability was 0.50% and ∼40%, respectively., Conclusion: BI 1265162 single or multiple doses up to 6.5 days were well tolerated. Systemic exposures mainly represent drug absorbed through the lungs and not the gastrointestinal tract, with ∼40% of the inhaled dose reaching the systemic circulation. Accumulation was minimal. Twice-daily dosing is supported for future development., Competing Interests: Conflict of interest: A. Mackie is an employee of Boehringer Ingelheim. Conflict of interest: J. Rascher has nothing to disclose. Conflict of interest: M. Schmid is an employee of Boehringer Ingelheim. Conflict of interest: V. Endriss is an employee of Boehringer Ingelheim. Conflict of interest: T. Brand is an employee of Boehringer Ingelheim. Conflict of interest: W. Seibold is an employee of Boehringer Ingelheim., (Copyright ©ERS 2021.)

Inhibition of the epithelial sodium channel (ENaC) represents an important, mutation-agnostic therapeutic approach to restore airway surface liquid in patients with cystic fibrosis (CF). A phase II trial of the ENaC inhibitor BI 1265162, inhaled via the Respimat® Soft Mist™ inhaler, in patients aged ≥12 years with CF is being conducted to assess the efficacy and safety of BI 1265162, on top of standard CF treatment (www.clinicaltrials.gov identifier NCT04059094). BALANCE-CF™ 1 is a multinational, randomised, double-blind, placebo-controlled, parallel-group, dose-ranging trial consisting of 2 weeks' screening, 4 weeks' randomised treatment and 1 week follow-up. 98 patients, including ≥21 adolescents, will be randomised. First, 28 patients will be allocated to the highest dose of BI 1265162 (200 µg twice daily) or placebo in a 1:1 ratio. The remaining 70 patients will be allocated to one of five treatment arms (200 µg, 100 µg, 50 µg, 20 µg or placebo twice daily), with a final distribution ratio of 2:1:1:1:2. Recruitment and randomisation will begin with adult patients. An independent data monitoring committee will review safety data to advise on inclusion of adolescents and study continuation. A futility analysis will be conducted after 28 patients to prevent exposure of further patients in case of insufficient evidence of clinical efficacy. The design ensures that potential for effect is assessed ahead of wider enrolment, allowing investigation of a dose-response effect with minimal patient numbers. The results will increase understanding of efficacy, safety and optimal dosing of the inhaled ENaC inhibitor BI 1265162 in adults and adolescents with CF., Competing Interests: Conflict of interest: C.H. Goss reports funding for conducting exacerbation studies in cystic fibrosis (CF) from the Cystic Fibrosis Foundation, funding to study the role of microbiome in the treatment of exacerbation in CF from the European Commission, funding to conduct a study of home monitoring in pulmonary exacerbation from the NIH (NHLBI), and funding to support clinical research in CF and clinical trials in other disease entities from the NIH (NIDDK and NCRR), during the conduct of the study; personal fees for serving as a Chair of a Grant Review Committee from Gilead Sciences, personal fees for serving as a DSMB Chair for a trial supported by Novartis and the European Commission from Novartis, funding to study a novel antimicrobial in CF from the NIH and the FDA, serving a US lead in a phase 2 trial of novel therapy for CF, receiving travel expenses and an honorarium for meeting participation, and a future site contract for trial participation from Boehringer Ingelheim, and honoraria and travel expenses for talk at Nottingham LEAD conference from Vertex Pharmaceuticals, outside the submitted work. None of the work presented in this opinion piece was influenced by the funding sources noted above. The funding sources that support other ongoing research played no role in writing this manuscript or in the decision to submit for publication. Conflict of interest: R. Jain reports grants and personal fees from Vertex Pharmaceuticals, personal fees from Gilead Sciences, and grants from the CF Foundation, outside the submitted work. Conflict of interest: W. Seibold is an employee of Boehringer Ingelheim. Conflict of interest: A-C. Picard is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: M-C. Hsu is an employee of Boehringer Ingelheim (China) Investment Co. Ltd. Conflict of interest: A. Gupta is an employee of Boehringer Ingelheim International GmbH. Conflict of interest: I. Fajac reports grants and personal fees for study conduct and expert advice from Boehringer during the conduct of the study, and from Proteostasis Therapeutics and Vertex Pharmaceuticals outside the submitted work., (Copyright ©ERS 2020.)

Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) was initiated in the first year of the Innovative Medicines Initiative (IMI). It was an ambitious plan to tackle the understanding of asthma through an integration of clinical and multi-'omics approaches that necessitated the bringing together of industry, academic, and patient representatives because it was too large to be managed by any one of the partners in isolation. It was a novel experience for all concerned. In this review, we describe the main features of the U-BIOPRED experience from the industry perspective. We list some of the key advantages and learnings from the perspective of the authors, and also improvements that we feel could be made in future projects., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

U-BIOPRED is a European Union consortium of 20 academic institutions, 11 pharmaceutical companies and six patient organisations with the objective of improving the understanding of asthma disease mechanisms using a systems biology approach.This cross-sectional assessment of adults with severe asthma, mild/moderate asthma and healthy controls from 11 European countries consisted of analyses of patient-reported outcomes, lung function, blood and airway inflammatory measurements.Patients with severe asthma (nonsmokers, n=311; smokers/ex-smokers, n=110) had more symptoms and exacerbations compared to patients with mild/moderate disease (n=88) (2.5 exacerbations versus 0.4 in the preceding 12 months; p<0.001), with worse quality of life, and higher levels of anxiety and depression. They also had a higher incidence of nasal polyps and gastro-oesophageal reflux with lower lung function. Sputum eosinophil count was higher in severe asthma compared to mild/moderate asthma (median count 2.99% versus 1.05%; p=0.004) despite treatment with higher doses of inhaled and/or oral corticosteroids.Consistent with other severe asthma cohorts, U-BIOPRED is characterised by poor symptom control, increased comorbidity and airway inflammation, despite high levels of treatment. It is well suited to identify asthma phenotypes using the array of "omic" datasets that are at the core of this systems medicine approach., (Copyright ©ERS 2015.)

Background: Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting beta-agonists (LABAs)., Methods: In two replicate, randomized, controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs, we compared the effect on lung function and exacerbations of adding tiotropium (a total dose of 5 μg) or placebo, both delivered by a soft-mist inhaler once daily for 48 weeks. All the patients were symptomatic, had a post-bronchodilator forced expiratory volume in 1 second (FEV(1)) of 80% or less of the predicted value, and had a history of at least one severe exacerbation in the previous year., Results: The patients had a mean baseline FEV(1) of 62% of the predicted value; the mean age was 53 years. At 24 weeks, the mean (±SE) change in the peak FEV(1) from baseline was greater with tiotropium than with placebo in the two trials: a difference of 86±34 ml in trial 1 (P=0.01) and 154±32 ml in trial 2 (P<0.001). The predose (trough) FEV(1) also improved in trials 1 and 2 with tiotropium, as compared with placebo: a difference of 88±31 ml (P=0.01) and 111±30 ml (P<0.001), respectively. The addition of tiotropium increased the time to the first severe exacerbation (282 days vs. 226 days), with an overall reduction of 21% in the risk of a severe exacerbation (hazard ratio, 0.79; P=0.03). No deaths occurred; adverse events were similar in the two groups., Conclusions: In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation. (Funded by Boehringer Ingelheim and Pfizer; ClinicalTrials.gov numbers, NCT00772538 and NCT00776984.).

Objective: The aim of this study was to determine the occurrence of apoptosis in relation to the proliferative response in the intimal layer after experimental balloon angioplasty of a pre-existing plaque., Methods: After induction of an intimal plaque in the right carotid artery by electrical stimulation, 26 rabbits underwent balloon angioplasty. Twelve animals served as a control group without performance of angioplasty after plaque induction. To study the time course of intimal apoptosis and cell proliferation the vessels were excised on day 7, 14 and 28 after balloon angioplasty. For in situ detection of apoptosis, the TUNEL-technique (TdT-mediated d-UTP fluorescein nick end labeling) was used. In addition, bromodeoxyuridine labeling in all animals allowed the determination of the percentage of cells undergoing DNA synthesis in the neointimal area. Additionally, smooth muscle cells were detected by immunostaining of alpha-actin and macrophages by a specific antibody (RAM 11)., Results: Within 28 days of balloon angioplasty, the number of cells undergoing apoptosis remained at a very low level and was not significantly different to the control group without interventional treatment (controls: 0.1 +/- 0.15%; 7 days: 0.44 +/- 0.68%; 14 days: 0.13 +/- 0.11%; 28 days: 0.1 +/- 0.1%). In contrast, the number of cells undergoing DNA synthesis was significantly increased at day 7 after angioplasty (3.72 +/- 2.0% vs. 0.51 +/- 0.29% in controls), resulting in an increase of the total intimal area from 0.088 +/- 0.037 mm2 in the control animals up to 0.256 +/- 0.172 mm2 at day 28 following balloon dilatation., Conclusions: Our data showed that significant changes in the occurrence of apoptosis are not involved in the regulation of cellular turnover during the examined time period after vessel wall injury. The lacking up-regulation of apoptosis in comparison to the increased cell proliferation in order to maintain the tissue balance is perhaps an important regulatory mechanism leading to intimal hyperplasia after vascular injury in this animal model. Overall, we suggest that there may be a delicate balance between cell proliferation and apoptosis in smooth muscle cells of the vessel wall, and only small shifts in this balance could account for both cellular accumulation in restenotic lesions as well as cell death in mature atheroma.

Background: Antioxidant treatment seems to reduce the development of restenosis after percutaneous transluminal angioplasty. In this study, the effect of Nicanartine, a new antioxidant drug with both antiproliferative and lipid-lowering properties, on the proliferative and inflammatory response after balloon angioplasty was investigated in a rabbit model of restenosis., Methods: To induce pre-interventional plaques in the common carotid artery of 48 New Zealand White rabbits, electrostimulation was carried out for 28 days. After a break of 7 days, balloon angioplasty was performed in 36 animals, of which 18 received Nicanartine at a dose of 120 mg/kg body weight; the other 18 served as a control group. The vessels were excised by day 7 and 28 after balloon angioplasty and examined for intimal plaque size, macrophage content and proliferative activity. Bromodeoxyuridine labeling was used to determine proliferating cells in the dilated segment; macrophages were detected using the RAM-11 antibody., Results: In the Nicanartine-treated group, immunohistological quantification 7 days after intervention showed a statistically significant (P< 0.05) reduction of both cells undergoing DNA synthesis (1.6+/-1.4% versus 3.7+/-2.2%) and intimal macrophages (0.7+/-1.2% versus 1.3+/-0.6%). Twenty-eight days after balloon angioplasty, proliferative activity in both groups was decreased to a level comparable to the non-dilated control groups. A clear trend towards smaller plaques could be seen in the Nicanartine group (0.146+/-0.077 mm2 versus 0.255+/-0.174 mm2). Total cholesterol levels did not differ significantly between the groups., Conclusion: Under treatment with Nicanartine a clear reduction in the proliferative and inflammatory response after balloon angioplasty was observed. Antioxidant treatment, especially with compounds having antiproliferative and lipid-lowering properties, appears to be an effective secondary preventive strategy after interventional treatment in patients with coronary artery disease.