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Competing Interests: ML reports grants for research or clinical trials, paid to his institution, from AstraZeneca, Deutsche Forschungsgemeinschaft (DFG), and GSK; and consulting fees, travel expenses, or honoraria for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, Leti, Novartis, MSD, Sanofi, Stallergenes, and Teva. RB reports grants, paid to his institution, from Boehringer Ingelheim, GSK, Novartis, and Roche; speaker fees from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Sanofi, Roche, and Teva; and payment for advisory board participation from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, Novartis, Sanofi, Roche, and Teva. GWC reports research or clinical trial grants, paid to his institution, from Menarini, AstraZeneca, GSK, Sandi, and Genzyme; and personal fees for lectures and advisory board participation from Menarini, AstraZeneca, Chiesi, Faes Farma, Genentech, Guidotti-Malesci, GSK, HAL Allergy, Innovacaremed, Novartis, OM Pharma, Red Maple, Sanofi-Aventis, Sanofi-Genzyme, Stallergenes, and Uriach Pharma. CDR reports funding for travel and speaker fees from Novartis, Sanofi, GSK, TEVA, MSD, Almirall, AstraZeneca, Chiesi, Menarini, Stallergens, ALK-Abello, Allergy Therapeutics, HAL Allergy, Immunotek, and Royal. HN reports grants from GSK and personal fees from AstraZeneca, GSK, Kyorin Pharmaceutical, Novartis, and Sanofi; he is a scientific advisor for GSK. GGB reports personal fees for advisory board participation and lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, and Sanofi, outside of the submitted work. DJJ has received an investigator-initiated research grant from AstraZeneca and reports fees for advisory board participation and lectures from AstraZeneca, Sanofi, and GSK. In the past 5 years, IDP has received honoraria for speaking at sponsored meetings from AstraZeneca, Aerocrine, Chiesi, Sanofi/Regeneron, Menarini, and GSK; payments for organising educational events from AstraZeneca, GSK, Sanofi/Regeneron, and Teva; honoraria for advisory panel participation from Genentech, Sanofi/Regeneron, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Teva, Merck, Circassia, Chiesi, and Knopp; and sponsorship to attend international scientific meetings from GSK, AstraZeneca, Teva, and Chiesi. SK reports consulting fees and speaker fees from AstraZeneca, GSK, Chiesi, Sanofi, and Novartis. KM reports consulting fees and speaker frees from AstraZeneca, GSK, and Sanofi; and speaker fees from Chiesi and Novartis. JCV reports research grants from DFG, Land Mecklenburg-Vorpommern, GSK, and MSD; he has given independent lectures for and received honoraria from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Lupin, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Regeneron, Revotar, Sandoz-Hexal, Sanofi-Aventis, Stallergens, TEVA, UCB/Schwarz-Pharma, and Zydus/Cadila; and participated on advisory boards and provided independent advice for AstraZeneca, Avontec, Bayer, Bencard, Boehringer Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Regeneron, Revotar, Roche, Sanofi-Aventis, Sandoz-Hexal, TEVA, and UCB/Schwarz-Pharma. CT declares no competing interests.

Introduction: The Severe Asthma Registry, founded by German Asthma Net (GAN) in 2011, is a prospective registry recording clinical parameters from participating centers in Germany, Austria and Switzerland. This article presents the baseline characteristics of severe asthma patients from Austrian centers., Methods: We analyzed the baseline visit data of all patients recruited to the GAN Severe Asthma Registry from participating Austrian centers., Results: Baseline visit data were available for 214 Austrian severe asthma patients from 6 Austrian centers from 2013 to 2022. Mean age was 53.7 years. Mean BMI was 26.4 kg/m2. More than a third (37.4%) of all patients had daily daytime asthma symptoms at baseline and had to use their reliever medication at least once per day. Forty-one percent of patients were classified as uncontrolled according to GINA and 24.8% as partially controlled at baseline visit. The median annual exacerbation frequency was 3 in the previous 12 months. At the time of baseline visit, 23.4% of all patients had regular treatment with oral corticosteroids. Furthermore, 23.9% had received any severe asthma monoclonal antibody prior to the baseline visit. There were no notable differences in baseline characteristics between patients categorized by smoking history or measurable type 2 inflammation., Conclusions: This study provides the first multi-center characterization of Austrian severe asthma patients. Patients in this cohort had better asthma control and less frequent exacerbations compared to most international registries., Competing Interests: Declaration of competing interest Andreas Renner: None. Slagjana Stoshikj: Speaker fees from AstraZeneca, all outside the submitted work. Wolfgang Pohl: Speaker fees from AstraZeneca, Chiesi, GSK, Novartis, and Sanofi, all outside the submitted work. Christina Bal: speaker fees from AstraZeneca and IVEPA, all outside the submitted work. Matthias Reisinger: None. Judith Löffler-Ragg: None. Angela Zacharasiewicz: None. Roland Buhl: Grants to Mainz University and personal fees from Boehringer Ingelheim, GSK, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi, and Teva, all outside the submitted work. Eckard Hamelmann: funded by the German Ministry of Education and Reserch (BMBF) as consortional partner in CHAMP (01GL1742D) for research in severe asthma in children. Christian Taube: None. Stephanie Korn: speaker fees from AstraZenca, GSK, Novartis, and Sanofi, all outside the submitted work. Marco Idzko: lecture fees from AstraZeneca, Bayer, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Menarini, MSD, Novartis, Roche, Sanofi, and Thermofischer; and advisory board fees from Alk-Pharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, CSL-Behring, GSK, Novartis, and Sanofi, all outside the submitted work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Recently, criteria for evaluation of response to biologics have been proposed and the concept of clinical remission has gained attention as a possible goal even in severe asthma., Objective: To analyze the response and remission in the German Asthma Net severe asthma registry cohort., Methods: We included adults not using a biologic at baseline (V0) and compared patients treated between V0 and 1-year visit (V1) without using a biologic (group A) to patients starting with a biologic after V0 and continuing it up to V1 (group B). We applied the Biologics Asthma Response Score to quantify composite response in good, intermediate, or insufficient. We defined clinical remission (R) as absence of significant symptoms (Asthma Control Test score ≥ 20 at V1) in the absence of exacerbations and oral corticosteroid therapy., Results: Group A included 233 and group B 210 patients, the latter receiving omalizumab (n = 33), mepolizumab (n = 40), benralizumab (n = 81), reslizumab (n = 1), or dupilumab (n = 56). At baseline, group B had less often an allergic phenotype (35.2% vs 41.6%), lower Asthma Control Test score (median, 12 vs 14), more exacerbations in the past year (median, 3 vs 2), and more often high-dose inhaled corticosteroid treatment (71.4% vs 51.5%) than group A. After 1 year of treatment, rates of response (good: 61.4% vs 34.8%; intermediate: 26.7% vs 42.9%; insufficient: 11.9% vs. 22.3%) and/or clinical remission (37.6% vs 17.2%) were higher in group B than in group A., Conclusions: Despite more severe asthma at baseline, patients treated with biologics had a markedly higher probability of achieving good clinical response and/or remission than patients treated without biologics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The management of asthma has fundamentally changed during the past decades. The present guideline for the diagnosis and treatment of asthma was developed for respiratory specialists who need detailed and evidence-based information on the new diagnostic and therapeutic options in asthma. The guideline shows the new role of biomarkers, especially blood eosinophils and fractional exhaled NO (FeNO), in diagnostic algorithms of asthma. Of note, this guideline is the first worldwide to announce symptom prevention and asthma remission as the ultimate goals of asthma treatment, which can be achieved by using individually tailored, disease-modifying anti-asthmatic drugs such as inhaled steroids, allergen immunotherapy or biologics. In addition, the central role of the treatment of comorbidities is emphasized. Finally, the document addresses several challenges in asthma management, including asthma treatment during pregnancy, treatment of severe asthma or the diagnosis and treatment of work-related asthma., Competing Interests: Eine Übersicht der Interessenkonflikte findet sich im Internet unter http://awmf.org; AWMF-Registriernummer 020-009., (Thieme. All rights reserved.)

The Global Initiative for Asthma (GINA) was established in 1993 by the World Health Organization and the US National Heart Lung and Blood Institute to improve asthma awareness, prevention and management worldwide. GINA develops and publishes evidence-based, annually updated resources for clinicians. GINA guidance is adopted by national asthma guidelines in many countries, adapted to fit local healthcare systems, practices, and resource availability. GINA is independent of industry, funded by the sale and licensing of its materials. This review summarizes key practical guidance for primary care from the 2022 GINA strategy report. It provides guidance on confirming the diagnosis of asthma using spirometry or peak expiratory flow. GINA recommends that all adults, adolescents and most children with asthma should receive inhaled corticosteroid (ICS)-containing therapy to reduce the risk of severe exacerbations, either taken regularly, or (for adults and adolescents with "mild" asthma) as combination ICS-formoterol taken as needed for symptom relief. For patients with moderate-severe asthma, the preferred regimen is maintenance-and-reliever therapy (MART) with ICS-formoterol. Asthma treatment is not "one size fits all"; GINA recommends individualized assessment, adjustment, and review of treatment. As many patients with difficult-to-treat or severe asthma are not referred early for specialist review, we provide updated guidance for primary care on diagnosis, further investigation, optimization and treatment of severe asthma across secondary and tertiary care. While the GINA strategy has global relevance, we recognize that there are special considerations for its adoption in low- and middle-income countries, particularly the current poor access to inhaled medications., (© 2023. The Author(s).)

Competing Interests: Declaration of interests ML has received consulting fees or honoraria, or both for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GSK, HAL Allergy, Leti, Novartis, MSD, Sanofi, and TEVA; and grants for research or clinical trials, or both from Deutsche Forschungsgemeinschaft, AstraZeneca, and GSK. GGB has received honoraria for lectures from AstraZeneca, GSK, Boehringer Ingelheim, Novartis, Chiesi, and Sanofi. GWC has received consulting fees or honoraria, or both for lectures from AstraZeneca, Chiesi, Novartis, Sanofi, Menarini, Stallergenes Greer, GSK, and HAL Allergy. DJJ has received consulting fees or honoraria or both for lectures from AstraZeneca, GSK, and Sanofi; and grants for research from AstraZeneca. PN has received personal fees or grants, or both from AstraZeneca, TEVA, Sanofi, Equillium, Foresee, Arrowhead Pharma, Cyclomedica, and GSK. RB has received consulting fees or honoraria, or both for lectures from ALK, Allergopharma, AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GSK, HAL Allergy, Leti, Novartis, Roche, Sanofi, and TEVA; and grants for research or clinical trials, or both from Boehringer Ingelheim, GSK, Novartis, and Roche. JCV has received consulting fees or honoraria, or both for lectures from AstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer Ingelheim, Chiesi, Genzyme, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed (Altana), Pfizer, Regeneron, Revotar, Sanofi, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, and Cadila; and received grants for research or clinical trials, or both from Deutsche Forschungsgemeinschaft, GSK, and MSD.

The Global Initiative for Asthma (GINA) Strategy Report provides clinicians with an annually updated evidence-based strategy for asthma management and prevention, which can be adapted for local circumstances (e.g., medication availability). This article summarizes key recommendations from GINA 2021, and the evidence underpinning recent changes. GINA recommends that asthma in adults and adolescents should not be treated solely with short-acting β 2 -agonist (SABA), because of the risks of SABA-only treatment and SABA overuse, and evidence for benefit of inhaled corticosteroids (ICS). Large trials show that as-needed combination ICS-formoterol reduces severe exacerbations by ≥60% in mild asthma compared with SABA alone, with similar exacerbation, symptom, lung function, and inflammatory outcomes as daily ICS plus as-needed SABA. Key changes in GINA 2021 include division of the treatment figure for adults and adolescents into two tracks. Track 1 (preferred) has low-dose ICS-formoterol as the reliever at all steps: as needed only in Steps 1-2 (mild asthma), and with daily maintenance ICS-formoterol (maintenance-and-reliever therapy, "MART") in Steps 3-5. Track 2 (alternative) has as-needed SABA across all steps, plus regular ICS (Step 2) or ICS-long-acting β 2 -agonist (Steps 3-5). For adults with moderate-to-severe asthma, GINA makes additional recommendations in Step 5 for add-on long-acting muscarinic antagonists and azithromycin, with add-on biologic therapies for severe asthma. For children 6-11 years, new treatment options are added at Steps 3-4. Across all age groups and levels of severity, regular personalized assessment, treatment of modifiable risk factors, self-management education, skills training, appropriate medication adjustment, and review remain essential to optimize asthma outcomes., (Copyright © 2021 by the American Thoracic Society. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Conflict of interest: L.B. Bacharier reports receiving royalties for textbooks from Elsevier; consulting fees from GlaxoSmithKline, Teva, AstraZeneca, Sanofi, Regeneron, Vectura, Circassia, Kinaset, Merck and Boehringer Ingelheim; honoraria for lectures from GlaxoSmithKline, Genentech/Novartis, Teva Honoraria, AstraZeneca, Sanofi/Regeneron and WebMD/Medscape; participation on a data safety monitoring board or advisory board for DBV Technologies, AstraZeneca and Vertex (CF Foundation); leadership or fiduciary roles in other board, society, committee or advocacy group, paid or unpaid for AAAAI Board of Directors (unpaid) and ABAI Board of Directors, in the past 36 months. E.D. Bateman reports receiving advisory board, consultant and speaker fees from AstraZeneca, Sanofi Genzyme, Regeneron, Novartis and ALK; speaker fees from Boehringer Ingelheim, Menarini and Orion; and advisory board and speaker fees from Chiesi, since the initial planning of this work; E.D. Bateman reports receiving consulting fees from AstraZeneca, Sanofi Genzyme, Regeneron, Novartis and ALK; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Menarini, Orion, Novartis, Regeneron, Sanofi Genzyme, Chiesi and ALK; support for attending meetings and/or travel from Novartis (to attend European Respiratory Society Congress 2021); participation on a data safety monitoring board or advisory board from AstraZeneca, ALK, Sanofi Genzyme, Regeneron, Novartis and Chiesi; leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid for Global Initiative for Asthma (Member of Board and Science Committee, unpaid), in the past 36 months. L-P. Boulet reports grants paid to institution for multicentre or investigator-generated clinical studies from Amgen, AstraZeneca, GlaxoSmithKline, Merck, Novartis and Sanofi-Regeneron; royalties from UpToDate; consultancy fees from AstraZeneca, Novartis, GlaxoSmithKline, Merck and Sanofi-Regeneron; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Covis, GlaxoSmithKline, Novartis, Merck and Sanofi; and is Chair of the Global Initiative for Asthma (GINA) Board of Directors, President of the Global Asthma Organisation (Interasma), member of the Canadian Thoracic Society Respiratory Guidelines Committee, and Laval University Chair on Knowledge Transfer, Prevention and Education in Respiratory and Cardiovascular Health. C.E. Brightling reports receiving grants or contracts from GSK, AZ, Novartis, Chiesi, BI, Mologic, 4DPharma, Gossamer, Merck and Roche/Genentech (all paid to institution); consulting fees from AZ, Novartis, Chiesi, BI, Mologic, TEVA, 4DPharma, Gossamer, Regeneron, Sanofi and Roche/Genentech (all paid to institution), in the past 36 months. G.G. Brusselle reports receiving payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Sanofi and Teva; participation on a data safety monitoring board or advisory board for AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, MSD, Novartis, Sanofi and Teva, in the past 36 months. R. Buhl reports grants from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche; lecture honoraria from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline, Novartis, Roche, Sanofi, Teva; participation on advisory board from AstraZeneca, Berlin-Chemie, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Novartis, Roche, Sanofi, Teva; outside the submitted work; and has acted as a Member of the Scientific Committee of the Global Initiative for Asthma (GINA). A.A. Cruz reports lecture honoraria from Abdi Ibrahim, AstraZeneca, Boehringer Ingelheim, Chiesi, Glennmark, GSK, Mylan, Novartis and Sanofi; travel support from AstraZeneca, Boehringer Ingelheim and Chiesi, outside the submitted work. L. Duijts reports grants from European Union's Horizon 2020 research and innovation programme (LIFECYCLE, grant agreement number 733206, 2016; EUCAN-Connect grant agreement number 824989; ATHLETE, grant agreement number 874583), outside the submitted work. J.M. FitzGerald reports grants from AstraZeneca, GSK, TEVA, Sanofi, CIHR and NIH; consulting fees and lecture honoraria from AstraZeneca, GSK, TEVA and Sanofi; outside the submitted work. L.J. Fleming reports consulting fees from GSK, Sanofi, Respiri UK and AstraZeneca; lecture honoraria from Novartis and Teva, outside the submitted work. H. Inoue reports grants to institution from Boehringer Ingelheim, GlaxoSmithKline, Kyorin, MerckSharp&Dohme and Ono; personal consulting fees from Boehringer Ingelheim; lecture honoraria from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Kyorin, MerckSharp&Dohme, Novartis and Sanofi; has participated on an advisory board for AstraZeneca, GlaxoSmithKline, Novartis and Sanofi; board leadership with Japanese Respiratory Society (Board of Directors and Chairman of Education Committee) and Japanese Society of Allergology (Former Chairman of Education Committee), outside the submitted work. F.W. Ko reports support for travel from Novartis, Boehringer Ingelheim and GSK, outside the submitted work. J.A. Krishnan reports grants from Regeneron Pharmaceuticals, Sergey Brin Family Foundation, Patient Centered Outcomes Research Institute, COPD Foundation and American Lung Association; consulting fees from GlaxoSmithKline for COVID-19 mAb; board leadership at COPD Foundation and Respiratory Health Association, outside the submitted work. M.L. Levy reports grants from Consorzio Futuro in Ricerca and AstraZeneca; royalties from Class Publishing and Taylor & Francis; consulting fees from Respiri, Ltd, TEVA and NSHI Ltd; lecture honoraria from TEVA, Novartis, Chiesi and Orion; payment for expert testimony from HM Coroner Walthamstow, London, and HM Coroner, Waltham Forrest, London; travel support from Orion Pharmaceuticals, Menarini Pharmaceuticals, Napp Pharmaceuticals and TEVA; participation on advisory board at Chiesi, Novartis, GSK and Sandoz; and board leadership at GINA (Board of Directors), outside the submitted work. K. Mortimer has participated as member of advisory boards for AstraZeneca, outside the submitted work. P.M. Pitrez reports consulting fees and lecture honoraria from AstraZeneca, Boehringer Ingelheim, GSK, Sanofi and Novartis; travel support from GSK and Boehringer Ingelheim; and held an unpaid position as President of the Brazilian Severe Asthma Group, outside the submitted work. H.K. Reddel reports grants from AstraZeneca, GlaxoSmithKline and Novartis; consulting fees from Novartis; lecture payments from AstraZeneca, GlaxoSmithKline, Teva, Boehringer Ingelheim, Sanofi and Chiesi; participation on advisory boards for AstraZeneca, GlaxoSmithKline, Novartis, Chiesi and Sanofi; acted as Chair of Scientific Committee and Member of Board of Directors for Global Initiative for Asthma, and acted as Member of Australian Asthma Guidelines Committee for National Asthma Council, outside the submitted work. A. Sheikh reports grants from HDRUK BREATHE Hub, and Asthma UK Centre for Applied Research; and participated in the AstraZeneca Unmet Asthma Need Working Group; outside the submitted work. A.A. Yorgancioglu reports grants from MSD, AstraZeneca, Sanofi and Novartis; consulting fees from AstraZeneca, GSK, Novartis, Sanofi, Chiesi and Deva; lecture honoraria from AstraZeneca, Abdi İbrahim, GSK, Novartis, Sandoz, Chiesi and Vem İlaç; advisory board participation from GSK and AstraZeneca; outside the submitted work. All other authors have nothing to disclose.

The development of mepolizumab, an anti-IL-5 monoclonal antibody for the treatment of severe eosinophilic asthma, is an example of a clinical development program that evolved over time based on sound, basic scientific principles. Initial clinical data on the effects of mepolizumab on lung function in a general asthmatic population were disappointing. However, it became clear that mepolizumab may be more effective against other clinical endpoints, particularly asthma exacerbations, in patients with more severe disease. Furthermore, a developing understanding of asthma disease pathobiology led to the identification of an appropriate target population and predictive biomarker for mepolizumab treatment: patients with severe eosinophilic asthma and blood eosinophil count. Mepolizumab use provides clinically meaningful benefits in this target population, fulfilling an unmet need. This Clinical Commentary Review describes the clinical development of mepolizumab and details of how this program informed the development of other biologic therapies in patients with severe asthma. This account highlights how a personalized approach toward treatment of patients with severe eosinophilic asthma, supported by a large body of scientific evidence, ultimately led to new and effective treatments and improved patient outcomes., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The Global Initiative for Asthma recommends a stepwise approach to adjust asthma treatment to the needs of individual patients; inhaled corticosteroids (ICS) remain the core pharmacological treatment. However, many patients remain poorly controlled, and evidence-based algorithms to decide on the best order and rationale for add-on therapies are lacking. We explore the challenges of asthma management in primary care and review outcomes from randomised controlled trials and meta-analyses comparing the long-acting muscarinic antagonist (LAMA) tiotropium with long-acting β 2 -agonists (LABAs) or leukotriene receptor antagonists (LTRAs) as add-on to ICS in patients with asthma. In adults, LAMAs and LABAs provide a greater improvement in lung function than LTRAs as add-on to ICS. In children, results were positive and comparable between therapies, but data are scarce. This information could aid decision-making in primary care, supporting the use of add-on therapy to ICS to help improve lung function, control asthma symptoms and prevent exacerbations.

This review explores the effect of tiotropium Respimat® add-on therapy on asthma exacerbations and worsenings, adverse events (AEs) related to exacerbations and symptoms and any effects on seasonality across the 10 UniTinA-asthma® clinical trials comprising over 6000 patients. When added on to inhaled corticosteroids ± additional therapies, tiotropium significantly reduced the risk of exacerbations and worsenings in adults with symptomatic severe asthma and provided a non-significant improvement in worsenings in adults with symptomatic moderate and mild asthma, which was significant for patients with moderate asthma receiving tiotropium 2.5 µg once daily vs. placebo. Trials in paediatric patients were not powered to assess exacerbations or worsenings, but when AEs related to asthma exacerbations and symptoms were grouped into a composite endpoint and pooled, tiotropium improved outcomes vs. placebo (rate ratio 0.76; 95% confidence interval 0.63, 0.93). The reduction in exacerbations with tiotropium is apparent across all patients during the observed seasonal peaks of these events.

Background: Asthma is a chronic inflammatory airway disease that usually causes variable airway obstruction. It affects 5-10% of the German population., Methods: This review is based on relevant publications retrieved by a selective search, as well as on national and international guidelines on the treatment of mild and moderate asthma in adults., Results: The goal of treatment is to attain optimal asthma control with a minimal risk of exacerbations and mortality, loss of pulmonary function, and drug side effects. This can be achieved with a combination of pharmacotherapy and non-drug treatment including patient education, exercise, smoking cessation, and rehabilitation. Pharmacohterapy is based on inhaled corticosteroids (ICS) and bronchodilators. It is recommended that mild asthma should be treated only when needed, either with a fixed combination of ICS and formoterol or with short-acting bronchodilators. For moderate asthma, maintenance treatment is recommended, with an inhaled fixed combinations of ICS and long-acting beta-mimetics, possibly supplemented with longacting anticholinergic agents. Allergen immunotherapy, i.e., desensitization treatment, should be considered if the allergic component of asthma is well documented and the patient is not suffering from uncontrolled asthma. Asthma control should be monitored at regular intervals, and the treatment should be adapted accordingly., Conclusion: The treatment of asthma in adults should be individually tailored, with anti-inflammatory treatment as its main component.

Introduction: Mometasone furoate (MF) is the inhaled corticosteroid (ICS) component in the long-acting β 2 -agonist (LABA)/ICS fixed-dose combination of indacaterol/MF, delivered via Breezhaler®, in development for asthma. MF at low (80 μg) and high (320 μg) doses delivered via Breezhaler® is expected to be comparable to MF at low (200 μg) and high (800 μg) doses respectively, delivered via Twisthaler®., Methods: This was a randomized, double-blind, double-dummy, four-week, parallel-group study of 739 adolescents and adults with persistent asthma. Eligible patients were receiving ICS treatment up to the maximum dose per day on a stable regimen for at least four weeks before screening. The study population was enriched for patients who were responsive to ICS therapy. The primary objective of the present study was to show non-inferiority of these doses, i.e. the low (80 μg) and high (320 μg) doses of MF delivered via Breezhaler® once daily, compared with the corresponding low (200 μg) and high (800 μg) doses of MF delivered via Twisthaler® once daily. The primary endpoint was 24 h post-dose trough forced expiratory volume in 1 s (FEV 1 ), after four weeks of treatment in patients with asthma. A secondary objective was to evaluate the efficacy of MF 80 μg and 320 μg delivered via Breezhaler®, and MF 200 μg and 800 μg delivered via Twisthaler® in terms of Asthma Control Questionnaire-5 (ACQ-5) after one, two, three and four weeks of treatment., Results: The LS mean difference in trough FEV 1 after four weeks of treatment between MF low dose 80 μg (Breezhaler®) and MF low dose 200 μg (Twisthaler®) was 27 mL (95% CI -34, 89); for MF high dose 320 μg (Breezhaler®) and MF high dose 800 μg (Twisthaler®) the difference was 0 mL (95% CI -60, 61). These differences were neither clinically nor statistically significant. All treatment arms provided similar clinically relevant improvements in ACQ-5 after four weeks of treatment compared with baseline. Both treatments showed a similar safety profile with a low incidence of adverse events., Conclusion: The similarities in effects on lung function and ACQ after four weeks of treatment demonstrate the comparability of MF at low (80 μg) and high (320 μg) doses delivered with Breezhaler® with MF at low (200 μg) and high (800 μg) doses delivered with Twisthaler®, respectively. The study formally demonstrated that MF, delivered via Breezhaler®, is non-inferior to MF, delivered via Twisthaler® at corresponding ICS doses., Competing Interests: Declarations of competing interest RB reports grants to Mainz University and personal fees from Boehringer Ingelheim, GlaxoSmithKline, Novartis, and Roche, as well as personal fees from AstraZeneca, Chiesi, Cipla, Sanofi and Teva, all outside the submitted work. AMT, MH, ID, FP, BH and HCT are employees of Novartis Pharma AG and own Novartis Pharma AG shares. WC is an employee of Novartis Pharmaceuticals Corporation. CB and JJ are employees of Novartis Pharma AG. DZ is an employee of Novartis Pharma AG and owns Novartis Pharma AG shares. DZ has led the development of Breezhaler® dry powder inhaler and was the technical project leader for the development of the Breezhaler® mometasone drug product. FK reports personal grants or fees for scientific work, presentations and Advisory boards in the last 5 years from Mundipharma, Astra Zeneca, Novartis and TEVA. However, all of these are outside the submitted work., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Mepolizumab has demonstrated favorable safety and efficacy profiles in placebo-controlled trials of 12 months' duration or less; however, long-term data are lacking., Objective: We sought to evaluate the long-term safety and efficacy of mepolizumab in patients with severe eosinophilic asthma (SEA)., Methods: COLUMBA (Open-label Long Term Extension Safety Study of Mepolizumab in Asthmatic Subjects, NCT01691859) was an open-label extension study in patients with SEA previously enrolled in DREAM (Dose Ranging Efficacy And Safety With Mepolizumab in Severe Asthma, NCT01000506). Patients received 100 mg of subcutaneous mepolizumab every 4 weeks plus standard of care until a protocol-defined stopping criterion was met. Safety end points included frequency of adverse events (AEs), serious AEs, and AEs of special interest. Efficacy end points included annualized exacerbation rates, changes from baseline in Asthma Control Questionnaire 5 scores, and blood eosinophil counts. Immunogenicity was also assessed., Results: Overall, 347 patients were enrolled for an average of 3.5 years (maximum, 4.5 years; total exposure, 1201 patient-years). On-treatment AEs were reported in 94% of patients (exposure-adjusted rate, 3688 events/1000 patient-years). The most frequently reported on-treatment AEs were respiratory tract infection, headache, bronchitis, and asthma worsening. Seventy-nine (23%) patients experienced 1 or more on-treatment serious AEs; there were 6 deaths, none of which were assessed as related to mepolizumab. For patients with 156 weeks or greater enrollment, the exacerbation rate was 0.74 events/y (weeks 0-156), a 56% reduction from the off-treatment period between DREAM and COLUMBA. For all patients, at the first postbaseline assessment, the mean Asthma Control Questionnaire 5 score was reduced by 0.47 points, and blood eosinophil counts were reduced by 78%, with similar improvements maintained throughout the study. The immunogenicity profile (8% anti-drug antibodies) was consistent with previous studies., Conclusion: These data support the long-term safety and efficacy of mepolizumab in patients with SEA., (Copyright © 2018 GlaxoSmithKline. Published by Elsevier Inc. All rights reserved.)

Rationale: Reslizumab is a humanized anti-IL-5 monoclonal antibody used as add-on maintenance treatment for patients with uncontrolled eosinophilic asthma., Objectives: To predict response and nonresponse to intravenous reslizumab at 52 weeks with an algorithm we developed based on clinical indicators from pivotal clinical trials., Methods: Patients aged 18 years and older who met Global Initiative for Asthma 4 or 5 criteria and received intravenous reslizumab (n = 321) in two trials ( www.clinicaltrials.gov identifiers, NCT01287039 and NCT01285323) were selected as the data source. A mathematical model was constructed that was based on change from baseline to 16 weeks in Asthma Control Questionnaire and Asthma Quality of Life Questionnaire scores and FEV 1 , and number of clinical asthma exacerbations during the year before enrollment and in the first 16 weeks of treatment, and these measures were evaluated for their ability to predict the outcome at 52 weeks: responder, nonresponder, or indeterminate., Measurements and Main Results: The algorithm predicted that 276 patients would be classified as responders; in 248 (89.9%), the prediction was correct. In comparison, 26 patients were predicted to be nonresponders; 50.0% of these predictions were correct. Nineteen patients were classified as indeterminate. The algorithm had 95.4-95.5% sensitivity and 40.6-54.1% specificity. Jackknife and cross-study validation confirmed the robustness of the algorithm., Conclusions: Our algorithm enabled prediction at 16 weeks of treatment of the response to intravenous reslizumab treatment at 52 weeks, but it was not suitable for predicting nonresponse. A positive score at 16 weeks should encourage continued treatment, and a negative score should prompt close monitoring to determine whether discontinuation is warranted.

Background: Chronic non-specific respiratory symptoms are difficult to manage. This trial aimed to evaluate the association between baseline fractional exhaled nitric oxide (FeNO) and the response to inhaled corticosteroids in patients with non-specific respiratory symptoms., Methods: In this double-blind randomised placebo-controlled trial, we enrolled undiagnosed patients, aged 18-80 years, with cough, wheeze, or dyspnoea and less than 20% bronchodilator reversibility across 26 primary care centres and hospitals in the UK and Singapore. Patients were assessed for 2 weeks before being randomly assigned (1:1) to 4 weeks of treatment with extrafine inhaled corticosteroids (QVAR 80 μg, two puffs twice per day, equivalent to 800 μg per day beclomethasone dipropionate) or placebo. Randomisation was stratified by baseline FeNO measurement: normal (≤25 parts per billion [ppb]), intermediate (>25 tp <40 ppb), and high (≥40 ppb). The primary endpoint was change in Asthma Control Questionnaire (ACQ7) mean score. We used generalised linear modelling to assess FeNO as a predictor of response, estimating an interaction effect between FeNO and treatment on change in ACQ7. We did our primary and secondary analyses in the per-protocol set, which excluded patients with non-completion of the primary endpoint, non-compliance to treatment (ascertained by patient report), and study visits made outside the predefined visit windows. This study is registered on ClinicalTrials.gov, number NCT02294279., Findings: Between Feb 4, 2015, and July 12, 2016, we randomly assigned 294 patients to extrafine inhaled corticosteroid treatment (n=148) or placebo (n=146). Following exclusions due to protocol violations, we analysed 214 patients (114 extrafine inhaled corticosteroids and 100 placebo). We observed a significant interaction between baseline FeNO and treatment group for every 10 ppb increase in baseline FeNO, with the change in ACQ7 greater in the extrafine inhaled corticosteroids group than in the placebo group (difference between groups 0·071, 95% CI 0·002 to 0·139; p=0·044). The most common adverse events were nasopharyngitis (18 [12%] patients in the treatment group vs 13 [9%] in the placebo group), infections and infestations (25 [17%] vs 21 [14%]), and respiratory, thoracic, and mediastinal disorders (13 [9%] vs 17 [12%])., Interpretation: FeNO measurement is an easy and non-invasive tool to use in clinical practice in patients with non-specific respiratory symptoms to predict response to inhaled corticosteroids. Further research is needed to examine its role in patients with evidence of other airway diseases, such as chronic obstructive pulmonary disease., Funding: Sponsored by OPRI with partial funding by Circassia and study drugs provided by TEVA., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Identifying patients at risk of future severe asthma exacerbations, those whose asthma might be less treatment responsive, or both might guide treatment selection., Objective: We sought to investigate predictors for failure to achieve Global Initiative for Asthma (GINA)-defined good current asthma control and severe exacerbations on treatment and to develop a simple risk score for exacerbations (RSE) for clinical use., Methods: A large data set from 3 studies comparing budesonide/formoterol maintenance and reliever therapy with fixed-dose inhaled corticosteroid/long-acting β2-agonist therapy was analyzed. Baseline patient characteristics were investigated to determine dominant predictors for uncontrolled asthma at 3 months and for severe asthma exacerbations within 12 months of commencing treatment. The RSE, right censored at 6 months to include all 3 studies, was based on the dominant predictors for exacerbations in two thirds of the data set and validated in one third., Results: Patients (n = 7446) whose symptoms were not controlled on GINA treatment steps 3 and 4 and with 1 or more exacerbations (as judged by a clinician based on patient records, history, or both) in the previous year were included. On multivariate analysis, GINA step, reliever use, postbronchodilator FEV1, and 5-item Asthma Control Questionnaire score were dominant (all P < .001) predictors for both the risk of uncontrolled asthma and severe exacerbations. Additional dominant predictors for uncontrolled asthma were smoking status and asthma symptom scores and an additional predictor for severe exacerbation was body mass index. An exponential increase in risk was observed with increments in RSE based on 5 selected predictors for exacerbations., Conclusion: Risk of uncontrolled asthma at 3 months and a severe exacerbation within 12 months can be estimated from simple clinical assessments. Prospective validation of these predictive factors and the RSE is required. Use of these models might guide the management of asthmatic patients., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The most prevalent phenotype of asthma is characterized by eosinophil-dominated inflammation that is driven by a type 2 helper T cell (Th2). Therapeutic targeting of GATA3, an important transcription factor of the Th2 pathway, may be beneficial. We evaluated the safety and efficacy of SB010, a novel DNA enzyme (DNAzyme) that is able to cleave and inactivate GATA3 messenger RNA (mRNA)., Methods: We conducted a randomized, double-blind, placebo-controlled, multicenter clinical trial of SB010 involving patients who had allergic asthma with sputum eosinophilia and who also had biphasic early and late asthmatic responses after laboratory-based allergen provocation. A total of 40 patients could be evaluated; 21 were assigned to receive 10 mg of SB010, and 19 were assigned to receive placebo, with each study drug administered by means of inhalation once daily for 28 days. An allergen challenge was performed before and after the 28-day period. The primary end point was the late asthmatic response as quantified by the change in the area under the curve (AUC) for forced expiratory volume in 1 second (FEV1)., Results: After 28 days, SB010 attenuated the mean late asthmatic response by 34%, as compared with the baseline response, according to the AUC for FEV1, whereas placebo was associated with a 1% increase in the AUC for FEV1 (P=0.02). The early asthmatic response with SB010 was attenuated by 11% as measured by the AUC for FEV1, whereas the early response with placebo was increased by 10% (P=0.03). Inhibition of the late asthmatic response by SB010 was associated with attenuation of allergen-induced sputum eosinophilia and with lower levels of tryptase in sputum and lower plasma levels of interleukin-5. Allergen-induced levels of fractional exhaled nitric oxide and airway hyperresponsiveness to methacholine were not affected by either SB010 or placebo., Conclusions: Treatment with SB010 significantly attenuated both late and early asthmatic responses after allergen provocation in patients with allergic asthma. Biomarker analysis showed an attenuation of Th2-regulated inflammatory responses. (Funded by Sterna Biologicals and the German Federal Ministry of Education and Research; ClinicalTrials.gov number, NCT01743768.).

For many years, pathogenetic concepts and the results of clinical trials supported the view that anti-IgE treatment is specifically effective in allergic asthma. However, there is now growing clinical and mechanistic evidence suggesting that treatment with the anti-IgE antibody omalizumab can be effective in patients with intrinsic asthma. Therefore, large and well-controlled clinical trials with anti-IgE are urgently warranted in patients with intrinsic asthma. In addition, there is a need to find new biomarkers which can identify patients with asthma who respond to anti-IgE treatment.

Omalizumab is an add-on therapy for patients with uncontrolled severe allergic asthma. In Europe, patients must fulfil a number of additional criteria to become eligible for omalizumab therapy, creating a challenge for epidemiology studies to quantify the potential patient pool. Thus, and in the absence of robust data, the number of omalizumab-eligible patients has remained unclear. To assess eligible patient numbers, a chart-audit design approach was employed to measure epidemiology variables based on patient-level data. 770 patient charts were reviewed in designated towns in Germany and Italy, in collaboration with >200 primary care physicians (PCPs) and respiratory specialists (RS). This study sample represents >50% and >70% of local RS in these designated towns of Germany and Italy, respectively. Of patient charts evaluated, 4 patients were currently receiving omalizumab. A further 31 patients (12 PCP; 19 RS) were evaluated as omalizumab-eligible (i.e. fulfilled all product label criteria) but were not receiving the drug. Extrapolating to a national level, this yields >6500 eligible patients in Germany, and >3200 in Italy. Furthermore, this study sample revealed a significant number of PCPs treating uncontrolled severe asthma patients without referral to RS; these patients are not consistently evaluated for FEV1, aero-allergen sensitivity, a qualitative understanding of severe exacerbations, and day and night-time symptoms. This study suggests that significant numbers of omalizumab-naïve severe allergic asthma patients in Germany/Italy are eligible for omalizumab therapy. Despite proven benefits in uncontrolled severe allergic asthma, adjunctive omalizumab therapy is underutilized., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Benefit of treatment with the monoclonal anti-IgE-antibody omalizumab in severe IgE-dependent asthma requires a significant reduction of serum free IgE concentrations. It is unclear if monitoring free serum IgE is clinically meaningful once omalizumab treatment is initiated., Methods: Free IgE and omalizumab serum concentrations were quantified in 22 patients with severe asthma (68% female, 47 ± 11 yrs, mean (±SD) pre-bronchodilator FEV(1) 62 ± 13%, baseline mean (±SEM) free serum IgE 652 ± 136 ng/ml) treated with omalizumab for 4 months using a Recovery-ELISA., Results: Omalizumab treatment reduced free serum IgE prior to the second omalizumab injection by 73%, after 16 weeks by 81% to 58 ± 12 ng/ml (p < 0.001 vs. baseline). 17 patients responded to anti-IgE therapy as judged by physician-rated global evaluation of treatment effectiveness. There was neither a relation between free serum IgE concentrations and treatment response nor a significant or clinically relevant correlation between free IgE levels and changes in lung function, exhaled NO, asthma control, and quality of life. Serum concentrations of omalizumab were detected in all patients and reached a stable phase within 8 weeks., Conclusions: Monitoring free IgE and omalizumab serum concentrations in patients treated with omalizumab does not predict clinical response nor does it add to the decision to continue or stop treatment. However, routine measurements of free IgE may be clinically relevant to demonstrate an adequate reduction in free IgE in patients not responding to omalizumab therapy., (Copyright © 2012. Published by Elsevier Ltd.)

Background: Some patients with severe asthma have recurrent asthma exacerbations associated with eosinophilic airway inflammation. Early studies suggest that inhibition of eosinophilic airway inflammation with mepolizumab-a monoclonal antibody against interleukin 5-is associated with a reduced risk of exacerbations. We aimed to establish efficacy, safety, and patient characteristics associated with the response to mepolizumab., Methods: We undertook a multicentre, double-blind, placebo-controlled trial at 81 centres in 13 countries between Nov 9, 2009, and Dec 5, 2011. Eligible patients were aged 12-74 years, had a history of recurrent severe asthma exacerbations, and had signs of eosinophilic inflammation. They were randomly assigned (in a 1:1:1:1 ratio) to receive one of three doses of intravenous mepolizumab (75 mg, 250 mg, or 750 mg) or matched placebo (100 mL 0·9% NaCl) with a central telephone-based system and computer-generated randomly permuted block schedule stratified by whether treatment with oral corticosteroids was required. Patients received 13 infusions at 4-week intervals. The primary outcome was the rate of clinically significant asthma exacerbations, which were defined as validated episodes of acute asthma requiring treatment with oral corticosteroids, admission, or a visit to an emergency department. Patients, clinicians, and data analysts were masked to treatment assignment. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01000506., Findings: 621 patients were randomised: 159 were assigned to placebo, 154 to 75 mg mepolizumab, 152 to 250 mg mepolizumab, and 156 to 750 mg mepolizumab. 776 exacerbations were deemed to be clinically significant. The rate of clinically significant exacerbations was 2·40 per patient per year in the placebo group, 1·24 in the 75 mg mepolizumab group (48% reduction, 95% CI 31-61%; p<0·0001), 1·46 in the 250 mg mepolizumab group (39% reduction, 19-54%; p=0·0005), and 1·15 in the 750 mg mepolizumab group (52% reduction, 36-64%; p<0·0001). Three patients died during the study, but the deaths were not deemed to be related to treatment., Interpretation: Mepolizumab is an effective and well tolerated treatment that reduces the risk of asthma exacerbations in patients with severe eosinophilic asthma., Funding: GlaxoSmithKline., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Since initial registration, the omalizumab clinical trial database has expanded considerably, with a doubling of patients exposed in the clinical trial environment. Previous pooled data (2003) from phase I to III studies of omalizumab showed a numeric imbalance in malignancies arising in omalizumab recipients (0.5%) compared with control subjects (0.2%). The previous analysis was based on limited available data, warranting further investigation., Objective: We sought to examine the incidence of malignancy using comprehensive pooled data from clinical trials of omalizumab-treated patients., Methods: This pooled analysis included data from 67 phase I to IV clinical trials. The prespecified primary analysis assessed the incidence of primary malignancy in 32 randomized, double-blind, placebo-controlled (RDBPC) trials., Results: There were 11,459 unique patients in all clinical trials (7,789 received omalizumab). The primary analysis identified malignancies in 25 patients (RDBPC trials): 14 in 4,254 omalizumab-treated patients and 11 in 3,178 placebo-treated patients. Incidence rates per 1,000 patient-years of observation time for omalizumab- and placebo-treated patients were 4.14 (95% CI, 2.26-6.94) and 4.45 (95% CI, 2.22-7.94), respectively; the corresponding rate ratio was 0.93 (95% CI, 0.39-2.27). Primary malignancies were of varying histologic type and occurred in a number of different organ systems; no cluster of histologies was identified., Conclusions: In this pooled analysis no association was observed between omalizumab treatment and risk of malignancy in RDBPC trials; the rate ratio was below unity. The data suggest that a causal relationship between omalizumab therapy and malignancy is unlikely., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Studies with inhaled corticosteroids (ICS) in smoking asthmatics have mostly shown poorer treatment responses than in non-smoking asthmatics., Methods: EuroSMART, an open, randomised, 6-month study, compared budesonide/formoterol (Symbicort (®) Turbuhaler(®))(h) maintenance and reliever therapy (Symbicort SMART(®)) at two maintenance doses of budesonide/formoterol (160/4.5 μg), 1 × 2 and 2 × 2, in patients with asthma who were symptomatic despite treatment with ICS ± long-acting β(2)-agonists. The 8424 randomised patients included 886 smokers (11%; aged <40 years or with a smoking history <10 pack-years if older), who were compared with a propensity-matched group of non-smokers. At baseline, smokers had lower post-bronchodilator peak expiratory flow, lower peak flow reversibility and used more reliever medication per day. Severe asthma exacerbations were counted and changes in five-item Asthma Control Questionnaire (ACQ-5) scores from baseline calculated., Results: There were 48 and 47 exacerbations in smokers and non-smokers, respectively. Mean time to first severe exacerbation was not statistically different between the two groups. The mean change in ACQ-5 score was significantly greater in non-smokers. Considering the two treatment options there was a statistically significant prolonged time to first severe exacerbation with 2 × 2 versus 1 × 2 in the smokers, but not in the non-smokers. In smokers, the reductions in ACQ-5 scores, asthma symptoms, use of as-needed medication and awakenings were also all significant in favour of 2 × 2 with similar or greater changes than in smokers treated with 1 × 2., Conclusion: Asthmatic patients with a limited smoking history benefit from treatment with budesonide/formoterol maintenance and reliever therapy with dosing 2 × 2 being superior to 1 × 2., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Recommended treatment for moderate to severe asthma is the combination of an inhaled corticosteroid and a long-acting beta2-agonist. The present study was designed to evaluate the efficacy of a newly developed fixed combination of ciclesonide and formoterol in comparison to the marketed fixed combination of fluticasone and salmeterol in patients with moderate asthma. This was a phase II, multi-centre, randomized, parallel-group, double-blind, double-dummy study. After a 2-week run-in period, 160 patients with moderate asthma were randomized to a 6-week treatment with ciclesonide/formoterol 320/9 μg bid (CIC/F) or fluticasone propionate/salmeterol 250/50 μg bid (FP/S), both delivered as powder formulations. The primary outcome FEV1 increased during treatment by 0.356 L in the CIC/F group and by 0.288 L in the FP/S group (p < 0.0001). The increases were statistically significant and clinically relevant. The between-treatment analysis demonstrated non-inferiority of CIC/F to FP/S treatment (p < 0.0001). A significant improvement from baseline in lung function, symptom score and rescue medication use was observed in both groups at all time points. No differences were observed between treatments in the frequency of adverse events and overnight urinary cortisol/creatinine ratio. The studied fixed combination of ciclesonide/formoterol is not inferior to the marketed fixed combination of fluticasone/salmeterol in terms of efficacy and tolerability., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: Baseline inhaled corticosteroid (ICS) dose may be a factor for prescribers to consider when they select a budesonide/formoterol maintenance and reliever therapy regimen for symptomatic asthmatics., Methods: A 6-month randomized study compared two maintenance doses of budesonide/formoterol 160/4.5 µg, 1 × 2 and 2 × 2, plus as needed, in 8424 asthma patients with symptoms when treated with ICS ± an inhaled long-acting β(2)-agonist (LABA). In the total study population, 1339 (17%) were high-dose ICS (HD) users (≥ 1600 µg/day budesonide). This HD stratum was compared with the rest of the study population, divided into low-dose (LD; 400 µg/day) and medium-dose strata (MD; 401-1599 µg/day) with regard to severe asthma exacerbations and mean changes in five-item Asthma Control Questionnaire (ACQ(5)) scores from baseline., Results: In all three strata there were fewer exacerbations in the 2 × 2 treatment groups (yearly rates 0.268, 0.172 and 0.094) than in the 1 × 2 treatment groups (yearly rates 0.232, 0.138 and 0.764). In no stratum was the difference between the treatment groups statistically significant. There was no statistically significant difference in time to the first severe exacerbation between the treatments 2 × 2 and 1 × 2 in the HD group (hazard ratio 0.944, p = 0.75). The adjusted mean changes in ACQ(5) scores in the HD, MD and LD strata were -0.89, -0.61 and -0.65, respectively, with 1 × 2 treatment and -0.90, -0.74 and -0.76, respectively, with 2 × 2 treatment. In the MD and LD strata, the difference between doses was significant in favour of 2 × 2 (MD p < 0.0001; LD p = 0.004), but not in the HD stratum (p = 0.870). No difference in serious adverse events was seen., Conclusion: Compared with the LD and MD strata, the HD stratum patients had more exacerbations and a shorter time to first exacerbation. However, there were no differences in response between the 1 × 2 and 2 × 2 groups in any of the strata. This indicates that patients using budesonide/formoterol maintenance and reliever therapy, irrespective of baseline ICS dose, can be switched to 1 × 2 with its lower steroid load. ACQ(5) scores improved more in the HD stratum than in the MD and LD strata indicating, among other things, that HD patients were not overtreated at baseline.

Background: Omalizumab is approved for the treatment of severe allergic asthma., Objectives: To compare the efficacy of omalizumab therapy in patients 50 years or older with patients younger than 50 years., Methods: Between November 2005 and November 2007 a total of 174 asthma patients 50 years or older (40.7% male, 51.1% taking oral corticosteroids, and mean [SD] serum IgE level of 315 [353] U/L) and 297 asthma patients younger than 50 years (40.0% male, 50.5% taking oral corticosteroids, and mean [SD] serum IgE level of 363 [431] U/L) who met the European Union criteria for add-on therapy with anti-IgE were treated prospectively with omalizumab for 4 months as part of 2 postmarketing surveillance trials., Results: Compared with the pretrial period omalizumab treatment reduced the rate of severe exacerbations in patients 50 years or older by 68.9% (P < .001) and in patients younger than 50 years by 75.4% (P < .001). After 4 months there was a marked reduction of daily asthma symptoms and nocturnal awakenings by 67.8% and 72.6% in the older and by 79.3% and 82.5% in the younger patients, respectively (P < .001, all 4 comparisons). In 60% of patients 50 years or older lung function improved compared with 69% of patients younger than 50 years. Efficacy of omalizumab was rated as excellent or good by most physicians in patients 50 years or older (68.4%) and younger than 50 years (76.8%, P = .05 elderly vs younger). Adverse events were reported in 35.5% of patients 50 years or older and 32.1% of patients younger than 50 years. There was a higher rate of discontinuation of omalizumab therapy in older patients (20.9% vs 11.1%, P = .006)., Conclusions: The present study confirms the clinical efficacy of omalizumab in patients with severe allergic asthma irrespective of age in a real-life setting outside the omalizumab trial program., (Copyright © 2010 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Asthma guidelines emphasize both maintaining current control and reducing future risk, but the relationship between these 2 targets is not well understood., Objective: This retrospective analysis of 5 budesonide/formoterol maintenance and reliever therapy (Symbicort SMART Turbuhaler(*)) studies assessed the relationship between asthma control questionnaire (ACQ-5) and Global Initiative for Asthma-defined clinical asthma control and future risk of instability and exacerbations., Methods: The percentage of patients with Global Initiative for Asthma-defined controlled asthma over time was assessed for budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies; higher dose inhaled corticosteroid (ICS), same dose ICS/long-acting beta(2)-agonist (LABA), and higher dose ICS/LABA plus short-acting beta(2)-agonist. The relationship between baseline ACQ-5 and exacerbations was investigated. A Markov analysis examined the transitional probability of change in control status throughout the studies., Results: The percentage of patients achieving asthma control increased with time, irrespective of treatment; the percentage Controlled/Partly Controlled at study end was at least similar to budesonide/formoterol maintenance and reliever therapy versus the 3 maintenance therapies: higher dose ICS (56% vs 45%), same dose ICS/LABA (56% vs 53%), and higher dose ICS/LABA (54% vs 54%). Baseline ACQ-5 score correlated positively with exacerbation rates. A Controlled or Partly Controlled week predicted at least Partly Controlled asthma the following week (>or=80% probability). The better the control, the lower the risk of an Uncontrolled week. The probability of an exacerbation was related to current state and was lower with budesonide/formoterol maintenance and reliever therapy., Conclusions: Current control predicts future risk of instability and exacerbations. Budesonide/formoterol maintenance and reliever therapy reduces exacerbations versus comparators and achieves at least similar control.

Severe persistent asthma causes a substantial morbidity and mortality burden and is frequently inadequately controlled despite intensive guideline-based therapy. Targeting allergic inflammatory processes that underlie the pathogenesis of severe persistent asthma improves asthma control in a significant proportion of patients. Omalizumab, a humanized monoclonal anti-immunoglobulin E (IgE) antibody, has been developed to target IgE, which is central to triggering and maintaining allergic airway inflammation. In a comprehensive program of clinical trials, omalizumab has been shown to reduce asthma exacerbation and emergency visit rates, and to improve quality of life in patients with severe persistent allergic asthma. It is difficult to predict which patients would most benefit from omalizumab treatment; accurate selection and dosing of patients are essential to achieve benefit. Patients need to have convincing IgE-mediated asthma and be dosed according to pre-treatment serum total IgE level and body weight, using a specified dosing table. Based on clinical trial data analysis, it is recommended that treatment response is evaluated by the physician after 16 weeks of therapy. Treatment should only be continued in responders, i.e. those judged by the physician to have achieved a marked improvement or complete asthma control. Omalizumab is generally well tolerated. Anaphylactic-like reactions are rare (0.1% of patients) and less common than encountered with other biologics.

Background: An inhaled corticosteroid (ICS) or an ICS/long-acting beta(2)-agonist (LABA) combination plus short-acting beta(2)-agonist (SABA) as needed for symptom relief is recommended for persistent asthma. Additionally, budesonide/formoterol maintenance and reliever therapy (Symbicort) SMART, AstraZeneca, Sweden) has been approved for adults in the European Union. This option is well tolerated and offers greater reductions in asthma exacerbations together with similar improvements in daily symptom control, at a lower overall steroid load, compared with fixed-dose ICS/LABA plus SABA., Methods: Two large clinical trials investigated the use of budesonide/formoterol as maintenance and reliever compared with medium or high doses of an ICS/LABA combination as controller plus SABA as reliever in adults (aged >or= 18 years). COMPASS was a 6-month, double-blind, randomized trial, while COSMOS was a 1-year, dose titration study which reflected routine clinical practice., Results: Among adults, the studies confirmed a 21-39% reduction in severe exacerbations in patients treated with budesonide/formoterol maintenance and reliever therapy compared with titrated salmeterol/fluticasone plus SABA (COSMOS) or fixed higher budesonide/formoterol or salmeterol/fluticasone plus SABA (COMPASS), respectively. Similar levels of daily asthma control were achieved with budesonide/formoterol maintenance and reliever therapy at a significantly lower overall steroid load compared with salmeterol/fluticasone or budesonide/formoterol plus SABA. Budesonide/formoterol maintenance and reliever therapy was as well tolerated as combination therapies., Conclusion: In adult patients, budesonide/formoterol maintenance and reliever therapy is a safe and simplified approach to asthma management, using a single inhaler, which reduces severe exacerbations and maintains similar daily asthma control at a lower drug load compared with the traditional strategy of ICS/LABA plus SABA.

Background: Patients with severe persistent asthma experience daily symptoms and frequent serious exacerbations that contribute to a significant impairment of health-related quality of life (QoL)., Methods: A pooled analysis was completed of six controlled clinical trials that evaluated the effect of add-on omalizumab on asthma-related QoL in patients with severe persistent allergic (IgE-mediated) asthma. Asthma-related QoL was assessed at baseline and treatment endpoint using the well-validated Juniper Asthma Quality of Life Questionnaire (AQLQ). Change from baseline in AQLQ total score was compared between treatments using analysis of covariance methods. The percentage of patients who achieved a clinically meaningful (> or = 0.5-point) improvement in AQLQ total score was compared using the Mantel-Haenszel Chi-square test., Results: The pooled patient population comprised 2548 patients (omalizumab, n = 1342; control, n = 1206), of whom 96% had severe persistent asthma according to the GINA 2002 classification. Omalizumab produced significantly greater improvements in AQLQ total score vs the control group (mean increases of 1.01 and 0.61 points, respectively; p < 0.001). In addition, significantly more omalizumab-treated patients achieved a clinically meaningful improvement in AQLQ total score than patients in the control group (66.3% vs 52.4%; p < 0.001)., Conclusions: Add-on therapy with omalizumab improves QoL to a significant and clinically meaningful level in patients with severe persistent allergic asthma.

Background: Inhaled corticosteroids are the mainstay of therapy in asthma, but local and systemic side effects and adherence remain a concern. Ciclesonide is an inhaled corticosteroid with on-site lung activation that provides potent anti-inflammatory activity and has been shown to have a good safety profile, even at high doses., Objective: The aim of this study was to compare the efficacy and safety of once-daily ciclesonide versus twice-daily fluticasone propionate at comparable daily doses in patients with asthma., Methods: In this multicenter, randomized, double-blind, double-dummy, parallel group study, 529 patients were randomized to ciclesonide 160 microg once daily or fluticasone propionate 88 microg twice daily for 12 weeks. The primary endpoint was change in lung function., Results: Both ciclesonide and fluticasone propionate significantly improved forced expiratory volume in 1s, forced vital capacity, and morning peak expiratory flow compared with baseline (p<0.0001 for all variables). Both medications reduced asthma symptoms and rescue medication use within the first 24 h. At the tested dose, both medications were equally safe and well tolerated., Conclusion: Ciclesonide 160 microg once daily was as effective as fluticasone propionate 88 microg twice daily in improving lung function and asthma symptoms, and in reducing rescue medication use in patients with asthma.

Purpose of Review: Allergic asthma is a hypersensitivity reaction initiated by immunologic mechanisms mediated by IgE antibodies. IgE plays a central role in the initiation and propagation of the inflammatory cascade and thus the allergic response. Targeting factors involved in the allergic response, such as IgE, is a novel strategy for new therapies. Attenuating allergic disease by specifically inhibiting IgE and the development of the monoclonal anti-IgE antibody, omalizumab, were major breakthroughs in asthma management., Recent Findings: Several studies have shown that omalizumab has significant anti-inflammatory effects and that it may act on multiple components of the inflammatory cascade. Specific binding of IgE by omalizumab reduces both the early allergic response and the late allergic response and symptoms of IgE-mediated allergy. The long-term clinical efficacy of omalizumab has been demonstrated along with improvements in quality of life. As add-on therapy in severe asthma, omalizumab reduces the requirement for inhaled corticosteroids and improves disease control. Clinical studies have shown that the patients who benefit most from omalizumab therapy are those at high risk of exacerbations, those with poorly controlled and/or severe asthma, and those with IgE-mediated comorbidities., Summary: Omalizumab is a significant addition to current asthma treatments and shows great promise as a therapy for allergic asthma and for patients with concomitant allergic rhinitis. This is particularly true for difficult-to-treat patients with moderate to severe allergic asthma who have poorly controlled disease on conventional therapies, experience severe adverse effects secondary to high-dose or prolonged corticosteroid treatment, have frequent exacerbations, and/or are at high risk of hospitalization. Future studies will continue to investigate the anti-inflammatory mechanisms of anti-IgE therapy. Because many of these mechanisms are common to all IgE-mediated allergic diseases, the efficacy of omalizumab in other allergic diseases should be further explored.

Budesonide/formoterol (Symbicort), AstraZeneca plc) is a novel treatment for asthma, combining an inhaled corticosteroid - budesonide, and a long-acting beta(2)-agonist - formoterol, in a single inhaler, the Turbuhaler. Randomised, clinical studies in patients with asthma have demonstrated that budesonide/formoterol is more effective than the inhaled corticosteroids, budesonide and fluticasone alone, and at least as effective as both monocomponents in separate inhalers. Results from clinical studies suggest a synergistic effect when both drugs are administered via one inhaler, although the mechanisms for this are not fully understood. Budesonide/formoterol has a rapid onset of effect, apparent within 1 min of treatment, which is largely because of the properties of formoterol. Once- and twice-daily dosing with budesonide/formoterol are effective treatment options for patients with mild or moderate asthma. Studies have also shown that the beneficial safety profiles and dose relationships of both budesonide and formoterol allow dose adjustments of budesonide/formoterol in response to variations in the patient's asthma. Findings from the budesonide/formoterol adjustable maintenance dosing programme, comparing fixed and adjustable, symptom-guided dosing regimens, demonstrate that patients achieve equally good asthma control with adjustable dosing (from one inhalation twice-daily to more than four inhalations twice-daily), but at a significantly lower overall drug load. Adverse events, mainly expected inhaled corticosteroid and long-acting beta(2)agonist class effects, have been few in number and mild in nature. In addition, there is growing evidence that budesonide/formoterol is also effective in patients with chronic obstructive pulmonary disease. The future for treatment with budesonide/formoterol may include as-needed administration in addition to maintenance therapy.