Contents:

ABOUT OUR HEALTHCARE 2 About the Infectious Diseases and Respiratory (ID&R) analysis team 2 Chapter 1. Executive summary 3 Scope of the report 3 Contributing experts 3 Our insight into asthma phenotypes 4 Chapter 2. Asthma background and epidemiology 11 Disease definition 11 Causes of asthma: environment and genes 11 Etiology 14 Disease classification and phenotypes 16 Phenotypes 18 Prevalence 21 Chapter 3. Asthma diagnosis and treatment options 24 Presentation and diagnosis 24 Treatment options and guidelines 25 Bronchodilators 26 Beta2-agonists 27 Anticholinergics 28 Combination beta2-agonist/anticholinergic 28 Anti-inflammatories 29 Inhaled corticosteroids 29 Systemic corticosteroids 30 Non-steroidal anti-inflammatory drugs (NSAIDs) 30 ICS/LABA combinations 32 Biologicals 33 Future trends in asthma treatment 33 Asthma biomarkers 34 Chapter 4. Clinical or physiological phenotypes 38 Severity-defined asthma 38 Prevalence 40 Refractory asthma 42 Pathobiology 44 The refractory asthma patient 46 Prevalence 47 Treatment 48 The exacerbation-prone subtype of refractory asthma 50 Chronic airflow obstruction in asthma 51 Pathobiology 51 The asthma patient with chronic airflow obstruction 54 Prevalence 56 Treatment 59 Asthma defined by age of onset 60 The early- versus late-onset patient 60 Treatment 62 Nocturnal asthma 63 Pathobiology 64 Prevalence 65 Treatment 66 Viral infections during childhood 66 Asthma and obesity 68 Chapter 5. Phenotypes related to certain triggers 72 Environmental allergens 72 Pathobiology 73 The allergic march 75 The allergic versus non-allergic asthma patient 77 Prevalence 79 Treatment 82 Immunotherapy 82 Aspirin- and NSAID-sensitive asthma 85 The aspirin-sensitive asthma patient 85 Prevalence 86 Treatment 88 Occupational allergens or irritants 89 Prevalence 92 Treatment 93 Menses-related asthma 94 Exercise-induced asthma 95 Treatment 96 Chapter 6. Inflammatory phenotypes 98 Eosinophilic inflammatory asthma 99 Prevalence 100 Neutrophilic inflammatory asthma 103 The neutrophilic asthma phenotype 105 Prevalence 106 Pauci-granulocytic inflammatory asthma 108 Prevalence 108 Chapter 7. Asthma phenotypes in the future 111 Why and how could we use phenotypes? 112 Phenotypes and endpoints 113 New endpoints 114 The battle over asthma control 116 Phenotypes and biomarkers 117 How can we progress the identification of phenotypes? 118 Which phenotype should we target first? 120 Case study 1: Xolair (omalizumab) in severe allergic asthma 125 Case study 2: Immunotherapy in severe allergic asthma 127 Case study 3: an anti-inflammatory drug in neutrophilic asthma 129 REFERENCES 132 Disclaimer List of Tables Table 1: Asthma prevalence and diagnosed population by country and age, 2007 23 Table 2: Diagnosed asthma by country and severity for children and adults/elderly, 2007 41 Table 3: Prevalence of severe/refractory asthma by country, 2007 47 Table 4: Prevalence of exacerbation-prone severe/refractory asthma by country, 2007 51 Table 5: Prevalence of chronic airflow obstruction in diagnosed adult/elderly and pediatric asthma population by country (000s), 2007 58 Table 6: Prevalence of diagnosed asthma patients with nocturnal symptoms in the seven major markets (million), 2007 65 Table 7: The prevalence of allergic and non-allergic asthma in the seven major markets, 2007 (000) 80 Table 8: Prevalence of allergic asthma according to severity in the seven major markets, 2007 (000) 81 Table 9: Range of prevalence of diagnosed asthma patients with aspirin/NSAID sensitive asthma, 2007 88 Table 10: Prevalence of occupational asthma in the diagnosed adult asthma population, 2007 93 Table 11: Prevalence of diagnosed asthma patients with predominantly eosinophilic inflammation, 2007 (000) 102 Table 12: Prevalence of diagnosed asthma patients with predominantly neutrophilic inflammation, 2007 107 Table 13: Prevalence of different inflammatory phenotypes in diagnosed asthmatic children, adults and elderly, 2007 (000) 110 Table 14: Marketed and pipeline therapies in eosinophilic and neutrophilic inflammation List of Figures Figure 1: Basic etiology of asthma 16 Figure 2: Levels of asthma control according to the GINA guidelines 18 Figure 3: Early/childhood onset phenotypes 20 Figure 4: Late/adult onset phenotypes 20 Figure 5: Percentage of asthma patients who experience daily or weekly symptoms by age, 2004 24 Figure 6: Management approach based on asthma control 26 Figure 7: Novel asthma therapies are moving towards targeted therapy 34 Figure 8: The role of biomarkers related to asthma therapy 36 Figure 9: Overview of clinical or physiological phenotypes 38 Figure 10: Classification of asthma by clinical, pretreatment features 39 Figure 11: ATS workshop consensus for definition of refractory asthma 43 Figure 12: A normal airway compared to the process in airway remodeling 53 Figure 13: Early-onset versus late-onset asthma 61 Figure 14: Circadian alterations in lung function in healthy subjects and patients with nocturnal asthma 63 Figure 15: Viral infections have been implicated in at least three ways with asthma pathogenesis 67 Figure 16: Overview of phenotypes related to certain triggers 72 Figure 17: The early and late allergic response 73 Figure 18: Proposed systemic inflammatory mechanisms linking the upper and lower airways 75 Figure 19: The allergic march 77 Figure 20: Prevalence of aspirin-sensitive asthma according to studies versus key opinion leaders (KOLs) 87 Figure 21: Categories and subcategories of occupational asthma 90 Figure 22: Overview of inflammatory phenotypes 98 Figure 23: Characteristics of eosinophil-positive (+) and eosinophil-negative (-) severe asthma 104 Figure 24: The complex relation between various triggers of airway inflammation and the diseases associated with them 111 Figure 25: Exacerbations in patients following guideline-therapy and sputum-identification therapy 113 Figure 26: How can we progress the identification of asthma phenotypes? 119 Figure 27: The reaction of neutrophils to CXC chemokines in the early phase of inflammation 123 Figure 28: The difference between potential US peak sales and actual US sales of Xolair in allergic asthma 127 Figure 29: Possible US peak sales of Grazax in allergic asthma 129 Figure 30: Possible US peak sales of a novel anti-inflammatory in neutrophilic asthma 131