1. Immunology of Asthma through Biologics Private Practice & St Michael’s Hospital Lecturer, Division of Clinical Immunology & Allergy Department of Medicine, University of Toronto Jason Lee, MD, FRCPC

2. Learning Objectives To understand the pathophysiologic basis of biologics in asthma To become familiar with various biologics that have been tried for asthma and the rationale behind these t reatment approaches  learn the immunology

3. Why the need for Biologics? Patients with severe asthma who are uncontrolled with maximum doses of inhaled “conventional” therapies Although only 5% of all asthmatic patients are severe and these patients represent ~50% of health care spending Biologics and asthma is a fascinating topic with a lot of exciting new advances Barnes, JACI. 2012

4. Biologics are the future Current monoclonal antibodies are the fastest growing segment of the pharmaceutical industry Produced based on understanding the underlying immunology: -Cytokines -Monoclonal antibodies -Fusion proteins Albrecht H, Radosevich JA, Babich M. Fundamentals of antibody-related therapy and diagnostics. Drugs Today (Barc) 2009

5. Why use Biologics? Easiest way to form a customized target medication Reduce the number of “collateral damage” thereby limiting side effects 12

11. What is happening?

12. Healthy airway Smooth muscle

13. Cells have no reaction to allergens Healthy airway

14. With asthma Constricted airway during a n asthma attack Mucus

15. Cells see allergens as pathogens = With asthma

16. Major Inflammatory Cells Mast CellEosinophil 12

17. Mast Cell Activation

27. Role of IgE in Asthma Initially controversial IgE cross-linking leads to : - More IL4 - More CD40L on T cells - Induction of Eosinophilic inflammation In some asthma patients non-IgE mediated pathways that enhance Th2 cytokines = Even more IgE production

29. - IgE not acting in Isolation. - Expression of FcεRI receptor has been reported to be increased in fatal asthma Fatal asthm a (n=10) Non-pulmonary d eaths (n=9) Mild-intermittent a sthma † (n=16) *p<0.05 vs other groups; † biopsy Fregonese L, et al. Am J Respir Crit Care Med 2004 (abstract) 1,200 1,000 800 600 400 200 0 FceRI receptor expression in lamina propria (+ cells/mm 2 ) 1,085 *

30. Eosinophil Activation

34. Biologics used for asthma OmalizumabAnti-il-5 mAbs 12

35. Omalizumab

42. Omalizumab (n=209) Placebo (n=210) 0.6 0.5 0.4 0.3 0.2 0.1 0 ∆ –50.0% p=0.002 Omalizumab (n=209) Placebo (n=210) 0.6 0.5 0.4 0.3 0.2 0.1 0 ∆ –43.9% p=0.038 Severe exacerbation rateTotal emergency visit rate Humbert M, et al. Allergy 2005 Omalizumab significantly reduces severe exacerbation s and emergency visits

43. Omalizumab significantly reduces the need for systemic corticosteroid bursts Steroid bursts (mean) Omalizumab (n=2,511) Control (n=1,797)) 0.8 0.6 0.4 0.2 0 Relative risk: –43.0% p<0.001 Maykut R, et al. J Allergy Clin Immunol 2006 (abstract) Busse W, et al. Curr Med Res Opin 2007;2379-2386

44. OCS is reduced or stopped in 79% of patients following omalizumab therapy * Steroid bursts (mean) 60 50 40 30 20 10 0 78.8% ReducedStoppedNot reduced/stopped Patients (%) 54.5 Niven R, et al. Thorax 2007 (abstract)

45. Anti-IL-5 mAbs

46. Mepolizumab - Has been shown to reduce bronchial mucosa eosinophilia - In a subgroup: has clinical improvement or FEV1, B HR, peak flows - Reduces some extracellular matrix protein remodeling - 100% reduction in sputum eosinophils and airway eosinophils by 55%

47. Future Therapies - TGF-B - Anti-IL-4 - Anti-IL-5 - Anti-IL-9 - Anti-IL-13 - Inhibition of Th2 cytokines - Inhaled anti-inflammatories targeting neutrophils - Novel classes of bronchodilators (Ro 25-1553, Rho kinase inhibitors - Targeting neutrophilic inflammatory mediators - Masitinib -> a tyrosine kinase inhibitor that blocks c-Kit - Cytokine receptor antagonists - TLR 4 and 9 agonists - Syk Kinase inhibitors - GATA3 antagonists

48. Thank you! Q&A