Immunology of Asthma through Biologics

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

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 treatment approaches  learn the immunology

3. Why the need for Biologics? Patientswith 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 Barnes, JACI. 2012 Biologics and asthma is a fascinating topic with a lot of exciting new advances

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

5. Why use Biologics? 1 2 Reduce the number of “collateral damage” thereby limiting side effects Easiest way to form a customized target medication

11. What is happening?

12. Healthy airway Smooth muscle

13. Healthy airway Cells have no reaction to allergens

14. With asthma Constricted airway during an asthma attack Mucus

15. With asthma Cells see allergens as pathogens =

16. Major Inflammatory Cells 1 2 Mast Cell Eosinophil

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 = Even more IgE production In some asthma patients non-IgE mediated pathways that enhance Th2 cytokines

29. - IgE not acting in Isolation. - Expression of FcεRIreceptor has been reported to be increased in fatal asthma FceRI receptor expression in lamina propria (+ cells/mm2) 1,085 * 1,200 1,000 800 600 400 200 0 Non-pulmonary deaths (n=9) Mild-intermittent asthma†(n=16) Fatal asthma (n=10) *p<0.05 vs other groups; †biopsy Fregonese L, et al. Am J RespirCrit Care Med 2004 (abstract)

30. Eosinophil Activation

34. Biologics used for asthma 1 2 Omalizumab Anti-il-5 mAbs

35. Omalizumab

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

43. Omalizumab significantly reducesthe need for systemic corticosteroid bursts Steroid bursts (mean) Relative risk: –43.0%p<0.001 0.8 0.6 0.4 0.2 0 Omalizumab (n=2,511) Control (n=1,797)) 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) 78.8% Patients (%) 60 50 40 30 20 10 0 54.5 Reduced Stopped Not reduced/stopped 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, BHR, 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 Jason Lee MD, FRCPC