Immunology of Asthma through Biologics

Private Practice & St Michael’s Hospital

Lecturer, Division of Clinical Immunology & Al-lergy Department of Medicine, University of Toronto

Jason Lee, MD, FR-CPC

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

Why the need for Biologics?

Patients with severe asthma who are uncon-trolled with maximum doses of inhaled “conven-tional” 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

Biologics are the future

Current monoclonal antibodies are the fastest growing segment of the pharmaceutical in-dustry

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

Why use Biolog-ics?

Easiest way to form a custom-

izedtarget medication

Reduce the num-ber

of “collateral damage” thereby

limitingside effects

1 2

What is happen-ing?

Healthy air-way

Smooth muscle

Cells have no reaction to aller-gens

Healthy air-way

With asthma

Constricted airway dur-ing an asthma attack

Mucus

Cells see allergens as pathogens

=

With asthma

Major Inflammatory Cells

Mast Cell Eosinophil

1 2

Mast Cell Activa-tion

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

- IgE not acting in Isolation. - Expression of FcεRI receptor has been reported to be increased in fatal asthma

302328

Fatal asthma(n=10)

Non-pulmonary deaths(n=9)

Mild-intermit-tent asthma†

(n=16)

*p<0.05 vs other groups; †biopsy Fregonese L, et al. Am J Respir Crit Care Med 2004 (abstract)

1,2001,000

800600400200

0

FceRI receptor expression in lamina propria (+ cells/mm2)

1,085*

Eosinophil Activa-tion

Biologics used for asthma

Omalizumab Anti-il-5 mAbs

1 2

Omal-izumab

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 rate Total emergency visit rate

Humbert M, et al. Allergy 2005

Omalizumab significantly reduces severe ex-acerbations and emergency visits

Omalizumab significantly reducesthe need for systemic corticosteroid bursts

0.4

0.6

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

OCS is reduced or stopped in 79% of patients following omalizumab therapy*

Steroid bursts (mean)

24.221.2

60

50

40

30

20

10

0

78.8%

Reduced Stopped Not reduced/stopped

Patients (%)

54.5

Niven R, et al. Thorax 2007 (abstract)

Anti-IL-5 mAbs

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%

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

Thank you! Q&A

Jason Lee MD, FRCPC