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Asthma Phenotypes, Immunology and

Implications for Therapy

J R Hansbrough MD, Ph.D.

Graves Gilbert Clinic

Bowling Green, Kentucky

Definition of Asthma

A chronic disorder of the airways that is complex and

characterized by variable and recurring symptoms,

airflow obstruction, bronchial hyperresponsiveness,

and an underlying inflammation.

Inflammatory disease of the airway

Reversibility of airway obstruction (with time and

treatment)

Waxing and waning symptoms

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Asthma Prevalence, Morbidity and Mortality

Approximately 11 People Die From Asthma Each Day in the US

13.6 Million Unscheduled Office Visits

Annually

0.5 Million Hospitalizations

Annually

Approximately 4000 Asthma-

Related Deaths

22.2 Million People Are Currently

Diagnosed With Asthma

National Center for Health Statistics, CDC, 2005;

http://www.cdc.gov/nchs/products/pubs/pubd/hestats/asthma/asthma.html

1.8 Million Emergency Room Visits

Annually

Mainstay of Asthma Therapy

• Inhaled steroids are by far the most effective therapy for chronic therapy.

• Should be utilized for anyone with chronic symptoms (use of rescue inhaler 2 or more times a week or evidence of chronic airflow obstruction).

• Long acting beta agonists (LABA) in combination with inhaled steroids improve control. Cardiovascular side effects have been of some concern.

Environmental Control

• Smoking history and exposure

• Pets, plants, basement, damp living spaces, carpet.

• Exposure to fumes or smoke (wood burning stoves)

• Known triggers to asthma symptoms

• Specific IgE sensitivity (RAST or ImmunoCAP prolifes)

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Stepwise Approach for Managing Asthma

Step 1: Short-acting Beta2-agonists

Step 2: Low-dose Inhaled Corticosteroids (ICS)

Step 3: Low-dose ICS + Long-acting Beta2-agonists (LABA)

or Medium-dose ICS

Step 4: Medium-dose ICS + LABA

Step 5: High-dose ICS + LABA

and Consider Omalizumab

Step 6: High-dose ICS + LABA +

Oral Corticosteroids

and Consider Omalizumab

Poor

Patient A

dhere

nce

Phenotypes of Asthma

Extrinsic vs. Instrinsic

Allergic vs. Non Allergic

Thy-2 vs. Non Thy-2

IgE mediated

Eosinophilia Bronchitis

The more we know, the less we understand. Better characterization of asthma

phenotypes, the more heterogeneous the disease appears

Immunology of WBCs

• Monocytes

• Granulocytes---Polymorphonuclear leukocytes

– Neutrophils

– Eosinophils

– Basophils---Mast cells

• Lymphocytes

– T cells—regulatory cells

– B cells---Mature into immunoglobulin producing cells

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Immunoglobulins

Infection fighting proteins produced by matured B cells (Plasma Cells)

IgA

IgG

IgM

IgE---anti parasitic and allergy mediators

Interleukins (IL)

Interleukin are a group of cytokines (secreted proteins and signal molecules) that were first described as being expressed by white blood cells.

The function of the immune system depends in a large part on interleukins.

Produced by a large number of cell types

Local response to injury, inflammation or infection

Maturation and developed of different white cell types (Esp. T/B cells)

Most recent data describes 36 human interleukins

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Interleukins of interest in asthma

• IL-4---Stimulates B cell maturation to IgE producing plasma cells and

production of eosinophils

• IL-5---Maturation, production and stabilization of eosinophils

• IL-13--Stimulates B cell maturation to IgE producing plasma cells and

production of eosinophils

THIS IS A SIMPLIFICATION!!!!—As with all interleukins, they can have multiple and wide ranging effects

Pathophysiology of asthma

• Th2 pathways---T cell subtype associated with classic allergic (IgE mediated) mechanisms

– IL-4 and IL-13 mediated pathways

– IL-5—Eosinophil maturation and survival

• Non Th2 pathways---Less well defined. Explains may of the non-allergic mediated asthma

– Epithelial-extracellular matrix inflammation

– Response to infectious agents

– TGF-beta/Smad2 overexpression

– Airway remodeling

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Inflammatory Cascade

Storms. Am J Respir Med. 2002:1:361.

MacGlashan et al. J Immunol. 1997;158:1438.

B cell

T cell

IL-4,

IL-13 lgE

production

Antigen-

presenting

cell

Allergen

Activated

B cell

(plasma cell) Allergen

cross-linking

Mediator

release

Airway

wall

Mast cell

IgE FcRI

Storms. Am J Respir Med. 2002:1:361.

MacGlashan et al. J Immunol. 1997;158:1438.

Safety and efficacy have not been

established in other allergic conditions.

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Humanized Monoclonal Antibodies

• Revolutionary advance in the use of antibodies as therapy

• Monoclonal antibodies produced in animals/non human cell cultures

• Genetic sequence for the binding sites is spliced out of non human source and inserted into a human gene for IgG production

• Identified by the –mab ending.

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Omalizumab Biological Characteristics

• Humanized monoclonal antibody against IgE

• Binds circulating IgE regardless of specificity

• Forms small, biologically inert Xolair: IgE complexes

• Does not activate complement

CDR = complementarity-determining region. Adapted from Boushey. J Allergy Clin Immunol. 2001;108:S77. Please refer to the full Prescribing Information, including Boxed WARNING and

Medication Guide.

Murine CDRs (5% of molecule)

IgG1 kappa human

framework (95% of molecule)

In this simplistic model of asthma, specific antagonism of

selected mediators could be a very effective treatment for

asthma

Specific targets Specific Agents

IL-4 Dupilumab

IL-5 Mepolizumab

IL-13 Dupilumab

IgE Omalizumab*

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Recent Classification of Asthma Phenotypes

Early onset atopic with stable asthma

Early onset atopic asthma with poor control

Late onset female predominant asthma associated with

obesity

Late onset atopic asthma

Late onset with mixed inflammation

Am J Respir Crit Care Med Vol 181. pp 315–323, 2010

Theory: Response to treatment, especially treatment

with biological modifiers can be predicted by clinical

asthma phenotypes

Omalizumab—Anti IgE therapy

IgE mediated asthma with significant allergy triggers

Mepolizumab---Anti IL-5 therapy

Asthma with eosinophilia

Dupilumab---Anti IL-4 and Anti-13

Allergic asthma with eosinophilia

In actual practice, patient selection and response to

treatment is much more complicated

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Lancet 2000; 356: 2144–48. Effects of an interleukin-5 blocking

monoclonal antibody on eosinophils, airway hyper-responsiveness,

and the late asthmatic response

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Blood eosinophil--IL-5 especially (IL-4 and Il-13)

Periostin---IL-13

FeNO---IL-4, IL-5, IL-13

IgE---Allergic mediated, IgE blocking agents

Biomarkers useful in directing asthma

therapy

Biomarker based asthma therapy

Agent Target Markers

Omalizumab IgE IgE, FeNO, atopy

?eosinophil

Mepolizumab Il-5 Blood Eosinophilia

Dupilumab IL-4/Il-13 FeNO, Periostin,

Eosinophilia

Biological Modifiers in Asthma

•Omalizumab

•1st Monoclonal antibody on market for asthma treatment

•Selective IgE Blocker

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Overview of IgE-Mediated Inflammatory Cascade

Storms. Am J Respir Med. 2002:1:361.

MacGlashan et al. J Immunol. 1997;158:1438.

B cell

T cell

IL-4,

IL-13 lgE

production

Antigen-

presenting

cell

Allergen

Activated

B cell

(plasma cell) Allergen

cross-linking

Mediator

release

Airway

wall

Mast cell

IgE FcRI

Storms. Am J Respir Med. 2002:1:361.

MacGlashan et al. J Immunol. 1997;158:1438.

Safety and efficacy have not been

established in other allergic conditions.

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Omalizumab Mechanism of Action (cont’d)

Omalizumab down-regulates

high-affinity receptors

Omalizumab inhibits mast-cell

degranulation

Omalizumab limits the release of

inflammatory mediators

Omalizumab helps prevent

exacerbations and improve symptoms

Allergen cross-linking

Mediator release

Airway wall

Other drugs

Storms Am J Respir Med. 2002:1:361.

MacGlashan et al. J Immunol. 1997;158:1438. Please refer to the full Prescribing Information, including Boxed WARNING and Medication Guide.

Mast cell

IgE

Safety and efficacy have not been

established in other allergic conditions.

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Omalizumab Mechanism of Action

Storms. Am J Respir Med. 2002:1:361.

MacGlashan et al. J Immunol. 1997;158:1438. Please refer to the full Prescribing Information, including Boxed WARNING and Medication Guide.

Omalizumab acts early

in the allergic cascade

to selectively target

lgE

Omalizumab binds serum-free lgE to

inhibit mediators of inflammation

Mast cell

IgE

Omalizumab

Safety and efficacy have not been

established in other allergic conditions.

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Relationship Between Asthma and Serum IgE Level

Asthma Risk Versus Total Serum IgE Concentration*

The risk for allergic asthma starts with relatively low IgE levels.

Od

ds r

ati

o

40

20

10

5

2.5

1

0 0.32 1 3.2 10 32 100 320 1000 3200

Serum IgE level (IU/mL)

Data from several population-based studies indicate that the overall geometric mean levels of IgE in the

general population range from 20 IU/mL to 40 IU/mL.1

*Results of a random, stratified cluster sample of 2657 patients that investigated the association of self-

reported asthma with serum IgE levels and skin-test reactivity to allergens. Adapted from Burrows et al. N Engl J Med. 1989;320:271.

1. Dolan et al. In: IgE and Anti-IgE Therapy in Asthma and Allergic Disease. 2002.

Clinical Summary of Omalizumab Therapy

• Clinical studies-50% reduction in asthma flares and significant improvement in symptoms and quality of life.

• Clinical experience-Outstanding drug for selected moderate to severe asthmatics.

• Cancer risk—most likely a statistical abnomity. • Anaphylaxis risk. (25 patients out of 39,510 patients treated)

• Duration of Therapy –Of patients stopping drug after 5-7 years,

75% maintained asthma control

Mepolizumab therapy in asthma (NEJM 2014)

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Dupilumab in Persistant Asthma with Elevated Eosinophil Levels

NEJM 368(26): 2455-2466 2013

Biological Modifiers in Asthma--Summary

• Omalizumab reduces exacerbations, improves symptom control, reduces glucocorticoid and β2-agonist usage, improves patient quality of life, together with significant improvements in lung function and has a favorable risk–benefit profile.

• Mepolizumab is efficacious in patients with specific phenotypes of severe asthma characterized by persistent, glucocorticosteroid-resistant eosinophilia.

• Dual inhibition of IL-4 and IL-13 with dupilumab represents a very promising avenue for biologic-based asthma therapy, but further large-scale clinical trials on patients with day-to-day asthma are required to fully validate such an approach.

Asthmatic Airway

Airway Smooth Muscle

Normal Airway Asthma Attack

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Bronchial Thermoplasty Rationale

Reduces Excessive Airway Smooth

Muscle (ASM)

Reduced Ability for

Bronchoconstriction

Reduced Asthma Symptoms

and Exacerbations

Improved Asthma Control and

Quality of Life

Bronchial Thermoplasty

• If airway smooth muscle is reduced, airway bronchoconstriction can be reduced, and therefore asthma symptoms and quality of life will potentially improve.

• Bronchial Thermoplasty with the Alair® System reduces airway smooth muscle through controlled thermal treatment to the airway wall.

The Alair® System

• The Alair Catheter is a flexible tube with an expandable wire array at the tip.

• The Alair Radiofrequency

Controller supplies energy via the Alair Catheter to heat the airway wall.

Censored MCBG

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UNTREATED

Reduced Airway Smooth Muscle 3 Years Post-Treatment (Canine Model)

Ciliated

Epithelium ASM

Parenchyma Parenchyma

Ciliated

Epithelium ASM Reduced

TREATED

Masson’s Trichrome stain

Treatment Method

All visible and

accessible airways

(3-10mm) distal to

mainstem bronchi are

treated

Series of contiguous

activations

3 treatment sessions

Danek et al. J Appl Physiol. 2004; 97: 1946-1953

https://www.youtube.com/embed/el_IbQPhH48

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Treated airway on left

Bronchoscopic View of Local

Methacholine Challenge

Cox et al. Eur Respir Journal. 2004; 24: 659-663

Treatment Effects of Bronchial Thermoplasty

Reduces, but does not eliminate ASM.

No clinical evidence of airway structure based on FEV1

values in human studies.

No clinical evidence of long-term (5 yr) bronchiectasis, decreased pulmonary function, or pneumonia based on CT scans.

Preclinical histology in canine model showed a reduction in ASM, persistent out to 3 years.

Miller et al. CHEST. 2005; 127(6): 1999-2006

Cox et al. AJRCCM. 2006; 173(9): 965-969

Danek et al. J Appl Physiol. 2004; 97: 1946-1953

Summary

• Asthma is a complex disease.

• Newer therapies will be directed based on both clinical phenotypes and biomarkers.

• Biological modifiers have and should continue to

have dramatic effects on the control of severe asthma.

• Bronchial Thermoplasty represents a promising, new, and novel treatment for asthma.