Punching Above its Weight:Asthma Research in Canada

Paul M O’ByrneEJ Moran Campbell Professor of Medicine

Firestone Institute for Respiratory Health,

St. Joseph’s Healthcare and McMaster University,

Hamilton, Ontario, Canada

Potential for Conflict of Interest

• Advisory Boards: Acetelion, AstraZeneca, GlaxoSmithKline, Merck, Resistentia, Topigen.

• Speakers Fees: AstraZeneca, Chiesi, GlaxoSmithKline.

• Grants-in-Aid: Alexion, AstraZeneca, Genentech, GlaxoSmithKline, Medimmune, Merck, Schering Plough, Wyeth.

Manny Pacquiao

• Filipino professional boxer• an eight division world

champion• the first boxer in history to

win ten world titles• the first to win in eight

weight divisions• named "Fighter of the

Decade" for the 2000's

9, 984,670 sg Km6.7% total land mass

Canada

Population 34M0.6% world’s population

17 Medical Schools133 in USA33 in UK22 in Australia/NZ

Since 1980: Asthma96K publications5.5K Canadian5.7% total

18 of 100 most cited asthma papers includeCanadian investigators

Pulmonary Citations 1998-2009

Lab Times 2011; 2:42-44

Canada: Third in the world for pulmonary

citations, behind USA and UK; but with a higher citation/article rate than

either

Most Cited Asthma Publications from Canadian Investigators

Canadian Centers of Excellence

Montreal

Quebec City

Toronto

Hamilton

Winnipeg

Saskatoon

Edmonton

Calgary

Vancouver

Game Changers: Asthma Diagnosis and Treatment

Canadian Consensus Guidelines

Juniper E, 1990OPTIMA A 2001

START 2003

FACET 1997OPTIMA B 2001

Boulet, 1997Cox G, 2007 Nair P, 2009

11

Bronchial Thermoplasty• Catheter has an expandable wire

array at the tip

Radiofrequency energy that is converted to heat in the airway wall

Monopolar radiofrequency (RF) energy Temperature controlled: 65 °C 10 seconds Signal for successful activation

Multiple safety algorithms to ensure controlled energy delivery

Bronchial Thermoplasty

Cox PG, et al. New Engl J Med 2007; 356:1327-37.

Bronchial Thermoplasty

Cox PG, et al. New Engl J Med 2007; 356:1327-37.

Induced Sputum

O’Byrne PM, Nair P. Lancet 2006; 368:794-308

Asthma Exacerbations

Nair P, et al. N Engl J Med 2009; 360:985-93.

NCE Clinical Investigator Collaborative

PM O’Byrne

GM Gauvreau

L-P Boulet

JM Fitzgerald

DW Cockcroft

I Mayers R Leigh

New Drugs for Asthma

• Modifications of existing drugs:– Untra-longacting inhaled β2-agonists

– Modified inhaled corticosteroids

– Glucocorticosteroid receptor agonists

– New ICS/LABA combinations

• New approaches– Anti-sense against IL-3, IL-3, GM-CSF and CCR

– Anti-sense IL-4R– Anti-IL-9 – Anti-IL-13– Anti-C5a

– Anti-Ox 40L– CXCR2 antagonist

Goblet cell hyperplasia, mucus production &

epithelial desquamationAltered neural

mediators

Increasedsmooth muscle

&altered function

Edema and lossof airway

tethering to parenchyma

Myofibroblasthyperplasia &

fibrosis

Dendritic cell, lymphocyte & mast cell

mediated events

Inflammatory cell production,recruitment andmediator release

Initial antigen recognition, T-cell orientation

and IgE production

AHRALLERGICASTHMA

FEV1

(L)

FEV1

(L)

Time Post-Inhalation (h)

0 1 2 3 4 5 6 7 8

3.0

3.5

4.0

4.5

5.0

3.0

3.5

4.0

4.5

5.0

Grass Pollen

House Dust Mite

CARTIER A , et al. J Allergy Clin Immunol 1982; 70:170-7

16

8

4

2

1

0.5

4

2

1

0.5

Days after Allergen Inhalation

0 1 2 3 4 5 6 7 8 9 17 19 45 73 129

Ratio Change

in Histamine

PC20

+2

0 SD

-2

+2

0 SD

-2

24h 2d 4d 7dTime Post Inhalation

0

5

10

15

20

SputumMCC

(x10 4 /ml)

0

100

200

300

SputumEosinophils

(x10 4 /ml)

24h 2d 4d 7d.5

1

2

4

8

MCh PC 20

(mg/ml)

-30

-20

-10

0

.5

1

2

4

8

GAUVREAU GM, et al. Am J Resp Crit Care Med 1999: 160; 640-7

Diluent Allergen

Baseline

Baseline

7h

7h

% Fall in FEV1

*

**

**

*

* * * **

Transcription

Nucleus

DNA(GENE)

RNA

1. Antisense(ssDNA)

RNAseH

2. siRNA(dsRNA)

RISC

Promoter

4. Decoy(dsDNA)

Transcription factor

5. Aptamer(DNA or RNA)

Translation

3. ISS/ CpG motif(ssDNA)

TLR9

Immuno-stimulation

mRNAdegradation

PROTEIN

“Blocks”receptorfunction!

Competition for TF“Blocks” transcription!

Oligonucleotide Therapeutic Approaches

RNAseH

Paolo Renzi MD.

Rationale:

• By down-regulating the expression of the eotaxin receptor (CCR3) and the common beta chain for IL-3, IL-5, and GM-CSF, – an inhaled anti-sense, ASM8 will inhibit the

migration and survival of eosinophils, basophils, mast cells.

– and thereby inhibit allergen-induced airway responses.

Effect of ASM8 on βc and CCR-3 mRNA in sputum cells

% c

han

ge

fro

m p

re-a

llerg

en le

vels

% c

han

ge

fro

m p

re-a

llerg

en le

vels

Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.

SPUTUM TOTAL CELLS COUNTPRE-DOSE (DAY 1) & 7 HRS POST-ALLERGEN (DAY 3)

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

5.0 PLACEBO

ASM8

PRE POST PRE POST

TO

TA

L C

EL

LS

CO

UN

T (

X1

06 C

EL

LS

)(M

ea

n +

/-

SE

M)

SPUTUM EOSINOPHILS CELL COUNTPRE-DOSE (DAY 1) & 7 HRS POST-ALLERGEN (DAY 3)

0.00

0.25

0.50

0.75

1.00

1.25

1.50 PLACEBO

ASM8

PRE POST PRE POST

* * p= 0.0059 (Placebo vs ASM8)

**

EO

SIN

OP

HIL

S C

EL

L C

OU

NT

(X

10

6 CE

LL

S)

(Me

an

+/-

S

EM

)

Sputum Cell CountsPre-dose vs Post Allergen

Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.

Allergen-Induced Sputum Eosinophilia

pre 7h 24h0.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

Baseline

8 mg OD

1 mg BID2 mg BID4 mg BID

Time Post Allergen Challenge

Sp

utu

m E

osi

no

ph

ils

(X 1

06 c

ells

)

screen 1 mg BID 2 mg BID 4 mg BID 8 mg OD0.00

0.25

0.50

0.75

1.00

1.25

1.50

1.75

Dose Level

Sp

utu

m E

osi

no

ph

ils

(X 1

06)

7 h

post

allerg

en

screen 1 mg BID 2 mg BID 4 mg BID 8 mg OD0.0

0.2

0.4

0.6

0.8

1.0

1.2

Dose Level

Sp

utu

m E

osi

no

ph

ils

(X 1

06)

24 h

po

st a

ller

gen

p=0.005

p=0.043

Allergen-induced Fall in FEV1

0 1 2 3 4 5 6 7

-5

0

5

10

15

20

25

30

35

40

Baseline 4 mg BID 8 mg OD1 mg BID 2 mg BID

Time (h)

Fal

l in

FE

V1 (

%)

EAR LAR

IL-4 and IL-13

Kasaian M, Miller D. Biochem Pharm 2008; 76:147-55

IL-13 in Asthmatic Sputum

Berry MA, et al. J Allergy Clin Immunol 2008; 121:685-91Berry MA, et al. J Allergy Clin Immunol 2004; 114:1106-9

IL-4 Mutene on Allergen-Induced Responses

Wenzel S, et al. Lancet 2007; 370:1422-31

Anti-IL-13

• Test product, dose, and mode of administration: IMA-638 hMab, humanized IgG12x2 mg/kg, subcutaneous

• Duration of treatment: 2 doses 7 days apart

• Reference therapy: placebo: SC formulation excipients only

Effect on Allergen-Induced Airway Responses

Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.

Effect on Allergen-Induced Airway Hyperresponsiveness

Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.

Effect on Allergen-Induced Sputum Eosinophilia

Gauvreau GM, et al. Am J Respir Crit Care Med 2011; 183:1007-14.

The Canadian Healthy Infant

Longitudinal Development

(CHILD) study

- a collaborative study of the effects of environment on

children’s health

CHILD – a 5-year study of 5,000 childrenIn-utero - recruitment: maternal, paternal and sibling studies;

clinical, stress and environment questionnaires

Delivery - delivery: outcomes, cord blood, meconium, urine

3 months - home visit: inspection, dust sampling, breast-milk

- infant lung function, stress (sub-cohorts), infections

6 months - telephone questionnaire follow-up

1 year - clinic: skin tests, blood, nasal, lung function, infections

1 ½ years - telephone questionnaire follow-up

2 years - telephone questionnaire follow-up

2 ½ years - telephone questionnaire follow-up

3 years - clinic: questionnaires, skin tests, lung function, blood

4 years - telephone questionnaire follow-up 5 years - clinic: questionnaires, clinical assessment, skin tests,

lung function, blood, physician assessment

Canadian Healthy Infant Longitudinal

Development (CHILD) investigators

Allan Becker Dean Befus Michael Brauer Jeff Brook Edith Chen Michael Cyr Denise Daley Sharon Dell Judah Denburg

Susan Elliott Hartmut Grasemann Kent HayGlass Rick Hegele Linn Holness Michael Kobor Tobias Kollman Tulay Koru-Sengul A nita Kozyrksyj

Catherine Laprise Wendy Lou Piush Mandhane Greg Miller Redwan Moqbel Peter Pare Clare Ramsey Felix Ratjen Andy Sandford

James Scott Jeremy Scott Malcolm Sears Fran Silverman PJ Subbarao Tim Takaro Scott Tebbutt Teresa To Stuart Turvey

Disciplines involved in developing the Canadian Healthy Infant Longitudinal Development study

• Epidemiology• Neonatology• Pediatrics • Population health• Environmental assessment• Environmental hygiene• Nutrition• Infectious disease• Genetics• Obstetrics • Geographic Information Systems• Endocrinology/metabolism• Mind-body

• Physiology• Immunology • Allergy• Air quality• Toxicology • Sociology • Molecular biology• Psychology • Neuroimmunology • Biostatistics• Ethics and legal• Respirology• Occupational health

Recruitment Sites for CHILD Study

Summary

• Canadian respiratory research is among the strongest in the world.

• Asthma research is a particular strength.

• This success is achieved in spite of the fact that funding for respiratory research is likely the worst for developed countries.

• Asthma research community is the most collegial in the world!!