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Targeted Therapies in Difficult-to-Control Asthma

Paul M O’ByrneEJ Moran Campbell Professor of MedicineFirestone Institute for Respiratory Health,

St. Joseph’s Healthcare and McMaster University, Hamilton, Ontario, Canada

Phenotyping

Empiric Treatment

GINA Guidelines 2011

Age 39.3 (12-73) 39.0 (12-74)Duration of asthma (years) 20.6 (1-61) 22.7 (2-60)BDP dose (mean [(μg/day) 570 (420-1008) 568 (336-840)Serum total IgE (IU/mL) 172.5 (20-860) 186.3 (21-702)FEV1 % predicted 64.6 (12.5) 64.1 (11.6)FEV1 reversibility (%) 26.9 25.9Puffs of rescue medication per day during run-in 4.9 (2.65) 4.8 (2.51)

Total asthma symptom score during run-in 4.31 (1.17) 4.24 (1.17)

Omalizumab and Difficult-to-Control Asthma

Omalizumab and Difficult-to-Control Asthma

Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90

Omalizumab and Difficult-to-Control Asthma

Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90

7

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

Miller J D et al. Chest 2005;127:1999-2006

Bronchial Thermoplasty

Bronchial Thermoplasty

Cox PG, et al. Am J Respir crit Care Med 2006; 173:965-9

Bronchial Thermoplasty

BRONCHIAL THERMOPLASTY CONTROLS

Age 39.4 41.7BDP dose (mean [(μg/day) 1351+963 1264+916Seasonal Allergies 62% 65%FEV1 % predicted 72.6+10.4 76.1+9.6Asthma SeverityModerate Persistent 38% 47%

Asthma SeveritySevere Persistent 62% 53%

Phenotyping

Empiric Treatment

GINA Guidelines 2011

Induced Sputum

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

0

20

40

60

80

100

120

BTSmanagement group

Sputummanagement group

SevereExacerbations

(number)

2 4 6 8 10 120

GREEN R, et al . LANCET 2002; 360: 1715-21

Time (months)

Num

ber/e

xace

rbat

ions

/yea

r(m

edia

n)

Clinical StrategySputum Strategy

Very Mild - Mild

Moderate - Severe

All subjects

0

1.5

1.0

0.5

0.77

0.46

1.0

0.50

p=0.01

p=0.03

Pizzichini MMM et al. ERS meeting 2003

LOMA study

Jayaram L, et al. Eur Respir J 2006; 27:483-94

Effect of SCH55700, a Humanized Anti-Human Interleukin-5 Antibody, in Severe Persistent Asthma

Blood Eosinophils FEV1

Kips J, et al. Am J Respir Crit Care Med 2003; 167:1655-9

26 severe asthmatics. FEV1 49-61% predicted.

All on high dose ICS or oral corticosteroids.

Mepolizumab in asthma

• Subjects: – moderate/severe asthma– inhaled corticosteroids up to 1000 mcg/day– symptoms mean 5 on 12 point scale– FEV1 68% predicted

• Treatment:– SB 240563 250 mg or 750 mg or placebo

Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71

Mepolizumab in asthma

AsthmaExacerbations

(% patients)

Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71

p=0.06

Subject characteristics

101059.359.3

nnAge, y (gender, M)Age, y (gender, M)

FEVFEV11 % predicted % predictedYears of symptomsYears of symptoms

ΔΔ FEV FEV11, exacerbation %, exacerbation %

9957.957.9

MepolizumabMepolizumab PlaceboPlacebo

9.29.211.811.8(7M)(7M)(4M)(4M)

68.268.265.565.545.045.043.743.7

ΔΔ FEV FEV11, SABA % , SABA % 27.427.417.117.1

LABA, nLABA, n

10101010Prednisone, mg (years )Prednisone, mg (years ) (8.0)(8.0)(9.7)(9.7)1000100010001000ICS, ICS, gg

9988 NAIR P, et al. N Engl J Med 2009; 360:985-93

Sputum and Blood Eosinophils

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

0

20

40

60

80

100

mepolizumab placebo

prednisone reduction as % of maximum possible

reduction

n=9 n=10

Prednisone Reduction

p<0.05

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

Asthma Exacerbations

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

Mepolizumab and Difficult-to-Control Asthma

MEPOLIZUMAB PLACEBOAge 48 50

BDP dose (mean [(μg/day) 2038 1711

Oral Prednisone 57% 53%

Seasonal Allergies 67.9% 68.8%

Post-BD FEV1 % predicted 78.1+20.9 77.6+24.1

Sputum eosinophils 6.84% 5.46%

ACQ score 1.98+1.07 2.38+1.35

Mepolizumab in Difficult-to-Control Asthma

Haldar P et al. N Engl J Med 2009; 360:973-984

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– CRTH2 antagonists

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

hang

e fr

om p

re-a

llerg

en le

vels

% c

hang

e fr

om 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

TOTA

L C

ELL

S C

OU

NT

(X10

6 CE

LLS

)(M

ean

+/-

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

OPH

ILS

CE

LL C

OU

NT

(X10

6 CE

LLS

)(M

ean

+/-

SE

M)

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

Sput

um E

osin

ophi

ls (X

106 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

Sput

um E

osin

ophi

ls (X

106 )

7 h

post

alle

rgen

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

Sput

um E

osin

ophi

ls (X

106 )

24 h

pos

t alle

rgen

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)

Fall

in F

EV1 (

%)

Summary

• Phenotyping is important to identify the best choice of treatment in difficult-to-control asthma.

• Bronchial thermoplasty is the only novel treatment recently approved for severe asthma.

• Anti-IL-5 mAbs appear very promising for asthma with a persisting airway eosinophilia

• Many other therapeutic approaches are being studied for the management of difficult-to-control asthma.