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Targeted Therapies in Difficult-to-Control
Asthma
Paul M O’Byrne
EJ Moran Campbell Professor of Medicine
Firestone Institute for Respiratory Health,
St. Joseph’s Healthcare and McMaster University,
Hamilton, Ontario, Canada
GINA Guidelines 2011
Phenotyping
Empiric Treatment
Omalizumab and Difficult-to-Control
Asthma
Age
39.3 (12-73)
Duration of asthma (years) 20.6 (1-61)
39.0 (12-74)
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
Puffs of rescue medication
4.9 (2.65)
per day during run-in
Total asthma symptom
4.31 (1.17)
score during run-in
25.9
4.8 (2.51)
4.24 (1.17)
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
Bronchial Thermoplasty
•
Catheter has an expandable wire
array at the tip



7
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
Miller J D et al. Chest 2005;127:1999-2006
Bronchial Thermoplasty
Cox PG, et al. Am J Respir crit Care Med 2006; 173:965-9
Bronchial Thermoplasty
Age
BDP dose (mean [(μg/day)
Seasonal Allergies
FEV1 % predicted
Asthma Severity
Moderate Persistent
Asthma Severity
Severe Persistent
BRONCHIAL
THERMOPLASTY
39.4
1351+963
62%
72.6+10.4
CONTROLS
41.7
1264+916
65%
76.1+9.6
38%
47%
62%
53%
GINA Guidelines 2011
Phenotyping
Empiric Treatment
Induced Sputum
O’Byrne PM, Nair P. Lancet 2006; 368:794-308
120
BTS
management group
100
80
Severe
Exacerbations 60
(number)
Sputum
management group
40
20
0
0
2
4
6
8
10
12
Time (months)
GREEN R, et al . LANCET 2002; 360: 1715-21
LOMA study
Clinical Strategy
Sputum Strategy
Number/exacerbations/year
(median)
1.5
p=0.01
1.0
1.0
p=0.03
0.77
0.50
0.5
0.46
0
Very Mild Mild
Moderate Severe
All
subjects
Pizzichini MMM et al. ERS meeting 2003
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
26 severe asthmatics.
FEV1 49-61% predicted.
All on high dose ICS or
oral corticosteroids.
Blood Eosinophils
FEV1
Kips J, et al. Am J Respir Crit Care Med 2003; 167:1655-9
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
Asthma
Exacerbations
(% patients)
p=0.06
Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71
Subject characteristics
Mepolizumab
n
Age, y (gender, M)
Years of symptoms
FEV1 % predicted
Δ FEV1, exacerbation %
Δ FEV1, SABA %
Prednisone, mg (years )
ICS, mg
LABA, n
9
57.9 (4M)
Placebo
10
59.3 (7M)
11.8
9.2
65.5
43.7
68.2
45.0
17.1
10 (9.7)
1000
8
27.4
10 (8.0)
1000
9
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
Prednisone Reduction
n=9
n=10
mepolizumab
placebo
100
80
prednisone reduction as %
of maximum possible
reduction
60
40
20
0
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
48
PLACEBO
50
BDP dose (mean [(μg/day)
2038
1711
Oral Prednisone
57%
53%
67.9%
68.8%
78.1+20.9
77.6+24.1
6.84%
5.46%
1.98+1.07
2.38+1.35
Age
Seasonal Allergies
Post-BD FEV1 % predicted
Sputum eosinophils
ACQ score
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
Oligonucleotide Therapeutic Approaches
3. ISS/ CpG motif
(ssDNA)
4. Decoy
(dsDNA)
Competition for TF
“Blocks” transcription!
5. Aptamer
(DNA or RNA)
Nucleus
Transcription factor
TLR9
DNA
(GENE)
Promoter
RNAseH
Transcription
Immunostimulation
“Blocks”
receptor
function!
RNA
Translation
PROTEIN
RNAseH
RISC
2. siRNA
(dsRNA)
mRNA
degradation
1. Antisense
(ssDNA)
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.
% change from pre-allergen levels
% change from pre-allergen levels
Effect of ASM8 on βc and CCR-3 mRNA
in sputum cells
Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.
Sputum Cell Counts
Pre-dose vs Post Allergen
SPUTUM TOTAL CELLS COUNT
PRE-DOSE (DAY 1) & 7 HRS POST-ALLERGEN (DAY 3)
TOTAL CELLS COUNT (X10 6 CELLS)
(Mean +/- SEM)
ASM8
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
PRE
POST
PRE
POST
1.50
EOSINOPHILS CELL COUNT (X10 6 CELLS)
(Mean +/- SEM)
PLACEBO
5.0
SPUTUM EOSINOPHILS CELL COUNT
PRE-DOSE (DAY 1) & 7 HRS POST-ALLERGEN (DAY 3)
PLACEBO
ASM8
1.25
1.00
0.75
**
0.50
0.25
0.00
PRE
POST
PRE
POST
* * p= 0.0059 (Placebo vs ASM8)
Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.
Allergen-Induced Sputum
Eosinophilia
1.75
1.25
1.00
p=0.005
1.25
1.00
0.75
0.50
0.25
0.00
screen
1 mg BID
2 mg BID
4 mg BID
8 mg OD
Dose Level
0.75
1.2
6
)
0.50
0.25
0.00
pre
7h
24h
Time Post Allergen Challenge
Sputum Eosinophils (X 10
24 h post allergen
Sputum Eosinophils (X 10
8 mg OD
1.50
7 h post allergen
Baseline
1 mg BID
2 mg BID
4 mg BID
6
cells)
1.50
Sputum Eosinophils (X 10
6
)
1.75
1.0
p=0.043
0.8
0.6
0.4
0.2
0.0
screen
1 mg BID
2 mg BID
Dose Level
4 mg BID
8 mg OD
Allergen-induced Fall in FEV1
-5
Baseline
1 mg BID
2 mg BID
4 mg BID
8 mg OD
0
5
Fall in FEV 1 (%)
10
15
20
25
30
35
40
0
1
2
3
4
Time (h)
5
6
7
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.