1. Grazie per aver scelto di utilizzare a scopo didattico questo materiale delle Guidelines 2011 libra. Le ricordiamo che questo materiale è di proprietà dell’autore e fornito come supporto didattico per uso personale.

2. 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

3. GINA Guidelines 2011
Phenotyping
Empiric Treatment

4. Omalizumab and Difficult-to-Control Asthma
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 ( )
568 ( )
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
25.9
Puffs 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)

5. Omalizumab and Difficult-to-Control Asthma
Busse WW, et al. J Allergy Clin Immunol 2001; 108:184-90

6. 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
The Alair system is composed of two components. The Alair catheter is a flexible tube with an expandable wire array at the tip. It is introduced into the lungs by way of the working channel of a standard bronchoscope. The Alair radiofrequency controller supplies monopolar RF energy to the catheter. The heat is delivered to the airway wall at a precisely controlled at 65° C for 10 seconds. The radiofrequency controller contains multiple sophisticated safety algorithms to ensure safety.
Monopolar radiofrequency (RF) energy
Temperature controlled: 65 °C
10 seconds
Signal for successful activation
Multiple safety algorithms to ensure controlled energy delivery 7 7

8. Bronchial Thermoplasty
Representative section of an airway from patient 4–04 resected 20 days after treatment with bronchial thermoplasty at 65°C. Left: An airway in cross-section stained with hematoxylin-eosin. Right: Trichrome-stained section at higher magnification. ASM is largely absent to the left of the arrow. (Magnification: left panel, 40×; right panel, 400×.)‏
Miller J D et al. Chest 2005;127:

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

10. Bronchial Thermoplasty
CONTROLS
Age
39.4
41.7
BDP dose (mean [(μg/day)
Seasonal Allergies
62%
65%
FEV1 % predicted
Asthma Severity
Moderate Persistent
38%
47%
Severe Persistent
53%

11. Bronchial Thermoplasty
Cox PG, et al. New Engl J Med 2007; 356:

12. Bronchial Thermoplasty
Cox PG, et al. New Engl J Med 2007; 356:

13. Bronchial Thermoplasty in Difficult-to-Control Asthma
Pavord I, et al. Am J Respir Crit Care Med 2007; 176:

14. Decreased Severe Exacerbations During Post-Treatment Period*
Castro M, et al. Am Rev Respir Crit Care Med 2010; 181:116-24

15. Days Lost from Work/ School/Activity due to Asthma
Castro M, et al. Am Rev Respir Crit Care Med 2010; 181:116-24

16. GINA Guidelines 2011
Phenotyping
Empiric Treatment

17. Induced Sputum
O’Byrne PM, Nair P. Lancet 2006; 368:

18. Severe Exacerbations (number) Time (months)
120
BTS
management group
100 80
Severe
Exacerbations
(number) 60
Sputum
management group 40 20 2 4 6 8 10 12
Time (months)
GREEN R, et al . LANCET 2002; 360:

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

20. All on high dose ICS or oral corticosteroids.
Effect of SCH55700, a Humanized Anti-Human Interleukin-5 Antibody, in Severe Persistent Asthma
26 severe asthmatics.
FEV % 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

21. Mepolizumab in asthma Subjects: Treatment: moderate/severe asthma
inhaled corticosteroids up to 1000 mcg/day
symptoms mean 5 on 12 point scale
FEV1 68% predicted
Treatment:
SB mg or 750 mg or placebo
Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:

22. Mepolizumab in asthma Asthma Exacerbations (% patients) p=0.06
Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:

24. Subject characteristics
Mepolizumab
Placebo n 9 10
Age, y (gender, M)
57.9
(4M)
59.3
(7M)
Years of symptoms
11.8
9.2
FEV1 % predicted
65.5
68.2
Δ FEV1, exacerbation %
43.7
45.0
Δ FEV1, SABA %
17.1
27.4
Prednisone, mg (years ) 10
(9.7) 10
(8.0)
ICS, mg
1000
1000
LABA, n 8 9
NAIR P, et al. N Engl J Med 2009; 360:985-93

25. Sputum and Blood Eosinophils
NAIR P, et al. N Engl J Med 2009; 360:985-93

26. prednisone reduction as % of maximum possible reduction
100 80
prednisone reduction as % of maximum possible reduction 60 40 20
mepolizumab
placebo
p<0.05
NAIR P, et al. N Engl J Med 2009; 360:

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

28. Mepolizumab and Difficult-to-Control Asthma
PLACEBO
Age 48 50
BDP dose (mean [(μg/day)
2038
1711
Oral Prednisone
57%
53%
Seasonal Allergies
67.9%
68.8%
Post-BD FEV1 % predicted
Sputum eosinophils
6.84%
5.46%
ACQ score

29. Mepolizumab in Difficult-to-Control Asthma
Haldar P et al. N Engl J Med 2009; 360:

30. New Drugs for Asthma Modifications of existing drugs: New approaches
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

31. Oligonucleotide Therapeutic Approaches
4. Decoy
(dsDNA)
3. ISS/ CpG motif
(ssDNA)
5. Aptamer
(DNA or RNA)
Competition for TF
“Blocks” transcription!
Nucleus
Transcription factor
TLR9
DNA
(GENE)
Immuno-
stimulation
Promoter
RNAseH
Transcription
“Blocks”
receptor
function!
RNA
Translation
PROTEIN
RNAseH
RISC
2. siRNA
(dsRNA)
mRNA
degradation
1. Antisense
(ssDNA)
Paolo Renzi MD.

32. 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.

33. Effect of ASM8 on βc and CCR-3 mRNA in sputum cells
% change from pre-allergen levels
% change from pre-allergen levels
Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.

34. Pre-dose vs Post Allergen
Sputum Cell Counts
Pre-dose vs Post Allergen
Gauvreau GM, et al. Am J Respir Crit Care Med 2008: 177:952-8.

35. Allergen-Induced Sputum Eosinophilia

36. Allergen-induced Fall in FEV1

37. 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.