1. Treatment Options for the Symptomatic Asthma Patient
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

2. Potential for Conflict of Interest
Advisory Boards: Abbott, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Medimmune, Merck.
Speakers Fees: AstraZeneca, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Takeda.
Grants-in-Aid: Amgen, AstraZeneca, Axican, Genentech, GlaxoSmithKline, Novartis, Sanofi.
Employed by McMaster University

3. The Goals of Asthma Management
Overall Asthma Control
achieving
reducing
Current control
Future risk
defined by
defined by
Symptoms
Reliever use
Instability/
worsening
Exacerbations
Activity
Lung function
Loss of lung function
Adverse effects of medication
NAEPP. Expert Panel Report
Taylor DR, et al. Eur Respir J 2008; 32:545–554

4. Asthma Paradox Effective and safe treatments: Inhaled corticosteroids
Short-acting inhaled β2-agonists
ICS/LABA combinations
Leukotriene receptor antagonists
Anti-IgE hMab
23%
59%
18%
Chapman KR, et al. Eur Respit J 2008; 31:320-5

5. KEYPAD QUESTION

6. Evaluation of Uncontrolled Asthma
Adherence, adherence, adherence (50%: 50%: 50%)
Co-morbidities
Rhino-sinusitis
Allergic bronchopulmonary aspergillosis
GERD
Obesity
Bronchiectasis
Vocal cord dysfunction
Smoking
Psychopathology
Persistent allergen/occupational exposure
Incorrect diagnosis
Severe refractory disease

7. Krishnan JA, et al. Am J Respir Crit Care Med 2004; 170:1281-5

8. 1 year risk of discontinuation:
Age <55 years
Female sex
Previous β2-agonist use
No other drugs used
Higher co-payment

9. Study Subjects n Intervention Results
Rasmussen et al. JACI 2005
300
Internet-based management tool
Better adherence, lung function, symptoms and QOL
Araujo et al. J Invest All Clin Immunol 2012 21
Web-based management tool
Better QOL only
Vollmer et al. Am J Manag Care 2011
8517
Interactive voice recognition calls
Better adherence, better asthma control
Wilson et al. AJRCCM 2010
612
Shared decision making
Better adherence. Some improvement AQLQ
Clark et al. Chron Resp Dis 2012
808
Asthma Care Plan developed with physician
Gamble et al. Respir Med 2011
239
Educational visit with specialist nurse
Better adherence. Less OCS use
Ulrik et al. Clin Respir Dis 2009
361
Compliance enhancement training sessions
No improvement in asthma control
Barnes CB, Ulrik S. Respir Care 2014: in press

10. GINA 2014
*For children 6-11 years, theophylline is not recommended, and preferred Step 3 is medium dose ICS
**For patients prescribed BDP/formoterol or BUD/ formoterol maintenance and reliever therapy

11. Well-controlled patients (%) Poorly-controlled patients (%)
FACET: Well vs Poorly Controlled Patients
Well-controlled patients (%)
Poorly-controlled patients (%) 80 20
62% 60 15
14%
46%
40% 40
37% 10 7% 6% 20 5 3%
BUD
200
BUD
800
BUD
200+ F
BUD
800+ F
BUD
200
BUD
800
BUD
200+ F
BUD
800+ F
O’Byrne PM, et al. Chest 2008; 134:

12. KEYPAD QUESTION

13. The Goal of Asthma Management is:
Overall Asthma Control
achieving
reducing
Current Control
Future Risk
defined by
defined by
Symptoms
Reliever use
Instability/
worsening
Exacerbations
Activity
Lung function
Lung function
loss
Medication
adverse effects
GINA 2006; NIH/NAEPP Expert Report No ; ATS/ERS Task Force on Asthma Severity & Control 2008

14. Sears MR et al. New Engl J Med 2003;349:1414-22.

15. START – study outline Part A Part B 1 2 3 Year 4 5 Visit 1 2 3 4 5 6 7
Children 11+ yrs and Adults
Budesonide 400 µg ONCE DAILY
+ usual therapy
Part B
Children < 11 yrs
Children 11+ yrs and Adults
Budesonide 200 µg ONCE DAILY
+ usual therapy
Budesonide 400 µg ONCE DAILY
+ usual therapy
Children < 11 yrs
Budesonide 200 µg ONCE DAILY
+ usual therapy
START – study outline
START is a multinational, multicentre, double-blind, parallel group study lasting for 3 years, followed by a 2-year open-label study. During the first 3 years (Part A), patients received Pulmicort once daily or placebo once daily, in addition to their usual asthma therapy.
In the final 2 years (Part B), all patients receive Pulmicort once daily, in addition to their usual asthma therapy.
Adults and Children
Placebo ONCE DAILY + usual therapy 1 2 3
Year 4 5
Visit 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

16. NoSARE is the subgroup with no Severe Asthma Related Event.
n=3284 (Budesonide), n=3178 (Placebo)
SCS is the subgroup with at least one systemic corticosteroid course due to asthma.
n=543 (Budesonide), n=808 (Placebo) (p<0.001)
SARE is the subgroup with at least one Severe Asthma Related Event requiring hospital management.
n=116 (Budesonide), n=192 (Placebo) (p<0.01)

17. START: 3-year change in post-bd FEV1%
O’Byrne PM, et al. Am J Respir Crit Care Med 2009; 179:19-24

18. Tailoring treatment for asthma
Chung et al, Lancet Respir 2013

19. Ortega HG et al. N Engl J Med 2014:371:1189-97
Asthma Exacerbations and FEV1 at 32 Weeks.
Figure 2. Asthma Exacerbations and FEV1 at 32 Weeks. Panel A shows the numbers of asthma exacerbations in patients receiving either intravenous or subcutaneous mepolizumab or placebo. The rate of exacerbations was reduced by 47% (95% confidence interval [CI], 29 to 61) among patients receiving intravenous mepolizumab and by 53% (95% CI, 37 to 65) among those receiving subcutaneous mepolizumab, as compared with those receiving placebo (P<0.001 for both comparisons). Panel B shows the mean forced expiratory volume in 1 second (FEV1) as a percentage of the predicted value. At week 32, there was greater improvement from baseline in the two mepolizumab groups than in the placebo group — a 100-ml greater increase in the intravenous-mepolizumab group than in the placebo group (P=0.02) and a 98-ml greater increase in the subcutaneous-mepolizumab group than in the placebo group (P=0.03). The I bars indicate 95% confidence intervals.
Ortega HG et al. N Engl J Med 2014:371:

20. Study Design
Wenzel S, et al. N Engl J Med 2013; 368:

21. Anti-IL4Rα in Asthma
Wenzel S, et al. N Engl J Med 2013; 368:

22. Thymic Stromal Lymphopoietin (TSLP)
Activated Dendritic Cell
OX40
OX40L
TSLP
Naïve T cell
Th2 Cell
Memory T Cell
IL-5
IL-9
IL-4/IL-13/IL-9
B Cell
Eosinophil
Goblet Cell
POLARIZE
ACTIVATE
Epithelium
Smooth Muscle

23. 12-Week Treatment Period
Screening Period
Placebo
Dose
AMG 157 IV 700 mg
Allergen Challenge
Day:
SI*
AHR SI
12-Week Treatment Period PB
Follow Up
FENO
Gauvreau GM, et al. N Engl J Med 2014: 370:

24. Percent Change in FEV1 (%) Time Post-Allergen Challenge (Hours)
Day -14
Day 42
Day 84 * * * *
Percent Change in FEV1 (%)
AMG 157
Placebo
Mean ±SEM percent FEV1-time curve at screening, day 42 and day 84. AMG 157 treatment significantly attenuated the early and late allergen-induced fall in FEV1 at days 42 and 84. *P<0.05 AMG 157 compared to placebo
Time Post-Allergen Challenge (Hours)
Gauvreau GM, et al. N Engl J Med 2014: 370:

25. * * * * * * * * * * * * * * * * * * * * * A B C AMG 157 Placebo
Blood Eosinophils (x106/L) B * * *
Sputum Eosinophils (%) * * * C *
Mean±SEM. Red arrows denote dosing, black arrows denote allergen inhalation challenge. *P<0.05 AMG 157 compared to placebo * * * * * * * * * *
Fractional Exhaled Nitric Oxide (ppb)
Study Day

26. CXCR1/2 Receptors and Neutrophil Activity
GRO-a
GRO-b
ENA-78
GCP2
Pharmacol Rev 2004; 56:

27. Median % change from baseline
Sputum neutrophils
10.00
0.00
-10.00
-20.00
Median % change from baseline
-30.00
-40.00
-50.00
Placebo
SCH
-60.00
Week 2
Week 4
Nair P, et al. Clin Exp Allergy 2012: 42:

28. Anti-CXCR2 results CXCR2 antagonist Placebo Baseline End of study
TCC (106/g)
4.6
3.1
5.5
Sputum NEUTR (%)
69.589
44.442
67.200
75.1*
Blood NEUTR (x109/L)
4.928
5.288
5.759
5.565
Sputum EOS (%)
3.321
13.026
10.355
8.91
FEV1 post bd (L)
2.197
2.054
1.851
1.681
FEV1 post bd (% pred)
67.995
63.775
60.421
54.50
PEF (am), L/min
315.45
303.43
316.04
285.82
ACQ
2.159
1.946
2.298
2.524
SABA (Puffs/day)
1.70
1.59
2.10
2.47
Mild exacerbations
1.3
2.25*
Nair P, et al. Clin Exp Allergy 2012: 42:

29. Brusselle G, et al. Thorax 2013; 68:322-9

30. The Goals of Asthma Management
Despite effective asthma treatments, many asthmatics remain uncontrolled
The most common reason for poor asthma control is poor adherence
Poor asthma control is associated with increased risk of asthma exacerbations
Asthma exacerbations can cause a decline in lung function
New asthma treatments should improve current symptom control, and/or reduce future risks of asthma exacerbations
Overall Asthma Control
achieving
reducing
Current control
Future risk
defined by
defined by
Symptoms
Reliever use
Instability/
worsening
Exacerbations
Activity
Lung function
Loss of lung function
Adverse effects of medication
NAEPP. Expert Panel Report
Taylor DR, et al. Eur Respir J 2008; 32:545–554