Evaluation and Treatment of Patients with Severe Asthma

Evaluation and Treatment of Patients with Severe Asthma

Evaluation and Treatment of Patients
with Severe Asthma
Paul M. O’Byrne, MD
Associate Professor of Pediatrics
EJ Moran Campbell Professor of Medicine
Firestone Institute for Respiratory Health,
St. Joseph’s Healthcare and McMaster
University, Hamilton, Ontario, Canada
Faculty Disclosure for
Paul M. O’Byrne
For the 12 months preceding this CME activity, I disclose the
following types of financial relationships:
Honoraria received from: AstraZeneca, Boehringer
Ingelheim, Chiesi Ltd., GlaxoSmithKline, Takeda
Pharmaceutical Company
Consulted for: AstraZeneca, Boehringer Ingelheim, Forest,
GlaxoSmithKline, Merck, Verona Pharma
Held common stock in: None
Research, clinical trial, or drug study funds received from:
AIM, Amgen, AstraZeneca, Axcan Pharma Inc., Genentech,
GlaxoSmithKline, Novartis, Ono Pharmaceutical
I will be discussing products that are investigational or not
labeled for the use under discussion.
The Goals of Asthma Management
Overall Asthma Control
achieving
Current control
defined by
reducing
Future risk
defined by
Symptoms
Reliever use
Instability/
worsening
Exacerbations
Activity
Lung function
Loss of
lung function
Adverse effects
of medication
NAEPP. Expert Panel Report 3. 2007
Taylor DR, et al. Eur Respir J 2008; 32:545–554
Severe refractory asthma makes
up 5-10% asthma population
Uncontrolled asthma and high
exacerbation risk despite
maximal conventional therapy
Evaluation of Severe Refractory
Asthma
• Adherence, adherence, adherence
• Co-morbidities
–
–
–
–
–
•
•
•
•
•
Rhino-sinusitis
GERD
Obesity
Bronchiectasis
Vocal cord dysfunction
Smoking
Psychopathology
Persistent allergen/occupational exposure
Incorrect diagnosis
Severe refractory disease
Canadian Consensus Guidelines
Lougheed D, et al. Can Respir J 2012; 19:127-64
Asthma Phenotypes/Endotypes
Wenzel SE. Pul Pharm Ther 2013; 26: 710 - 715
Asthma Phenotypes
Haldar P, et al. Am J Respir Crit Care Med 2008; 178:218-24
Inflammatory Phenotype:
Induced Sputum
O’Byrne PM, Nair P. Lancet 2006; 368:794-308
Current and Experimental Treatments
for Severe Asthma
Approach
Drug/Treatment
Oral corticosteroids
Prednisone, Medrol
Anti-IgE Mab
Omalizumab
Bronchial smooth muscle
Bronchial Thermoplasty
Once daily ICS/LABA
Relvar
Anticholinergics
Tiotropium
Anti-IL5 Mab
Mepolizumab, Reslizumab
Anti-IL5R Mab
Benzralizumab
Anti-IL4Rα MAb
Dupilimab
Anti-IL13 Mab
Lebrikizumab, Tralokinumab
Macrolide antibiotics
Several
C-kit & PDGFR tryosine kinase inhibitor
Masitinib
Anti-IL2Rα Mab
Daclizumab
CXCR2 receptor antagonist
SCH527123
CRTh2
Several
Anti-TNFα
Golimumab
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
Miller J D et al. Chest 2005;127:1999-2006
Pavord I, et al. Am J Respir Crit Care Med 2007; 176:1185-91
Bronchial Thermoplasty in
Difficult-to-Control Asthma
Pavord I, et al. Am J Respir Crit Care Med 2007; 176:1185-91
Current and Experimental Treatments
for Severe Asthma
Approach
Drug/Treatment
Oral corticosteroids
Prednisone, Medrol
Anti-IgE Mab
Omalizumab
Bronchial smooth muscle
Bronchial Thermoplasty
Once daily ICS/LABA
Relvar
Anticholinergics
Tiotropium
Anti-IL5 Mab
Mepolizumab, Reslizumab
Anti-IL5R Mab
Benzralizumab
Anti-IL4Rα MAb
Dupilimab
Anti-IL13 Mab
Lebrikizumab, Tralokinumab
Macrolide antibiotics
Several
C-kit & PDGFR tryosine kinase inhibitor
Masitinib
Anti-IL2Rα Mab
Daclizumab
CXCR2 receptor antagonist
SCH527123
CRTh2
Several
Anti-TNFα
Golimumab
Kerstjens HAM, et al. J Allergy Clin Immunol 2011; 128:308-14
Kerstjens HAM, et al. New Engl J Med 2012; 367:1198-207
Tiotropium in Poorly Controlled Asthma
Kerstjens HAM, et al. New Engl J Med 2012; 367:1198-207
Once Daily ICS/LABAs
O’Byrne PM et al. Eur Respir J 2013: in press
Woodruff PG, et al. Am J Respir Crit Care Med 2009; 180:388-95
Nair P, et al. N Engl J Med 2009; 360:985-93
Prednisone Reduction
n=9
n=10
100
80
prednisone reduction as %
of maximum possible
reduction
60
40
20
0
mepolizumab
placebo
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.
Haldar P et al. N Engl J Med 2009; 360:973-984
DREAM Study
n= 621
Pavord I, et al. Lancet 2012; 380:651-9
Anti-IL5Rα
Ghazi A, et al. Expert Opin Biol Ther 2012; 12:113-8
Laviolette M, et al. J Allergy Clin Immunol 2013; 132:1086-96.
IL-4 and IL-13
Ingram JL, Kraft M. J Allergy Clin Immunol 2012130:829-42
Anti-IL-13 Treatment in Adults with Asthma
Corren J et al. N Engl J Med 2011;365:1088-1098.
Severe Exacerbations
P=0.08
Rate
Corren J et al. N Engl J Med 2011;365:1088-1098.
P=0.375
P=0.072
Study Design
Wenzel S, et al. N Engl J Med 2013; 368:2455-66.
Anti-IL4Rα in Asthma
Wenzel S, et al. N Engl J Med 2013; 368:2455-66.
Anti-IL4Rα in Asthma
Wenzel S, et al. N Engl J Med 2013; 368:2455-66.
Conclusion: Despite statistically
significant associations, FENO
levels, IgE levels, blood eosinophil
and neutrophil counts, FEV1
percent predicted, and age are poor
surrogates, both separately
and combined, for accurately
predicting sputum eosinophil and
neutrophil percentages.
(J Allergy Clin Immunol 2013;132:72-80.)
FEV1
PEF
Reiter J, et al. Allergy 2013; 68:1040-9
Symptom scores
AQL
Reiter J, et al. Allergy 2013; 68:1040-9
Brusselle G, et al. Thorax 2013; 68:322-9
Conclusions
• Patients with severe refractory asthma are uncontrolled
despite optimal therapy with ICS/LABA .
• Tiotropium improves lung function in refractory asthma and
slightly reduce asthma exacerbation risk.
• Treatment with anti –IL-5 hMab reduces asthma
exacerbations in patients with airway eosinophilia, but the
effect on lung function has been variable.
• Treatment with anti-IL-13 or IL-4Rα improved lung function
and may reduce asthma exacerbations.
• Treatment with macrolides may reduce asthma exacerbations
in non-eosinophilic asthma.