New & Emerging Treatments of Severe Asthma
Dr. Parameswaran Nair Professor of Medicine, Division of Respirology – McMaster University
Management of Severe Asthma Recognizing the components of airway disease
Parameswaran Nair, MD, PhD, FRCP, FRCPC Frederick E. Hargreave Teva Innovation Chair Professor of Medicine, McMaster University Adjunct Professor of Medicine, McGill University Staff Respirologist, St Joseph’s Healthcare Hamilton, Ontario
Objectives • Define severe asthma • Recognize components that contribute to severity • Illustrate a “translational approach to management” • Segmentation of novel therapeutics
Disclosure I have grants from AZ, Teva, Sanofi & Novartis for investigatorinitiated studies. I am listed on a patent for a “sputum filtration device�
In the past 3 years, I have provided consultancy to Roche, Sanofi, Teva, Daiichi-Sankyo, Mitsubishi, Cellometrics
Definition of Severe Asthma Asthma which requires treatment with guidelines suggested medications for GINA steps 4–5 for the previous year or systemic CS for ≥50% of the previous year to prevent it from becoming ‘‘uncontrolled’’ or which remains ‘‘uncontrolled‘‘ despite this therapy Uncontrolled asthma defined as at least one of the following: 1) Poor symptom control: ACQ consistently > 1.5, ACT <20 2) Frequent severe exacerbations: two or more bursts of systemic CS (>3 days each) in the previous year 3) Serious exacerbations: at least one hospitalisation, ICU stay or mechanical ventilation in the previous year 4) Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% Controlled asthma that worsens on tapering of these high doses of ICS or systemic CS (or additional biologics) CHUNG KF et al, Eur Respir J 2014; 43: 343-73.
First principles
Consider alternate diagnosis Poor compliance Poor inhaler technique Vocal cord dysfunction Hyperventilation On-going allergen exposure Alternate causes for COPD, eg BO, AAT Poor steroid absorption
Vocal cord dysfunction
Components of asthma Why are your airways obstructed? Spirometry
Methacholine
FEV1
PC20
Sputum bronchitis
rigid scarring (COPD) muscle contraction
inflammation
eosinophils
neutrophils
often allergic
often infection
treat with steroids
may need antibiotics
puffers prednisone
Reduce steroids
Heterogeneity of bronchitis Stable (n=664)
Exacerbation (n=115)
Inflammatory subtypes of bronchitis (%)
Inflammatory subtypes of bronchitis (%)
Dâ&#x20AC;&#x2122;SILVA L, et al. Can Respir J 2011; 18: 144-8.
Hamilton experience
16,000 sputum examination in clinical practice 28 clinical trials Central laboratory for 12 clinical trials Training for over 30 laboratories
Jerry Dolovich, MD 1936-1997
Freddy Hargreave, MD 1938-2011
Hamilton Strategy (>25 years)
NAIR P, et al Clin Chest Med 2012; 33: 445-57.
Relative risk reduction of exacerbations FACET
50%
NEJM 1997
GOAL
10-15%
AJRCCM 2004
TALC
~5%
NEJM 2010
OMALIZUMAB
25%
ANN INTERN MED 2011
MONTELUKAST
~3%
BMJ 2003
THERMOPLASTY
32%
AJRCCM 2008
SPUTUM STRATEGY
49%
ERJ 2006
NAIR P. Eosinophils in Health & Disease, Eds Lee & Rosenberg 2012
What makes asthma ‘severe’? Severe AHR (no cellular bronchitis)
Remodelling (loss of FEV1)
Persistent Blood eos >300 Sputum eos >3%
Neutrophilic (infection)
Persistent Sputum TCC >10 Neutrophils >65%
Eosinophilic (“T2”) (~75%Th2)
n=132 ALEMAN F, et al. Immunol Allergy Clinics North America 2016 (in press)
Case history -1 60 years, female, non-atopic Asthma diagnosed at age of 21 years Prednisone-dependent in 2008 Recurrent sinus infections, nasal polyposis Blood (0.6) and sputum eosinophils (20%, granules) HES workup negative No pulmonary infiltrates ANCA negative, idiopathic phrenic nerve palsy, unilateral diaphragm weakness 3/6 ARA criteria for EGPA Prednisone 25 mg, Fluticasone 2000 mcg, salmeterol 100 mcg, montelukast,
Possible targets for monoclonals
ROBINSON DS. J Allergy Clin Immunol 2010; 126: 1081-91.
Exacerbation rates in recent anti-IL5 clinical trials baseline Mepolizumab (100 mg)
placebo
mAb
3.6
1.75
0.90
2.2
0.57
0.34
1.9
1.8
0.84
(Ortega et al NEJM 2014)
Benralizumab (100 mg) (Castro et al Lancet Respir Med 2014)
Reslizumab (3mg/kg) (Castro et al Lancet Respir Med 2015)
Sputum strategy INTERVENTION
1.2
0.65
(Jayaram et al ERJ 2006)
NAIR P. N Engl J Med 2014; 371: 1249-51.
Treatment of eosinophilic bronchitis n=9
n=11
120 100 80
% subjects who exacerbated
60 40 20
p<
0
120
n=9
n=11
mepolizumab 1/9 exacerbated (0 eos exacerbations, 1 neutr exacerbation)
100
placebo 10/11 exacerbated (9 eos exacerbations, 3 neutr exacerbations)
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.
Treatment of eosinophilic bronchitis
BEL E et al. N Engl J Med 2014; 371: 1189-97.
Blood vs Sputum eos in severe asthma
MUKHERJEE M, NAIR P. Lancet Respir Med 2015 (epub)
Uncontrolled defined as >3% sputum eosinophils.
Discordance between blood and sputum eosinophils
p=0.0689 p<0.05
Sputum IL13+ IL5+ ILC2 (x103 cells/mL)
0.5 0.4 0.3 0.2 0.1 0.0
Uncontrolled
Controlled
Uncontrolled
SMITH S et al. J Allergy Clin Immunol 2015 (epub)
Consequence of not suppressing sputum eosinophils or progenitor cells
SEHMI R, et al. Clin Exp Allergy 2015 (epub)
A potential consequence of inadequate mAb therapy
MUKHERJEE M, et al. Chest 2016 (under review)
A potential consequence of inadequate mAb therapy
Targeting IL4/IL-13 TRALOKINUMAB
BRIGHTLING CE, et al Lancet Respir Med 2015 (epub)
LEBRIKIZUMAB
CORREN J, et al N Engl J Med 2011; 365: 1088-98
Effect on blood eosinophil by targeting IL4/IL-13 DUPILUMAB
WENZEL S, et al N Engl J Med 2013; 168: 2455-66
LEBRIKIZUMAB
CORREN J, et al N Engl J Med 2011; 365: 1088-98
Case history -2 • 38 male, asthma since infancy, wheezy bronchitis • No history to suggest congenital lung diseases • Non-atopic, Never smoked • At least 25 ER/unscheduled specialist visits • Investigations negative for vasculitis, HES, normal AAT, immune deficiencies • FEV1/VC 1.9/2.5 (pred. 2.7/3.4, ratio 77%) • Prednisone 50 mg courses monthly, Symbicort 12 puffs Singulair, Uniphyl • FEV1/VC 2.4L (55%)/5.3 (97%), ratio 46% • No bronchodilator reversibility • Flow-volume curve suggest mild tracheobronchomalacia
Case history -4 Date
TCC
N
Eos
10/2/09
129
97
0.3
27/3/09
32
90
0
15/1/10
35
92
0
1/9/10
1.4
35.5
0
• Culture negative for bacteria, virus, mycobacteria • PCR negative for Chlamydia • Negative for CF mutations, normal sweat chloride • Normal neutrophil function (chemotaxis, oxidative burst) • Normal ciliary motility
Molecular diagnostics
Cox C, et al. Can Respir J 2015
Anti-CXCR2 results Variables
CXCR2 antagonist Baseline
TCC (106/g)
4.6
End of study 3.1
Placebo Baseline
End of study
4.6
5.5 75.1
Sputum NEUTR (%)
69.589
44.442
67.200
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
NAIR P, et al. Clin Exp Allergy 2012
Case history -3 • 45 female, 8-10 puffs of salbutamol daily • Non-Atopic, never smoked • Alport’s disease, Renal transplant • Leiomyomas of esophagus (esophagectomy), vulva (hysterectomy) • FEV1/VC 1.5/3.5 (pred. 2.9/3.5, ratio 44%), 16% reversibility, PC20 not checked • RV 170%, TLC 140%, KCO 81%, resistance 11 Raw • Sputum TCC 6.3, N 35.3%, E 0.6%, M 61.3%, L 2.8% • Fluticasone +salmeterol 500 bid, montelukast 10 mg, prednisone 5 mg, Cellcept 250 bid theophylline 200 mg
Case history -3 â&#x20AC;&#x153; the airway appeared to some extent normal, but several areas of narrowing with stranding of smooth muscle appeared to be contracted and tethering the mucosa within the airway. The airways were extremely reactive to touch with the tip of the bronchoscope and this seemed excessiveâ&#x20AC;?
Treatment of hyper-responsiveness
Cox, NEJM 2007
Summary Sputum at Initial presentation
EOSINOPHILS
• Establish minimum steroid dose • Investigate cause of eosinophilia • Sinus surgery • Novel therapies
NEUTROPHILS
• Reduce steroids • Investigate cause of neutrophilia • Molecular diagnostics for infections • Macrolides • Nebulised saline
NORMAL
• Reduce steroids • Other causes of AO eg, AAT, BO, VCD • Anti-cholinergic • Novel therapies eg thermoplasty
Hargreave & Nair, Chest 2011
What makes asthma “severe”? Segmentation of Asthma Therapeutics Severe AHR (no cellular bronchitis)
Symptomatic, Frequent SABA Thermoplasty
Remodelling ? (accelerated loss of FEV1)
Frequent exacerbations, Atopic Anti-IgE, Anti-IL5 Frequent exacerbations, eosinophilic, prednisone Anti-IL5
Neutrophilic (infection)
Atopic, Hyperresponsive bronchorrohea Anti-IL-4/IL-13, Anti-IgE
Neutrophilic, no infection Anti-CXCR2, Anti-IL17/23
Eosinophilic (“Th2”)
CRS, nasal polyposis, Aspirin sensitive Anti-IL5, Anti-CRTh2
n=132 NAIR P, et al. Clin Chest Med 2012; 33: 445-57.
The future: point of care tests • Metabolomics • Urine • Exhaled breath • Gene-expression profiles • Blood • Sputum • Cellular activity eg eosinophil/neutrophil peroxidase • Bioactive paper • Throat or nasal swabs
A point of care test Throat swab for eosinophil peroxidase
RANK M et al. Allergy 2015 (epub).
Our current efforts Hematological mechanisms TCR
Auto antibodies ?
PI3K
Steroid hyporesponsiveness
RTK
Persistent airway eosinophilia ↑steroids
↓HDAC
IL-17 IL-23
Macrophage dysfunction
↑miRNA ↑neutrophils
In-situ process, IL-5/ IL-13 dependent ? T-cell Non-T-cell TLR
↑infections