Dr. Param Nair - New Treatments in Severe Asthma

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