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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

GINA Guidelines 2011 Phenotyping Empiric Treatment

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 (420-1008) 568 (336-840) 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)

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

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

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

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;127:1999-2006

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

Bronchial Thermoplasty CONTROLS Age 39.4 41.7 BDP dose (mean [(μg/day) 1351+963 1264+916 Seasonal Allergies 62% 65% FEV1 % predicted 72.6+10.4 76.1+9.6 Asthma Severity Moderate Persistent 38% 47% Severe Persistent 53%

Bronchial Thermoplasty Cox PG, et al. New Engl J Med 2007; 356:1327-37.

Bronchial Thermoplasty Cox PG, et al. New Engl J Med 2007; 356:1327-37.

Bronchial Thermoplasty in Difficult-to-Control Asthma Pavord I, et al. Am J Respir Crit Care Med 2007; 176:1185-91

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

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

GINA Guidelines 2011 Phenotyping Empiric Treatment

Induced Sputum O’Byrne PM, Nair P. Lancet 2006; 368:794-308

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: 1715-21

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

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. FEV1 49-61% 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

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 240563 250 mg or 750 mg or placebo Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71

Mepolizumab in asthma Asthma Exacerbations (% patients) p=0.06 Flood-Page P, et al. Am J Respir Crit Care Med 2007; 176:1062-71

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

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

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; 360:985-93 .

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.

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 78.1+20.9 77.6+24.1 Sputum eosinophils 6.84% 5.46% ACQ score 1.98+1.07 2.38+1.35

Mepolizumab in Difficult-to-Control Asthma Haldar P et al. N Engl J Med 2009; 360:973-984

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

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.

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.

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.

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.

Allergen-Induced Sputum Eosinophilia

Allergen-induced Fall in FEV1

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.