Addressing Unmet Medical Needs in Severe Asthma Where

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Addressing Unmet Medical Needs in Severe Asthma: Where Do We Stand? An Expert Consensus

Addressing Unmet Medical Needs in Severe Asthma: Where Do We Stand? An Expert Consensus Presented by: Michael Blaiss, MD, FACAAI Mario Castro, MD, MPH Provided by the American College of Allergy, Asthma & Immunology in collaboration with Integrity Continuing Education, Inc. This webcast is supported by an educational grant from Boston Scientific. 1

Faculty Introductions Michael Blaiss, MD, FACAAI Executive Medical Director American College of Allergy, Asthma

Faculty Introductions Michael Blaiss, MD, FACAAI Executive Medical Director American College of Allergy, Asthma & Immunology Clinical Professor of Pediatrics Medical College of Georgia Roswell, Georgia Mario Castro, MD, MPH Alan A. and Edith L. Wolff Professor Pulmonary and Critical Care Medicine Professor of Medicine, Pediatrics, and Radiology Washington University School of Medicine St. Louis, Missouri 2

Faculty Disclosures Faculty Company Role Received Michael Blaiss, MD, FACAAI 1. ALK 2. Pfizer

Faculty Disclosures Faculty Company Role Received Michael Blaiss, MD, FACAAI 1. ALK 2. Pfizer 3. PMD Healthcare 4. Rx. Bands 5. Stallergenes 1. Consultant 2. Consultant 3. Consultant 4. Consultant 5. Consultant 1. Consulting fee 2. Consulting fee 3. Consulting fee 4. Consulting fee 5. Consulting fee Mario Castro, MD, MPH 1. Boston Scientific 2. Genentech 3. Holaira 4. Teva 5. Glaxo. Smith. Kline 6. Boehringer-Ingelheim 7. Elsevier 8. Neostem 1. Consultant, speaker 2. Consultant, speaker, advisory committee member 3. Consultant 4. Consultant, speaker 5. Speaker, DSMB committee 6. Speaker 7. Independent Contractor 8. Consultant 1. 2. 3. 4. 5. 6. 7. 8. Consulting fee, honorarium Honorarium Royalties Consulting fee 3

Disclaimer This CME program describes the outcomes from 2 virtual roundtable meetings of asthma

Disclaimer This CME program describes the outcomes from 2 virtual roundtable meetings of asthma and allergy experts on the management of patients with severe asthma. Roundtable Attendees • Michael Blaiss, MD, FACAAI (Chair) Roswell, Georgia • Mario Castro, MD, MPH St. Louis, Missouri • Bradley E. Chipps, MD Sacramento, California • Michael B. Foggs, MD Chicago, Illinois • Reynold A. Panettieri Jr, MD New Brunswick, New Jersey • Myron Zitt, MD Plainview, New Yok 4

Roundtable Attendee Disclosures Faculty Company Role Received Bradley E. Chipps, MD 1. Astra. Zeneca

Roundtable Attendee Disclosures Faculty Company Role Received Bradley E. Chipps, MD 1. Astra. Zeneca 2. Boehringer Ingelheim 3. Genentech 4. Meda 5. Merck 6. Novartis 1. Consultant 2. Speaker’s bureau 3. Advisory committee member 1. Consulting fee 2. Honorarium Michael B. Foggs, MD 1. Astra. Zeneca 2. Boehringer Ingelheim 3. Boston Scientific 4. Meda 5. Merck 6. Mylan 1. Consultant 2. Consultant, Speaking/teaching 3. Consultant 4. Consultant, Speaking/teaching 5. Consultant 6. Consultant 1. Consulting fee 2. Consulting fee, honorarium 3. Consulting fee 4. Consulting fee, honorarium 5. Consulting fee 6. Consulting fee Reynold A. Panettieri, MD 1. Astra. Zeneca 2. Novartis 3. Teva 1. Consultant, Speaker/teaching Advisory committee member 2. Speaking/teaching 3. Consultant, Speaker/teaching 1. Consultant fee, honorarium 2. Honorarium 3. Consulting fee, honorarium Myron Zitt, MD 1. Boston Scientific 2. Boehringer Ingelheim 3. Meda 1. Consultant, Speaker/teaching 2. Advisory committee member 3. Speaking/teaching 1. Consulting fee 2. Consulting fee 3. Honorarium 5

Program Learning Objectives • • Discuss current unmet medical needs in patients with severe

Program Learning Objectives • • Discuss current unmet medical needs in patients with severe asthma • Outline updated therapeutic decision-making guidance for patients with severe asthma that is based on biomarkers and other patient disease characteristics Describe asthma phenotypes and endotypes and evaluate the viability of routine biomarker testing for asthma subtypes in practice 6

Unmet Medical Needs in Severe Asthma 7

Unmet Medical Needs in Severe Asthma 7

Current Unmet Medical Needs • Absence of universal standard definition for severe asthma •

Current Unmet Medical Needs • Absence of universal standard definition for severe asthma • Identifying a patient’s asthma phenotype/endotype • Having guidances that accommodate newer treatments • Improving therapeutic drug monitoring • Improving access to care and newer treatments • Reducing exacerbations and emergency department visits/hospitalizations • Improving patient-reported outcomes and quality of life • Decreasing healthcare resource utilization 8

Current Unmet Medical Needs • Absence of universal standard definition for severe asthma •

Current Unmet Medical Needs • Absence of universal standard definition for severe asthma • Identifying a patient’s asthma phenotype/endotype • Having guidances that accommodate newer treatments • Improving therapeutic drug monitoring • Improving access to care and newer treatments • Reducing exacerbations and emergency department visits/hospitalizations • Improving patient-reported outcomes and quality of life • Decreasing healthcare resource utilization 9

Defining Severe Asthma 10

Defining Severe Asthma 10

Definitions of Severe/Uncontrolled Asthma NAEPP EPR-3 ATS/ERS GINA (2007) (2014) (2017) ATS, American Thoracic

Definitions of Severe/Uncontrolled Asthma NAEPP EPR-3 ATS/ERS GINA (2007) (2014) (2017) ATS, American Thoracic Society; EPR-3, Expert Panel Report 3; ERS, European Respiratory Society; GINA, Global Initiative on Asthma; NAEPP, National Asthma Education and Prevention Program. 11

NAEPP EPR-3 (2007) • ‘‘Severe asthma” (FEV 1<60% predicted, FEV 1/FVC reduced >5%) •

NAEPP EPR-3 (2007) • ‘‘Severe asthma” (FEV 1<60% predicted, FEV 1/FVC reduced >5%) • “Severe persistent asthma” (Requiring Steps 5 or 6 treatment) • Persistent symptoms throughout the day • Nighttime awakenings many times per week • Short-Acting Beta-Agonist (SABA) use several times per day • Significant impairment of normal activities FEV 1, forced expiratory volume in 1 second; FVC, forced vital capacity. 12

ATS/ERS (2014) • “Asthma (patients ≥ 6 years) which requires treatment with guidelines suggested

ATS/ERS (2014) • “Asthma (patients ≥ 6 years) which requires treatment with guidelines suggested medications for GINA steps 4 -5 asthma (high dose inhaled corticosteroid [ICS] and long -acting beta-agonist [LABA] or leukotriene receptor antagonists [LTRA]/theophylline) for the previous year or systemic corticosteroids (CS) for ≥ 50% of the previous year to prevent it from becoming ‘uncontrolled’ or which remains ‘uncontrolled’ despite this therapy. ” 13

ATS/ERS (2014), cont’d • Uncontrolled asthma defined as ≥ 1 of the following: –

ATS/ERS (2014), cont’d • Uncontrolled asthma defined as ≥ 1 of the following: – Poor symptom control: Asthma Control Questionnaire (ACQ) consistently >1. 5, ACT <20 (or ‘‘not well controlled’’ by NAEPP/GINA guidelines – Frequent severe exacerbations: ≥ 2 bursts of systemic CS (>3 days each) in the previous year – Serious exacerbations: ≥ 1 hospitalization, ICU stay, or mechanical ventilation in the previous year – Airflow limitation: after appropriate bronchodilator withhold, FEV 1 <80% predicted (in the face of reduced FEV 1/FVC, defined as less than the lower limit of normal) – Controlled asthma that worsens on tapering of these high doses of ICS or systemic CS (or additional biologics) ACT, Asthma Control Test; ICU, intensive care unit. 14

GINA (2017) • ‘‘Severe asthma is asthma that requires Step 4 or 5 treatment,

GINA (2017) • ‘‘Severe asthma is asthma that requires Step 4 or 5 treatment, e. g. high-dose ICS/LABA, to prevent it from becoming ‘uncontrolled’, or asthma that remains ‘uncontrolled’ despite this treatment. ’’ 15

Consensus Definition for Severe Asthma that requires high doses of inhaled corticosteroids plus a

Consensus Definition for Severe Asthma that requires high doses of inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from being uncontrolled, or that remains uncontrolled despite optimal adherence to this therapy. 16

Asthma Phenotypes, Endotypes, and Biomarkers 17

Asthma Phenotypes, Endotypes, and Biomarkers 17

Phenotype vs Endotype Phenotype Endotype The set of observable characteristics of an individual resulting

Phenotype vs Endotype Phenotype Endotype The set of observable characteristics of an individual resulting from the interaction of its genotype with the environment A specific biologic mechanism that explains observable properties of an organism Different asthma phenotypes and endotypes may respond differently to targeted therapies. 18

ATS/ERS Severe Asthma Phenotypes Characteristic Associations Severe allergic asthma Blood and sputum eosinophils High

ATS/ERS Severe Asthma Phenotypes Characteristic Associations Severe allergic asthma Blood and sputum eosinophils High serum immunoglobulin E (Ig. E) High fractional exhaled nitric oxide (Fe. NO) Eosinophilic asthma Blood and sputum eosinophils Recurrent exacerbations High Fe. NO Neutrophilic asthma Corticosteroid insensitivity Bacterial infections Chronic airflow obstruction Airway wall remodeling as increased airway wall thickness Recurrent exacerbations Sputum eosinophils Reduced response to ICS and/or oral corticosteroids (OCS) Corticosteroid insensitivity Increased neutrophils in sputum Chung KF, et al. Eur Respir J. 2014; 43(2): 343 -373. 19

PRACTALL (PRACtical ALLergy) Consensus on Asthma Endotypes Phenotype Endotypes Eosinophilic asthma Allergic asthma (adult),

PRACTALL (PRACtical ALLergy) Consensus on Asthma Endotypes Phenotype Endotypes Eosinophilic asthma Allergic asthma (adult), aspirin-sensitive asthma, severe late-onset hypereosinophilic asthma, allergic bronchopulmonary mycosis Exacerbation-prone asthma Allergic asthma (adult), aspirin-sensitive asthma, late-onset hypereosinophilic asthma, asthma predictive index (API)-positive preschool wheezer, allergic bronchopulmonary mycosis, viral-exacerbated asthma, premenstrual asthma Exercise-induced asthma Cross-country skiers’ asthma, other forms of elite-athlete asthma, allergic asthma, API-positive preschool wheezer Adult-onset asthma Fixed airflow limitation, infection-induced asthma, severe late-onset hypereosinophilic asthma Fixed airflow limitation Noneosinophilic (neutrophilic) asthma Poorly steroid-responsive asthma Noneosinophilic (neutrophilic) asthma, steroid-insensitive eosinophilic asthma, airflow obstruction caused by obesity Lӧtvall J, et al. J Allergy Clin Immunol. 2011; 127: 355 -360. 20

Inflammatory Phenotypes • • Eosinophilic (A) Neutrophilic (B) Mixed (C) Paucigranulocytic (D) Vijverberg SJ,

Inflammatory Phenotypes • • Eosinophilic (A) Neutrophilic (B) Mixed (C) Paucigranulocytic (D) Vijverberg SJ, et al. Biologics. 2013; 7: 199– 210. 21

Eosinophilic Phenotype in Severe Asthma EG 2+Cells/mm 2 150 P<. 05 100 P<. 05

Eosinophilic Phenotype in Severe Asthma EG 2+Cells/mm 2 150 P<. 05 100 P<. 05 50 0 Normal Mild Moderate Eos (−) Eos (+) Severe Overall P=. 001 Eos, eosinophil. Wenzel SE, et al. Am J Respir Crit Care Med. 1999; 160(3): 1001 -1008. 22

Predictive Value of Blood Eosinophils for Exacerbations ≤ 400 cells/µL (n=109, 319) >400 cells/µL

Predictive Value of Blood Eosinophils for Exacerbations ≤ 400 cells/µL (n=109, 319) >400 cells/µL (n=20, 929) 0 90, 290 (82. 6) 16, 338 (78. 1) 1 12, 437 (11. 4) 2, 762 (13. 2) 2 -3 4, 669 (4. 3) 1, 305 (6. 2) ≥ 4 1, 923 (1. 8) 524 (2. 5) 0 81, 114 (74. 2) 14, 771 (70. 6) 1 18, 306 (16. 7) 3, 734 (8. 5) 2 -3 7, 456 (6. 8) 1, 787 (3. 0) ≥ 4 2, 443 (2. 2) 637 (3. 0) Risk-domain asthma control 78, 976 (72. 2) 14, 369 (68. 7) Overall asthma control 46, 953 (43. 0) 7, 785 (37. 2) Severe exacerbation Acute respiratory event Patients with asthma and blood eosinophil counts greater than >400 cells/μL experience more severe exacerbations and have poorer asthma control. Price DB, et al. Lancet Respir Med. 2015; 3(11): 849 -858. 23

Blood Eosinophil Counts >400 cells/μL Are Associated with Greater Risk for Severe Exacerbations and

Blood Eosinophil Counts >400 cells/μL Are Associated with Greater Risk for Severe Exacerbations and Poor Asthma Control Adjusted RR and OR (95% CI) with blood eosinophils >400 cells per µL Severe exacerbations Acute respiratory events Risk-domain asthma control Overall asthma control RR 1. 42 (1. 36− 1. 47)* RR 1. 28 (1. 24− 1. 33)* OR 0. 78 (0. 75− 0. 80)* OR 0. 74 (0. 72− 0. 77)* 0. 7 0. 8 0. 9 Lower with blood eosinophilia 1 1. 2 1. 5 Higher with blood eosinophilia *Adjusted for age, sex, body-mass index (BMI), smoking status, and Charlson comorbidity index score. P<· 0001 for all comparisons. CI, confidence interval; OR, odds ratio; RR, rate ratio. Price DB, et al. Lancet Respir Med. 2015; 3(11): 849 -858. 24

Steroid Response in Eosinophilic and Noneosinophilic Asthma Eosinophilic Asthma Noneosinophilic Asthma + ve −

Steroid Response in Eosinophilic and Noneosinophilic Asthma Eosinophilic Asthma Noneosinophilic Asthma + ve − ve + ve −ve P Value (EA vs NEA) ACQ 48/60 (80%) 12/60 (20%) 13/28 (46%) 15/28 (54%) . 001 FEV 1 48/60 (80%) 12/60 (20%) 4/28 (14%) 24/28 (86%) <. 001 PC 20 AMP 36/49 (73%) 13/49 (27%) 12/28 (43%) 16/28 (57%) . 008 FENO 44/59 (75%) 15/59 (25%) 9/28 (32%) 19/28 (68%) <. 001 AMP, adenosine monophosphate; EA, eosinophilic asthma; NEA, noneosinophilic asthma; PC 20, provocation concentration that caused a decrease in FEV 1 of 20%. Cowan DC, et al. Thorax. 2010; 65(5): 384 -390. 25

Neutrophil-predominant Asthma Associated with High Doses of ICS and OCS Use • Cluster C

Neutrophil-predominant Asthma Associated with High Doses of ICS and OCS Use • Cluster C patients were being treated with high doses of ICSs, and 16% were being treated with concurrent OCSs (P=. 02 compared with cluster B)1 • Chronic systemic CS users are more likely to have a blood neutrophil count of more than >7, 000 cells/µL (P<. 001) and a lower % blood eosinophil count (P=. 012)2 1. Moore W, et al. J Allergy Clin Immunol. 2014; 133: 1557 -1563. 2. Wysocki K, et al. J Allergy Clin Immunol. 2014; 133(3): 915 -918. Paucigranulocytic Eosinophil Predominant Neutrophil Predominant Mixed Granulocytic 150 No. of Subjects • Cluster C patients were older and had the highest BMI (half with BMI >30 kg/m 2), and 38% were classified as having severe asthma 1 125 100 75 50 25 0 Cluster A Cluster B Cluster C Cluster D 26

Evaluation of Available and Future Treatments for Severe Asthma 27

Evaluation of Available and Future Treatments for Severe Asthma 27

Airway lumen Allergens Viruses Airway epithelium IL 4 Rα Dupilumab IL 4 Rα 3

Airway lumen Allergens Viruses Airway epithelium IL 4 Rα Dupilumab IL 4 Rα 3 Dupilumab PGD 2 Mast cell -13 , IL IL-4 Mepolizumab; Reslizumab Omalizumab ILC 2 CRTH 2 B cell 5 IL- FcɛRI Ig. E IL-5 Eosinophil IL -4 , IL -1 3 IL-13 Therapeutic Targets in Severe Asthma IL-5 Rα Mepolizumab; Reslizumab 1 IL- Benralizumab Allergen/ Antigen PGD 2 Muscarinic Th 2 R Smooth muscle R Muscarinic APC, antigen-presenting cell; CRTH 2, chemoattractant receptor–homologous molecule expressed on Th 2 lymphocytes; IL, interleukin; ILC 2, group 2 innate lymphoid cells; PGD 2, prostaglandin D 2; R, receptor agonist; Th, T helper. Fajt ML, et al. Allergy Asthma Immunol Res. 2017; 9(1): 3 -14. Bronchial Thermoplasty Tiotropium 28

Overview of Available and Future Therapies • Available – Tiotropium – Anti-Ig. E: omalizumab

Overview of Available and Future Therapies • Available – Tiotropium – Anti-Ig. E: omalizumab – Anti-IL-5: mepolizumab (SC) and reslizumab (IV) – Bronchial thermoplasty • Future – Anti-IL-5 Rα: benralizumab (SC) – Anti-IL-4 Rα: dupilumab (SC) IV, intravenous; SC, subcutaneous. 29

Evidence Review: Mepolizumab Sig ↓ in Exacerb. Steroid Use AQLQ/ SGRQ Study Pts Characteristics

Evidence Review: Mepolizumab Sig ↓ in Exacerb. Steroid Use AQLQ/ SGRQ Study Pts Characteristics FEV 1 DREAM 1 621 • High-dose ICS + ≥ 1 other controller, w/ or w/o OCS • Blood eosinophil (eos) ≥ 300 • ≥ 2 exacerb in previous year NS +56 -81 m. L ↓ 39%-52% Not reported AQLQ NS MENSA 2 75 mg IV 100 mg SC for 32 weeks 576 • High-dose ICS + ≥ 1 other controller, w/ or w/o OCS • Blood eos ≥ 150 • ≥ 2 exacerb in previous year +98 m. L ↓ 53% Not reported 7 -point improvement In St. George's Respiratory Questionnaire (SGRQ) SIRIUS 3 100 mg SC for 24 weeks (steroidsparing study) 135 • High-dose ICS + ≥ 1 other controller • 6 -month hx of OCS (5 -35 mg/day of prednisone or equivalent) • Blood eos ≥ 300 during the 12 -month period before screening or ≥ 150 during the optimization phase NS trend toward ↑ (114 m. L before bronchodilation and 128 m. L after bronchodilation) 32% • 23% had 90%-100% OCS reduction vs reduction pbo at Wk 24 • 54% with ≥ 50% ↓ in (P=0. 04) daily OCS dose • 56% pbo vs 36% mep had no decrease in OCS dose, a lack of asthma control, or withdrawal from treatment 75, 250, 750 mg IV for 52 weeks AQLQ, Asthma Quality of Life Questionnaire; Exacerb, exacerbations; hx, history; mep, mepolizumab; NS, not significant; pbo, placebo; Pts, patients; Sig, significant; w/, with; w/o, without. 1. Pavord ID, et al. Lancet. 2012; 380: 651 -659. 2. Ortega HG, et al. N Engl J Med. 2014; 371: 1198 -1207. 3. Bel EH, et al. N Engl J Med. 2014; 371(13): 1189 -1197. Clinically meaningful improvements in ACQ-5 at week 2 sustained up to Wk 24 vs pbo (P=0. 004) 30

Evidence Review: Mepolizumab Economic Analysis vs Standard Care Base-Case Clinical and Economic Outcomes from

Evidence Review: Mepolizumab Economic Analysis vs Standard Care Base-Case Clinical and Economic Outcomes from Payer Perspective: Lifetime Treatment Horizon Treatment QALYs Treatment Costs Nontreatment Costs (Exacerbations and Long-term OCS Use) ICER ($/QALY) Mepolizumab + Standard of Care 15. 12 $706, 111 $15, 465 $386, 000 Standard of Care Alone 13. 59 $98, 083 $33, 552 — The estimated cost effectiveness of mepolizumab exceeds value thresholds. To achieve cost effectiveness of approximately $150, 000 per QALY, mepolizumab would require a more than 60% price discount. ICER, incremental cost-effectiveness ratio; QALY, quality adjusted life year. Whittington MD, et al. Ann Allergy Asthma Immunol. 2017; 118(2): 220 -225. 31

Evidence Review: Reslizumab Study Pts Characteristics FEV 1 Corren 1 3. 0 mg/kg IV

Evidence Review: Reslizumab Study Pts Characteristics FEV 1 Corren 1 3. 0 mg/kg IV q 4 w for 16 weeks 496 • Inadequate control on medium-dose ICS and hx of exacerbation in last year • Unselected for eos • Blood eos <400 cells/μL in 80% • Blood eos ≥ 400 cells/μL in 20% NS Not reported Bjermer 2 0. 3 and 3 mg/kg IV q 4 w for 16 weeks 315 • Inadequate control on medium dose ICS and Hx of exacerbation in last year • Blood eos ≥ 400 cells/μL +115 m. L P=. 02 +160 m. L P=. 002 Not reported Clinically meaningful difference reached on AQLQ for 3 mg Castro 3 Duplicate RCTs; 3. 0 mg/kg IV q 4 w for 52 weeks 953 • Inadequate control on medium/high-dose ICS +220 m. L and ≥ 1 exacerbation in last year P<0. 0001 • Blood eos ≥ 400 cells/μL (pooled data at Week 52) q 4 w, every 4 weeks; RCT, randomized controlled trial. 1. Corren J, et al. Chest. 2016; 150(4): 799 -810 2. Bjermer L, et al. Chest. 2016; 150(4): 789 -798. 3. Castro M, et al. Lancet Respir Med. 2015; 3(5): 355 -366. Sig ↓ in Exacerb AQLQ 50%-59% reduction Clinically meaningful difference reached on AQLQ 32

Evidence Review: Benralizumab Study Pts Characteristics SIROCCO 1 30 mg SC q 4 w

Evidence Review: Benralizumab Study Pts Characteristics SIROCCO 1 30 mg SC q 4 w or q 8 w for 48 weeks 621 CALIMA 2 30 mg SC q 4 w or q 8 w for 48 weeks FEV 1 Sig ↓ in Exacerb AQLQ • Treatment with medium- or high- +106 -159 m. L dose ICS + LABA for ≥ 1 year ± OCS P=. 02 increase • Blood eos < and ≥ 300 cells/μL • ≥ 2 exacerb in previous year ↓ 45%-51% ≥ 300 cells/μL Significant for the q 8 w regimen regardless of eos status 1306 • Treatment with medium- or high- +116 -125 m. L dose ICS + LABA for ≥ 1 year ± OCS P<. 01 increase • Blood eos < and ≥ 300 cells/μL • ≥ 2 exacerb in previous year ↓ 28%-36% ≥ 300 cells/μL ↓ 30% <300 cells/μL ↓ 36%-40% <300 cells/μL Significant for the q 8 w regimen in pts with ≥ 300 cells/μL q 8 w, every 8 weeks. 1. Bleecker ER, et al. Lancet. 2016; pii: S 0140 -6736(16)31324 -1. 2. Fitz. Gerald JM, et al. Lancet. 2016; pii: S 0140 -6736(16)31322 -8. 33

Evidence Review: Dupilumab Study Pts Characteristics FEV 1 Wenzel Phase 2 b, Dupilumab SC

Evidence Review: Dupilumab Study Pts Characteristics FEV 1 Wenzel Phase 2 b, Dupilumab SC vs pbo 200 or 300 mg q 2 w or q 4 w for 24 weeks 769 • Medium-to-high-dose ICS (≥ 250 µg or equivalent) + LABA, no OCS • ≥ 1 exacerbation in past year • Blood eos ≥ 300 cells/μL +210 -260 m. L P<. 007 Sig ↓ in Exacerb Overall population ↓ 54%-71% Eos ≥ 300 cells/μL ↓ 66%-81% q 2 w, every 2 weeks. Wenzel S, et al. Lancet. 2016; 388: 31 -44. 34

Safety Review: Newer Biologics Serious AEs Leading to Withdrawal Similar across tx groups—Nasopharyngitis, headache,

Safety Review: Newer Biologics Serious AEs Leading to Withdrawal Similar across tx groups—Nasopharyngitis, headache, asthma, URTI, sinusitis, bronchitis, oropharyngeal pain, injection site reaction Pbo 14% Mep 7%-8% Pbo 2% Mep 1% 1, pbo arm Similar across tx groups—Asthma worsening, URTI, nasopharyngitis, sinusitis, headache, influenza, nausea, bronchitis Pbo 14% Res 8%-10% Pbo 3% Res 2%-4% 1, pbo arm Benralizumab (CALIMA 48 -week study) Similar across tx groups—Nasopharyngitis, asthma, bronchitis, URTI, headache, sinusitis, influenza, allergic rhinitis Pbo 14% Ben 9%-10% Pbo <1% Ben 2% 2, q 4 w arm 2, q 8 w arm Dupilumab (Wenzel et al, 24 -week study) Similar across tx groups—URTI, injection site redness, headache, nasopharyngitis, bronchitis, influenza, sinusitis Pbo 6% Dup 4%-10% Pbo 3% Dup 3%-6% 2, 300 -mg arm Agent Mepolizumab (MENSA 32 -week study) Reslizumab (Castro et al, 2 52 -week studies) Has anaphylaxis warning Most Common AEs (≥ 5% of Patients in Aforementioned Phase 3 Trials) AE, adverse event; Ben, benralizumab; Dup, dupilumab; Res, reslizumab; tx, treatment; URTI, upper respiratory tract infection. Deaths 35

Overview of Newer/Future Biologics Agent Asthma Control FEV 1 QOL Oral CS Use Exacerbations

Overview of Newer/Future Biologics Agent Asthma Control FEV 1 QOL Oral CS Use Exacerbations Mepolizumab* ACQ-5 +/- ↑ ↑ ↓ ↓ Reslizumab* ACQ-7 ↑ ↑ Ongoing ↓ Benralizumab*† ACQ-6 ↑ ↑ Ongoing ↓ Dupilumab*† ACQ-5 ↑ — Ongoing ↓ NS, not statistically significant; , statistically significant; QOL, quality of life. *No strong safety signals for any biologic vs pbo in clinical trials. †In phase 3 clinical development and expected to be available in 2017. 36

Evidence: Bronchial Thermoplasty (BT) • One-time treatment lasting for 5 years 1 – Patients

Evidence: Bronchial Thermoplasty (BT) • One-time treatment lasting for 5 years 1 – Patients (N=580, AIR 2) ICS 1, 000 µg/d beclomethasone or equivalent and LABA >100 µg/d salmeterol or equivalent; other meds including leukotriene modifiers, Om. Ab (if used for ≥ 1 year prior), and ≤ 10 mg/d OCS • 32% decrease in severe exacerbations (requiring systemic CS) vs no treatment 2 – Reduction in exacerbations at 1 year maintained for ≥ 5 years 1 • 84% reduction in ED visits for respiratory symptoms at 1 year vs no treatment 2 – Reduction in ED visits at 1 year maintained for ≥ 5 years 1 AIR 2, Asthma Intervention Research 2 trial; ED, Emergency department; Om. Ab, Omalizumab. 1. Wechsler M, et al. J Allergy Clin Immunol. 2013; 132(6): 1295 -1302. 2. Castro M, et al. Am J Respir Crit Care Med. 2010; 181(2): 116 -124. 37

Evidence: BT Adverse Events • Most common AE is temporary worsening of respiratory-related symptoms

Evidence: BT Adverse Events • Most common AE is temporary worsening of respiratory-related symptoms – Typically occurs within 24 hours post-procedure – Resolves within 7 days on average with standard care • Low risk (3. 4%) of these symptoms requiring hospitalization per procedure – Observed events were typical of airway irritation – Worsening asthma symptoms (ie, wheezing, chest discomfort, cough, and chest pain) – Upper respiratory tract infections 1. Wechsler M, et al. J Allergy Clin Immunol. 2013; 132(6): 1295 -1302. 2. Castro M, et al. Am J Respir Crit Care Med. 2010; 181(2): 116 -124. 38

Evidence: BT Cost Analyses vs Standard Care Costs • BT cost-effective at 5 and

Evidence: BT Cost Analyses vs Standard Care Costs • BT cost-effective at 5 and 10 years 1 – At 10 years, BT ICER was $29, 821/ QALY vs usual care Strategy 5 -year Δ ICER ($/QALY) 0. 175 $5495 0. 158 $62, 922 Base case† – At 5 years, BT remained cost-effective with an ICER of $45, 300/QALY Standard Care $49, 510 – $/QALY below society’s willingness to pay (WTP)/QALY of $50, 000 BT $50, 470 2. 964 $960 3. 138 Scenario analysis‡ • Drivers of cost-effectiveness ratio 2 Standard Care $30, 024 – Reduced exacerbations and costs BT $39, 983 – Improved Quality of Life (QOL)2 QALY 3. 975 $9959 4. 133 †Base case population defined as poorly controlled severe, persistent, asthma; those with >1 ED visit in prior 12 months. ‡Scenario analysis population defined as all patients with severe, persistent asthma. 1. Zein JG, et al. J Asthma. 2016; 53(2): 194 -200. 2. Castro M, et al. Expert Rev Pharmacoecon Outcomes Res. 2015; 15(2): 357 -364. 39

Therapeutic Decision Making Severe Asthma 40

Therapeutic Decision Making Severe Asthma 40

Step 1: Ensure That All Appropriate Assessments Are Done Medical & Treatment History Review

Step 1: Ensure That All Appropriate Assessments Are Done Medical & Treatment History Review • Confirm diagnosis • Confirm medication adherence • Review • Steroid burden and any recent escalation • Exacerbation history • Comorbidities Clinical Assessment • Symptom checks • ACT / ACQ • QOL / AQLQ Laboratory Testing • • • Spirometry Blood eosinophils Serum Ig. E Allergy testing (skin) Fe. NO 41

Step 2: Refer to the Guidelines (2017 GINA Shown) 42

Step 2: Refer to the Guidelines (2017 GINA Shown) 42

Step 3: Decide on the Best Course of Action for Your Patient • After

Step 3: Decide on the Best Course of Action for Your Patient • After all appropriate assessments, including an evaluation of steroid burden and medication adherence, stepup treatment by: – Consider: • Discontinuing ineffective therapies • Adding an alternative therapy • Trying a newer therapy such as a biologic or bronchial thermoplasty 43

Therapeutic Decision Making: Biologics • GINA 2017: For Step 5 treatment, add-on treatment options

Therapeutic Decision Making: Biologics • GINA 2017: For Step 5 treatment, add-on treatment options for patients with severe asthma uncontrolled on Step 4 treatment now also include tiotropium, omalizumab, mepolizumab and reslizumab Step 4 Step 5 Medium/high-dose ICS/LABA Refer for add-on tx eg, tiotropium*, anti. Ig. E, anti-IL 5* Add tiotropium High-dose ICS + LTRA (or + theophylline) Add low-dose OCS *Not indicated in children <12 years of age. 44

Therapeutic Decision Making: Bronchial Thermoplasty • GINA 2017: For highly selected adult patients with

Therapeutic Decision Making: Bronchial Thermoplasty • GINA 2017: For highly selected adult patients with uncontrolled asthma despite use of recommended therapeutic regimens and referral to an asthma specialty center (Step 5), bronchial thermoplasty is a potential treatment option Step 4 Step 5 Medium/high-dose ICS/LABA Refer for add-on tx eg, tiotropium*, anti. Ig. E, anti-IL 5* Add tiotropium High-dose ICS + LTRA (or + theophylline) Add low-dose OCS *Not indicated in children <12 years of age. 45

Consensus Guidances on Biologic Therapies and Bronchial Thermoplasty for Severe Asthma 46

Consensus Guidances on Biologic Therapies and Bronchial Thermoplasty for Severe Asthma 46

Guidance on the Use of Newer Biologics or Bronchial Thermoplasty After the Addition of

Guidance on the Use of Newer Biologics or Bronchial Thermoplasty After the Addition of Tiotropium But Prior to the Use of Oral Corticosteroid Maintenance Therapy Depending on Severe Asthma Phenotype Ig. E (allergic) Preferred 3 -mo. trial of anti-Ig. E then determine responsiveness Alternative BT Severe asthma (GINA 4/5): Asthma that requires high doses of inhaled corticosteroids plus a second controller and/or systemic corticosteroids to prevent it from being uncontrolled, or that remains uncontrolled despite optimal adherence to this therapy. Eosinophilic Preferred: Either biologic with observation then switch if non-responsive Alternative: BT Preferred 3 -mo. trial of anti-IL-5 then determine responsiveness Alternative BT Non-eosinophilic / Non-Ig. E (allergic) Preferred BT 47

Consensus Guiding Principles for Severe Asthma Assessment & Biomarker Testing Guideline-based Therapy • Confirm

Consensus Guiding Principles for Severe Asthma Assessment & Biomarker Testing Guideline-based Therapy • Confirm asthma diagnosis • Confirm adherence to standard of care • Testing at initial evaluation and during follow-up care • Red flags for therapeutic failures • Side-effect profiling • Need for add-on controllers or newer therapies • Discontinuation of ineffective therapies Appropriate Patient Selection for Stepping to Newer Therapies Long-term disease Modification • What do newer therapies offer? • Biologics • Bronchial thermoplasty 48

Summary • Patients with severe asthma struggle with their disease and continue to have

Summary • Patients with severe asthma struggle with their disease and continue to have many unmet medical needs • The timing and comprehensiveness of assessments for severe asthma may need to be improved to better individualize treatment • Current guidelines do not account for newer treatments and when it may be appropriate to give them • Updated treatment guidances may help healthcare providers make more informed decisions about therapies they intend to use for their patients with severe asthma 49

Addendum The following slide is an addendum based on an accepted publication in the

Addendum The following slide is an addendum based on an accepted publication in the Annals of Allergy, Asthma & Immunology. 50

Therapeutic Options for Severe Asthma Ig. E (allergic) Preferred: 3 -month trial of anti-Ig.

Therapeutic Options for Severe Asthma Ig. E (allergic) Preferred: 3 -month trial of anti-Ig. E (omalizumab) � determine responsiveness Alternatives: newer targeted biologics, or BT Eosinophilic Preferred: Either biologic type with observation � switch if nonresponsive Alternatives: BT Preferred: 3 -month trial of anti-IL-5 (mepolizumab or reslizumab) � determine responsiveness Alternatives: BT or new biologics*† (currently in development) Non-eosinophilic/Non-Ig. E (allergic) Preferred: BT Alternatives: theophylline or biologics in development* Note: Although chronic OCS is an accepted therapy in the NAEPP and GINA guidelines, the panel recommends that all otherapies be considered prior to employing maintenance OCS. *Dupilumab †Benralizumab