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

Transcription

1 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 & 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 1. Consultant 1. Consulting fee 2. Pfizer 2. Consultant 2. Consulting fee 3. PMD Healthcare 3. Consultant 3. Consulting fee 4. RxBands 4. Consultant 4. Consulting fee 5. Stallergenes 5. Consultant 5. Consulting fee Mario Castro, MD, MPH 1. Boston Scientific 1. Consultant, speaker 1. Consulting fee, honorarium 2. Genentech 2. Consultant, speaker, advisory 2. Consulting fee, honorarium 3. Holaira committee member 3. Consulting fee 4. Teva 3. Consultant 4. Consulting fee, honorarium 5. GlaxoSmithKline 4. Consultant, speaker 5. Honorarium 6. Boehringer-Ingelheim 5. Speaker, DSMB committee 6. Honorarium 7. Elsevier 6. Speaker 7. Royalties 8. Neostem 7. Independent Contractor 8. Consulting fee 8. Consultant 3 1

2 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. AstraZeneca 1. Consultant 1. Consulting fee 2. Boehringer Ingelheim 2. Speaker s bureau 2. Honorarium 3. Genentech 3. Advisory committee member 4. Meda 5. Merck 6. Novartis Michael B. Foggs, MD 1. AstraZeneca 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. AstraZeneca 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 asthma Describe asthma phenotypes and endotypes and evaluate the viability of routine biomarker testing for asthma subtypes in practice Outline updated therapeutic decision-making guidance for patients with severe asthma that is based on biomarkers and other patient disease characteristics 6 2

3 Unmet Medical Needs in Severe Asthma 7 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 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 3

4 Defining Severe Asthma 10 Definitions of Severe/Uncontrolled Asthma NAEPP EPR-3 (2007) ATS/ERS (2014) GINA (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%) 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 4

5 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: 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, e.g. high-dose ICS/LABA, to prevent it from becoming uncontrolled, or asthma that remains uncontrolled despite this treatment. 15 5

6 Consensus Definition for Severe Asthma 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 Phenotype vs Endotype Phenotype The set of observable characteristics of an individual resulting from the interaction of its genotype with the environment Endotype A specific biologic mechanism that explains observable properties of an organism Different asthma phenotypes and endotypes may respond differently to targeted therapies. 18 6

7 ATS/ERS Severe Asthma Phenotypes Characteristic Associations Blood and sputum eosinophils Severe allergic asthma High serum immunoglobulin E (IgE) High fractional exhaled nitric oxide (FeNO) Blood and sputum eosinophils Eosinophilic asthma Recurrent exacerbations High FeNO Neutrophilic asthma Chronic airflow obstruction Recurrent exacerbations Corticosteroid insensitivity Corticosteroid insensitivity Bacterial infections Airway wall remodeling as increased airway wall thickness Sputum eosinophils Reduced response to ICS and/or oral corticosteroids (OCS) Increased neutrophils in sputum Chung KF, et al. Eur Respir J. 2014;43(2): PRACTALL (PRACtical ALLergy) Consensus on Asthma Endotypes Phenotype Eosinophilic asthma Exacerbation prone asthma Exercise induced asthma Adult onset asthma Fixed airflow limitation Poorly steroid responsive asthma Endotypes Allergic asthma (adult), aspirin sensitive asthma, severe late onset hypereosinophilic asthma, allergic bronchopulmonary mycosis 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 Cross country skiers asthma, other forms of elite athlete asthma, allergic asthma, API positive preschool wheezer Fixed airflow limitation, infection induced asthma, severe late onset hypereosinophilic asthma Noneosinophilic (neutrophilic) asthma Noneosinophilic (neutrophilic) asthma, steroid insensitive eosinophilic asthma, airflow obstruction caused by obesity Lӧtvall J, et al. J Allergy Clin Immunol. 2011;127: Inflammatory Phenotypes Eosinophilic (A) Neutrophilic (B) Mixed (C) Paucigranulocytic (D) Vijverberg SJ, et al. Biologics. 2013;7:

8 Eosinophilic Phenotype in Severe Asthma EG2+Cells/mm P<.05 P<.05 P<.05 Overall P= Normal Mild Moderate Eos ( ) Eos (+) Severe Eos, eosinophil. Wenzel SE, et al. Am J Respir Crit Care Med. 1999;160(3): Predictive Value of Blood Eosinophils for Exacerbations 400 cells/µl (n=109,319) >400 cells/µl (n=20,929) Severe exacerbation 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) Acute respiratory event 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) 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): 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 ( )* RR 1.28 ( )* OR 0.78 ( )* OR 0.74 ( )* Lower with blood eosinophilia 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):

9 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): Neutrophil-predominant Asthma Associated with High Doses of ICS and OCS Use 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 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 No. of Subjects Paucigranulocytic Eosinophil Predominant Neutrophil Predominant Mixed Granulocytic Cluster A Cluster B Cluster C Cluster D 1. Moore W, et al. J Allergy Clin Immunol. 2014;133: Wysocki K, et al. J Allergy Clin Immunol. 2014;133(3): Evaluation of Available and Future Treatments for Severe Asthma 27 9

10 Airway lumen Viruses Allergens Airway epithelium Therapeutic Targets in Severe Asthma Dupilumab Allergen/ Antigen PGD2 Mast cell B cell FcɛRI IgE IL4Rα Benralizumab Mepolizumab; Reslizumab IL-5Rα Mepolizumab; Eosinophil IL-5 Reslizumab CRTH2 PGD2 IL4Rα Dupilumab ILC2 IL-13 Omalizumab Th2 Smooth muscle APC Bronchial Thermoplasty Tiotropium APC, antigen-presenting cell; CRTH2, chemoattractant receptor homologous molecule expressed on Th2 lymphocytes; IL, interleukin; ILC2, group 2 innate lymphoid cells; PGD2, prostaglandin D2; R, receptor agonist; Th, T helper. Fajt ML, et al. Allergy Asthma Immunol Res. 2017;9(1): Overview of Available and Future Therapies Available Tiotropium Anti-IgE: omalizumab Anti-IL-5: mepolizumab (SC) and reslizumab (IV) Bronchial thermoplasty Future Anti-IL-5Rα: benralizumab (SC) Anti-IL-4Rα: dupilumab (SC) IV, intravenous; SC, subcutaneous. 29 Evidence Review: Mepolizumab Sig in Study Pts Characteristics FEV 1 Exacerb. Steroid Use AQLQ/ SGRQ DREAM High dose ICS + 1 other controller, NS 39% 52% Not reported AQLQ NS 75, 250, 750 mg IV w/ or w/o OCS ml for 52 weeks Blood eosinophil (eos) exacerb in previous year MENSA High dose ICS + 1 other controller, +98 ml 53% Not reported 7 point 75 mg IV 100 mg w/ or w/o OCS improvement SC for 32 weeks Blood eos 150 In St. George's 2 exacerb in previous year Respiratory Questionnaire (SGRQ) SIRIUS High dose ICS + 1 other controller NS trend toward 32% 23% had 90% 100% OCS Clinically 100 mg SC for 24 6 month hx of OCS (5 35 mg/day of (114 ml reduction vs reduction meaningful weeks (steroidsparing study) Blood eos 300 during the 12 month bronchodilation (P=0.04) daily OCS dose ACQ 5 at week 2 prednisone or equivalent) before pbo at Wk 24 54% with 50% in improvements in period before and 128 ml after 56% pbo vs 36% mep sustained up to screening or 150 during bronchodilation) had no decrease in OCS Wk 24 vs pbo the optimization phase dose, a lack of asthma (P=0.004) control, or withdrawal from treatment 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: Ortega HG, et al. N Engl J Med. 2014;371: Bel EH, et al. N Engl J Med. 2014;371(13):

11 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 $706,111 $15,465 $386,000 Standard of Care Alone $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): Evidence Review: Reslizumab Study Pts Characteristics FEV 1 Sig in Exacerb AQLQ Corren Inadequate control on medium dose ICS and NS Not reported Not reported 3.0 mg/kg IV q4w hx of exacerbation in last year for 16 weeks Unselected for eos Blood eos <400 cells/μl in 80% Blood eos 400 cells/μl in 20% Bjermer and 3 mg/kg IV q4w for 16 weeks 315 Inadequate control on medium dose ICS and Hx of exacerbation in last year Blood eos 400 cells/μl +115 ml P= ml P=.002 Not reported Clinically meaningful difference reached on AQLQ for 3 mg Castro 3 Duplicate RCTs; 3.0 mg/kg IV q4w for 52 weeks 953 Inadequate control on medium/high dose ICS +220 ml and 1 exacerbation in last year P< Blood eos 400 cells/μl (pooled data at Week 52) 50% 59% reduction Clinically meaningful difference reached on AQLQ q4w, every 4 weeks; RCT, randomized controlled trial. 1. Corren J, et al. Chest. 2016;150(4): Bjermer L, et al. Chest. 2016;150(4): Castro M, et al. Lancet Respir Med. 2015;3(5): Evidence Review: Benralizumab Study Pts Characteristics FEV 1 Sig in Exacerb AQLQ SIROCCO 621 Treatment with medium or highdose ml 45% 51% 300 Significant for the q8w 1 30 mg SC ICS + LABA for 1 year ± OCS P=.02 cells/μl regimen regardless of eos q4w or q8w for 48 increase status weeks Blood eos < and 300 cells/μl 30% <300 2 exacerb in previous year cells/μl CALIMA 2 30 mg SC q4w or q8w for 48 weeks 1306 Treatment with medium or highdose ICS + LABA for 1 year ± OCS P< ml increase Blood eos < and 300 cells/μl 2 exacerb in previous year 28% 36% 300 cells/μl 36% 40% <300 cells/μl Significant for the q8w regimen in pts with 300 cells/μl q8w, every 8 weeks. 1. Bleecker ER, et al. Lancet. 2016;pii: S (16) FitzGerald JM, et al. Lancet. 2016;pii: S (16)

12 Evidence Review: Dupilumab Study Pts Characteristics FEV 1 Sig in Exacerb Wenzel Phase 2b, Dupilumab SC vs pbo 200 or 300 mg q2w or q4w 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 ml P<.007 Overall population 54% 71% Eos 300 cells/μl 66% 81% q2w, every 2 weeks. Wenzel S, et al. Lancet. 2016;388: Safety Review: Newer Biologics Agent Most Common AEs ( 5% of Patients in Aforementioned Phase 3 Trials) Serious AEs AEs Leading to Withdrawal Deaths Mepolizumab (MENSA 32 week study) 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 Reslizumab (Castro et al, 2 52 week studies) Has anaphylaxis warning 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, q4w arm 2, q8w 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 AE, adverse event; Ben, benralizumab; Dup, dupilumab; Res, reslizumab; tx, treatment; URTI, upper respiratory tract infection. 35 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

13 Evidence: Bronchial Thermoplasty (BT) One-time treatment lasting for 5 years 1 Patients (N=580, AIR2) ICS 1,000 µg/d beclomethasone or equivalent and LABA >100 µg/d salmeterol or equivalent; other meds including leukotriene modifiers, OmAb (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 AIR2, Asthma Intervention Research 2 trial; ED, Emergency department; OmAb, Omalizumab. 1. Wechsler M, et al. J Allergy Clin Immunol. 2013;132(6): Castro M, et al. Am J Respir Crit Care Med. 2010;181(2): 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): Castro M, et al. Am J Respir Crit Care Med. 2010;181(2): Evidence: BT Cost Analyses vs Standard Care Costs QALY BT cost-effective at 5 and 10 years 1 ICER Strategy 5 year Δ 5 year Δ At 10 years, BT ICER was $29,821/ ($/QALY) QALY vs usual care At 5 years, BT remained cost-effective Standard with an ICER of $45,300/QALY Care $49,510 Base case $/QALY below society s willingness to BT $50,470 $ $5495 pay (WTP)/QALY of $50,000 Drivers of cost-effectiveness ratio 2 Standard Care $30,024 Scenario analysis Reduced exacerbations and costs Improved Quality of Life (QOL) 2 BT case $39,983 population defined $9959 poorly controlled severe, persistent, asthma; $62,922 those with >1 Base as 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): Castro M, et al. Expert Rev Pharmacoecon Outcomes Res. 2015;15(2):

14 Therapeutic Decision Making Severe Asthma 40 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 IgE Allergy testing (skin) FeNO 41 Step 2: Refer to the Guidelines (2017 GINA Shown) 42 14

15 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 for patients with severe asthma uncontrolled on Step 4 treatment now also include tiotropium, omalizumab, mepolizumab and reslizumab Medium/high dose ICS/LABA Step 4 Step 5 Add tiotropium High dose ICS + LTRA (or + theophylline) Refer for add on tx eg, tiotropium*, anti IgE, anti IL5* 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 uncontrolled asthma despite use of recommended therapeutic regimens and referral to an asthma specialty center (Step 5), bronchial thermoplasty is a potential treatment option Medium/high dose ICS/LABA Step 4 Step 5 Add tiotropium High dose ICS + LTRA (or + theophylline) Refer for add on tx eg, tiotropium*, anti IgE, anti IL5* Add low dose OCS *Not indicated in children <12 years of age

16 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 Tiotropium But Prior to the Use of Oral Corticosteroid Maintenance Therapy Depending on Severe Asthma Phenotype IgE (allergic) Preferred 3 mo. trial of anti IgE then determine responsiveness Alternative BT Preferred: Either biologic with observation then switch if non responsive Alternative: BT Eosinophilic Preferred 3 mo. trial of anti IL 5 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. Non eosinophilic / Non IgE (allergic) Preferred BT 47 Consensus Guiding Principles for Severe Asthma Assessment & Biomarker Testing Confirm asthma diagnosis Confirm adherence to standard of care Testing at initial evaluation and during follow-up care Guideline-based Therapy 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 Biologics Bronchial thermoplasty Long-term disease Modification What do newer therapies offer? 48 16

17 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 the 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 Annals of Allergy, Asthma & Immunology. 50 Therapeutic Options for Severe Asthma IgE (allergic) Eosinophilic Preferred: 3-month trial of anti-ige (omalizumab) determine responsiveness Alternatives: newer targeted biologics, or BT 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) *Dupilumab Benralizumab Non-eosinophilic/Non-IgE (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 other therapies be considered prior to employing maintenance OCS. 17