Improving Control in Severe Asthma Stanley Fineman, MD, MBA Adjunct Assoc Professor of Pediatrics Emory Univ School of Medicine Atlanta Allergy & Asthma

Faculty Disclosures Speakers’ Bureaus: AstraZeneca Pharmaceuticals LP, Boehringer Ingelheim Pharmaceuticals, Inc., Shire/Takeda Contracted Research: Aimmune, BioCryst, DBV Technologies, Regeneron Pharmaceuticals

Learning Objectives Describe clinical criteria for severe asthma and outline an approach to assessing symptom control and disease burden Identify known phenotypes of severe asthma Describe and identify severe asthma endotypes that can inform treatment selection Develop an approach to the treatment of severe asthma that is personalized to the individual patient and describe the most recent clinical data on new and emerging therapies for severe asthma Identify strategies for improving communication to promote collaborative decision-making and the ability to self-manage among patients with severe asthma

Overview of Severe Asthma

Overview of Severe Asthma Asthma is a highly heterogeneous disease Affects an estimated 10% to 15% of the asthma population Characteristics of severe disease: Not responsive to high-dose ICS with or without additional controller therapies (ie, LABAs, LAMAs, LTRAs, and/or theophylline) Significantly impairs patient activity and QOL and increases patient risk for exacerbation Optimal treatment remains challenging Requires shift from guideline-directed management to a personalized approach to treatment in relation to disease characteristics ICS, inhaled corticosteroid; LABA, long-acting beta2-agonist; LAMA, long-acting muscarinic antagonist; LTRA, leukotriene receptor antagonist; QOL, quality of life. Chung KF, et al. Eur Respir J. 2014;43(2):343-373; Katial R, et al. J Allergy Clin Immunol Pract. 2017;5(2S):S1-S14; Hossny E, et al. World Allergy Organ J. 2017;10(1):28.

Epidemiology of Uncontrolled Asthma Prevalence of severe asthma is dependent on how it is defined Under aggressive treatment schemes, both controlled and uncontrolled asthma are considered severe Severe asthma symptoms are associated with: Lack of, and noncompliance with, essential asthma medications Poor patient education on asthma management Failure to implement guidelines on asthma diagnosis and treatment Severe asthma is associated with increased risk for hospitalization and death CDC Fact Sheet on Asthma. Available at: https://www.cdc.gov/asthma/asthma_stats/uncontrolled_asthma.htm. Poon AH, Hamid Q. Ann Am Thor Soc. 2016;13(suppl 1):68-77.

Economic Impact of Severe Asthma Chastek B, et al. JMCP. 2016;22(7):848-861.

Definition of Severe Asthma

ATS/ERS (2014): Uncontrolled Asthma One or more of the following: Poor symptom control: ACQ consistently >1.5, ACT <20 Frequent severe exacerbations: ≥2 bursts of systemic CS in the previous year Serious exacerbations: ≥1 hospitalization, ICU stay, or mechanical ventilation in the previous year Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted Controlled asthma that worsens on tapering of high doses of ICS, systemic CS, or additional biologics ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; CS, corticosteroid; ICU, intensive care unit; FEV1, forced expiratory volume in 1 second. Chung KF, et al. Eur Respir J. 2014;43(2):343-373.

ATS/ERS (2014): Severe Asthma Patients ≥6 years of age who require GINA Step 4 or 5 treatment to prevent asthma from becoming “uncontrolled,” or asthma remains “uncontrolled” despite Step 4 or 5 treatment, eg, high-dose ICS/LABA Consider low-dose ICS LTRA or low-dose theophylline Medium to high-dose ICS or low-dose ICS and LTRA or low-dose ICS and theophylline Add tiotropium* or high-dose ICS and LTRA or high-dose ICS and theophylline Add tiotropium*; add low-dose OCS Low-dose ICS Low-dose ICS/LABA Medium- or high-dose ICS/LABA Refer for add-on treatment (eg, anti-IgE, anti-IL-5) STEP 1 STEP 2 STEP 3 STEP 4 STEP 5 Preferred Controller Other Controller Options Reliever As needed SABA or low-dose ICS/LABA† As needed short-acting beta2-agonist (SABA) ATS, American Thoracic Society; ERS, European Respiratory Society; GINA, Global Initiative on Asthma; IgE, immunoglobin E; IL, interleukin; OCS, oral corticosteroid. *Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations; it is not indicated in children younger than 18 years old; †For patients prescribed beclomethasone/formoterol or budesonide/formoterol. Chung KF, et al. Eur Respir J. 2014;43(2):343-373; Chipps BE, et al. Ann Allergy Asthma Immunol. 2017;118:133-142.

Identification of Patients with Severe Asthma

Case Evaluation: Patient Description Kate is a 41-year-old female with worsening symptoms of asthma, including persistent cough, wheezing, chest tightness, and shortness of breath Diagnosed with: Sinusitis at age 30 Asthma at age 33 Recent discovery of nasal polyps ACT: 17 (<20=not well-controlled) 2 exacerbations during the past year Symptoms have limited normal activities and prevented Kate from sleeping through the night Current treatment regimen includes a fluticasone/salmeterol (500/50 bid) therapy and albuterol (prn) bid, twice daily; prn, as needed. 12

Case Evaluation: Discussion What would you do to assess Kate’s asthma?

Assessments to Distinguish Uncontrolled Asthma from Severe Asthma Watch patient use their inhaler Show correct method Identify poor adherence to ensure it does not contribute to lack of control Confirm adherence and check correct use of inhalers Confirm evidence of airflow obstruction If no evidence of reversibility, consider challenge test Confirm the diagnosis of asthma Check for risk factors or inducers such as smoking, beta-blockers or NSAIDs, or allergen exposure Check for and manage comorbidities Identify potential risk factors and assess for comorbidities Move step up to next slide. GINA. Global Strategy for Asthma Management and Prevention. Available at: https://ginasthma.org/2018-gina-report-global-strategy-for-asthma-management-and-prevention/.

Medical & Treatment History Patient Assessment Medical & Treatment History Current medication use and adherence Exacerbation history and need for systemic corticosteroids Comorbidities Clinical Assessment ACT/ACQ/AIS QOL/AQLQ Laboratory Testing Lung function (spirometry) Blood eosinophils Serum IgE Allergy testing (skin or serological) FeNO Chest imaging AIS, Asthma Impact Survey; AQLQ, Asthma Quality of Life Questionnaire. Chung KF, et al. Eur Respir J. 2014;43(2):343-373.

Kate, 41-year-old Female: Assessment Kate demonstrates correct use of inhaler Reports adherence to treatment and regular medication refills Confirm adherence and check correct use of inhalers FEV1: 60% 16% improvement with bronchodilator Evidence of airflow obstruction Confirmed comorbid sinusitis and nasal polyps No identifiable exposure to allergens or pollutants Nonsmoker Identify potential risk factors and assess and manage comorbidities What is the next step in Kate’s management? Consider treatment step-up 16

Differential Diagnosis More Common Less Common Chronic obstructive pulmonary disease (COPD) Gastroesophageal reflux disease (GERD) Heart failure Cystic fibrosis (CF) Vocal cord dysfunction (VCD) Congenital or acquired immunodeficiency Primary ciliary dyskinesia Trachea and mainstem bronchi obstruction Recurrent aspiration Bronchiolitis Psychogenic hyperventilation Drug side effects (eg, ACE inhibitor-induced cough) Pulmonary embolism ACE, angiotensin-converting enzyme. Chung KF, et al. Eur Respir J. 2014;43(2):343-373.

Severe Asthma Phenotypes and Endotypes

Asthma Is Not One Disease Heterogeneous Disease Symptoms Onset Responsiveness Severity

Inflammatory Mechanisms and Pathobiologic Features Leading to Severe Asthma Th, T helper cell; TSLP, thymic stromal lymphopoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; PGD2, prostaglandin D2; ILC, innate lymphoid cells; TGF-β, transforming growth factor beta; CXCL8, CXC motif chemokine ligand 8; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor alpha; BLT2, leukotriene B4 receptor 2. Israel E, Reddel HK. N Engl J Med. 2017;377:965-976.

Asthma Pathophysiology Normal Eosinophilic Asthma Noneosinophilic Asthma Airway smooth muscle Mast cell Epithelium and reticular basement membrane IgE Allergic eosinophilic inflammation Paucigranulocytic B cells Dendritic cell IL4/13 IL5 Th2 Allergens Pollutants, oxidative stress Eosinophil PGD2 Pollutants, microbes Pollutants, oxidative stress, microbes Dendritic cell PGD2 IL23 Nonallergic eosinophilic inflammation Th1/ Th17 Th1 + Th17 neutrophilic inflammation IL33 IL17 IL5 TSLP ILC3 ILC2 Goblet cell CXCL8 PGD2 Macrophage Mast cell Neutrophil Mixed granulocytic asthma Papi A, et al. Lancet. 2018. 24;391(10122):783-800.

Asthma Phenotype vs. Endotype 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.

Asthma Phenotypes Category Phenotype Trigger-induced asthma Allergic Nonallergic Aspirin-exacerbated respiratory disease (AERD) Infection Exercise-induced Occupational Category Phenotype Trigger-induced asthma Allergic Nonallergic Aspirin-exacerbated respiratory disease (AERD) Infection Exercise-induced Occupational Asthma patient characteristics Smoking Obesity Elderly Ethnicity Category Phenotype Trigger-induced asthma Allergic Nonallergic Aspirin-exacerbated respiratory disease (AERD) Infection Exercise-induced Occupational Asthma patient characteristics Smoking Obesity Elderly Black Clinical presentation of asthma Pre-asthma wheezing in infants Episodic (viral wheeze) Multi-trigger wheezing Exacerbation-prone asthma Asthma associated with apparent irreversible airflow limitation Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.

Inflammatory Markers of Asthma Type 2 asthma Eosinophilic High nitric oxide High IgE IL-4/IL-5/IL-13 mediated Non-type 2 asthma IL-6/IL-8/IL-17 IL-1/IL-6/IL-17/TNF-α mediated

Eosinophils Modulate the immune response Promote airway hyper-responsiveness and remodeling Cause bronchoconstriction Release granular proteins (eg, ECP, EDN, and MBP) Testing in blood or sputum Blood eosinophil counts as low as 150 cells/µL may predict treatment response with targeted therapies Associated cytokines: IL-5 IL-4 IL-13 ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; MBP, major basic protein. Douwes J, et al. Thorax. 2002;57(7):643-648; Eltboli O, Brightling C. Expert Rev Respir Med. 2013;1(7):33-42; Ortega HG, et al. Lancet Respir Med. 2016;4(7):549-556; Carr T, et al. Am J Respir Crit Care Med. 2018;197(1):22-37.

Higher Eosinophils Correlate with Higher Risk for Exacerbation Price Lancet Respiratory 2017 Adapted from: Price D, et al. J Asthma Allerg. 2016;9:1-12.

FeNO Under physiological conditions, NO acts as a weak mediator of smooth muscle relaxation and protects against airway hyperresponsiveness In the setting of asthma, NO may act as a proinflammatory mediator predisposing to airway hyperresponsiveness Up-regulation occurs with inflammation Associated with IL-13 cytokine Picture showing that this is epithelial derived, 4-13 aspect on epithelium. Show how this generated. FeNO, forced exhaled nitric oxide; NO, nitric oxide. Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.

Clinical Indications of FeNO FeNO Levels Clinical Indications Low <25 ppb in adults <20 ppb in children Eosinophilic inflammation and corticosteroid responsiveness is less likely Medium 25-50 ppb in adults 20-35 ppb in children Cautious interpretation necessary High >50 ppb in adults >35 ppb in children Eosinophilic inflammation and corticosteroid responsiveness likely ppb, parts per billion. Alving K, et al. Eur Respir J. 1993;6(9):1368-1370; Dwelk RA, et al. Am J Respir Crit Care Med. 2011;184(5):602-615.

IgE Binds to FcεRI on mast cells, basophils, and antigen-presenting dendritic cells Activates the release of inflammatory mediators Associated cytokines: IL-4 IL-13 Treatment with anti-IgE therapy is based on IgE ≥30 IU/mL Anti-IgE therapy may be more effective in patients with high Th2-associated biomarkers MHC, major histocompatibility complex. Ahmad Al Obaidl AH, et al. J Asthma. 2008;45(8):654-663; Matsui EC, et al. Allergy. 2010;65(11):1414-1422; Hanania NA, et al. Am J Respir Crit Care Med. 2013;187(8):804-811.

Additional Biomarkers of Severe Asthma Testing Method Role in Allergic Pathway Associated Cytokines Neutrophil Sputum Significantly associated with severe asthma Accumulates in the airways Prominent in airway secretions during exacerbations Associated with obesity, infections, and steroid resistance IL-6, IL-8, IL-17 Periostin† Serum, sputum Regulates eosinophil recruitment and eosinophilic tissue infiltration Active in Th2 mucosal inflammation, airway remodeling, and expression of inflammatory mediators IL-13 DPP-4† Serum Stimulates the proliferation of bronchial smooth muscle cells and human fetal lung fibroblasts Promotes fibronectin production †Not commercially available. DPP-4, dipeptidyl peptidase-4. Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.

Case Evaluation: Discussion How might biomarkers guide therapy?

Personalized medicine Improved Understanding of Pathophysiologic Mechanisms May Guide Personalized Medicine Empirical medicine Stratified medicine Personalized medicine One treatment for all Evidence-based Different treatments for each group Evidence-based Biomarker-led Individual treatments for each patient Evidence-based Patient-derived Willis JCD, Lord GM. Nat Rev Immunol. 2015;15:323-329.

Traditional and Personalized Approaches to Treating Asthma Personalized Approach to Asthma Diagnosis Determination of whether asthma is refractory Characterize subtype Phenotype Endotype Genotype Gender Age Obesity Ethnicity Smoking Hx Blood biomarkers Sputum biomarkers Other IgE Eosinophils Periostin Cytokines Neutrophils FeNO Tailored therapy Assess comorbidities Traditional Guidance-Based Asthma Management Diagnosis Assessment of asthma severity Avoidance of triggers and management of comorbidities: Laryngopharyngeal reflux Subacute bacterial infection Sinus disease Sleep apnea Vocal cord dysfunction Stepwise approach to therapy: SABA, ICS alone, ICS+LABA, ICS+LTRA, OCS, biologic therapy Hx, history. Katial R, et al. J All Clin Immunol In Practice. 2017;5(2):S1-S14.

Current Treatment Options

Kate, 41-year-old Female: Test Results Serum IgE: 41 IU/mL (no antigen-specific IgE) Blood eosinophil count: 215 cells/μL FeNO: 41 ppb Serum periostin level within normal limits. What modifications to her current therapeutic regimen would you consider making? What criteria would you use in selecting her treatment?

Place of Tiotropium in Severe Asthma Significantly improves FEV1 Reduces exacerbations independent of T2 phenotype/endotype Reduces overall risk for exacerbations requiring systemic glucocorticoids May be added to high-dose ICS+LABA therapy prior to stepping up to other types of therapies While phenotyping continues to emerge as an important component of evaluation, such information may not always be easily accessible (eg, for practices that lack access to experienced testing facilities). In general, tiotropium (which is known to reduce exacerbations and asthma worsening independent of T2 phenotype) may be added to high-dose ICS + LABA therapy prior to stepping up to other types of therapies (ie, OCS, newer biologics, or bronchial thermoplasty). Kerstjens J. Allergy Clin Immunol. 2011;128(2):308-314; Casale TB, et al. J Allergy Clin Immunol Pract. 2018;6(3):923-935.e9.

Kate, 41-year-old Female: Treatment & Discussion Kate is initiated on tiotropium therapy, but continues to demonstrate poor symptom control after 4 weeks. How long would you wait before recommending a switch in therapeutic approach? What type of therapy would you consider for Kate at this point?

Targeted Biologic Therapies for Severe Asthma Biologic Therapy Target Approval Date Indication Omalizumab IgE 2003 ≥6 years of age Positive skin test or in vitro reactivity to a perennial aeroallergen Mepolizumab IL-5 2015 Add-on maintenance ≥18 years of age Eosinophilic phenotype Reslizumab 2016 Benralizumab IL-5Rα 2017 ≥12 years of age Eosinophilic asthma Dupilumab IL-4/ IL-13 2018 Add-maintenance for moderate-to-severe asthma Corticosteroid dependent asthma regardless of phenotype At-home administration

Patients with Exacerbations (%) IgE-targeted Treatment with Omalizumab Reduces Exacerbations and Systemic Corticosteroid Use * * Patients with Exacerbations (%) *P<.05. BDP, beclomethasone dipropionate. Busse W, et al. J Allergy Clin Immunol. 2001;108(2):184-190.

Reduction in Asthma Exacerbation Rates in Low- and High-biomarker Subgroups –32 Asthma Exacerbation Rate (mean, 95% CI) Percent Reduction in Protocol-Defined n=193 n=201 n=383 n=414 n=279 n=255 P=.45* P=.001* P=.54* P=.005* P=.94* P=.07* 40 20 –20 –40 –60 –80 <19.5 ppb ≥19.5 ppb <260/µL ≥260/µL <50 ng/mL ≥50 ng/mL FeNO Eosinophils Periostin –16 –53 –9 –30 –3 *Exacerbation reduction P-values; omalizumab vs. placebo in each biomarker subgroup. Hanania N, et al. Am J Resp Crit Care Med. 2013;187:804-811.

Cumulative Number of Exacerbations Exacerbation Rates and FEV1 After 32 Weeks of Treatment with Mepolizumab P<.001 for both comparisons. Cumulative Number of Exacerbations 0 4 8 12 16 20 24 28 32 Week 250 200 150 100 50 Asthma Exacerbations Placebo Mepolizumab 75 mg, intravenously Mepolizumab 100 mg, subcutaneously FEV1 0 4 8 12 16 20 24 28 32 Week 75 70 65 60 Placebo Mepolizumab 75 mg, intravenously Mepolizumab 100 mg, subcutaneously FEV1 (% of Predicted Value) P=.02 in the intravenous-mepolizumab group. P=.03 in the subcutaneous-mepolizumab group. Ortega HG, et al. N Engl J Med. 2014;371:1198-1207.

Probability of Not Having CAE (%) IL-5-targeted Treatment with Reslizumab: Impact on Exacerbation Risk and Lung Function LS Mean Change from Baseline FEV1 (L) 0.40 0.30 0.20 0.10 0 4 8 12 16 20 24 28 32 36 40 44 48 52 End point Visit (week) Reslizumab 3.0 mg/kg Placebo † * Probability of Not Having CAE (%) 100 80 60 40 20 Placebo Reslizumab Placebo; n=244 Reslizumab 3.0 mg/kg; n=245 HR .575 (95% CI .440-.750) P<.0001 0 10 20 30 40 50 60 70 80 Time to First CAE (weeks) *P<·05. †P<·01. CAE, clinical asthma exacerbation. Castro M, et al. Lancet Respir Med. 2015;3:355-366.

IL-5-targeted Treatment with Benralizumab Reduces Exacerbations in Patients with Elevated Eosinophils 51%* 45%* 28%‡ 36%† SIROCCO CALIMA *P<.001; †P<.002; ‡P<.02 Q4W, every 4 weeks; Q8W, every 8 weeks. FitzGerald JM, et al. Lancet. 2016;388(10056):2128-2141; Bleecker ER, et al. Lancet. 2016;388(10056):2115-2127.

Change From Baseline Least-Squares Means (L) Change in FEV1 for Patients Receiving High-dose ICS+LABA According to Baseline Blood Eosinophils Eosinophils ≥300 cells per µL Eosinophils <300 cells per µL Change From Baseline Least-Squares Means (L) 0 4 8 16 24 32 40 48 56 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 * † 0 4 8 16 24 32 40 48 56 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 Change From Baseline Least-Squares Means (L) Placebo Benralizumab 30 mg Q4W Benralizumab 30 mg Q8W *P<.05 for benralizumab Q4W vs placebo and for benralizumab Q8W vs placebo; †P<.05 for benralizumab Q8W vs placebo. FitzGerald JM, et al. Lancet. 2016;388(10056):2128-2141.

Dupilumab: IL-4/IL-13 Antibody Targeting T2/Th2 Pathway Dupilumab is a fully human monoclonal antibody that targets the IL-4Rα of the IL-4 and IL-13 receptors Impaired KC differentiation Low AMPs production Increased expression of TARC and oxtaxin-3 (CCL26) ↑Airway inflammation ↑Mucus production ↑ Airway hyperresponsiveness ↑Airway remodeling Eosinophil recruitment Eosinophil IL-4 IL-13 Increased production of eotaxin-1 (CCL11) Fibroblast IgE production Th2 differentiation and survival AMPs, antimicrobial peptides; KC, keratinocyte; TARC, thymus- and activation-regulated chemokine. D’Erme AM. Drug Design Dev Ther. 2017;11:1473-1480.

Relative Risk vs. Placebo (95% CI) Dupilumab Reduced Risk of Severe Exacerbation Independent of Baseline Blood Eosinophil Count Dupilumab, 200 mg Q2W vs. Matched Placebo Number of Patients Subgroup Placebo Dupilumab Relative Risk vs. Placebo (95% CI) Overall 317 631 .52 (.41-.66) Eosinophil count ≥300 cells/mm3 148 264 .34 (.24-.48) ≥150 to <300 cells/mm3 84 173 .64 (.41-1.02) <150 cells/mm3 85 193 .93 (.58-1.47) FeNO ≥50 ppb 71 119 .31 (.18-.52) ≥25 to <50 ppb 91 180 .39 (.24-.62) <25 ppb 149 325 .75 (.54-1.05) 0.1 0.25 0.5 0.75 1 1.5 2 Dupilumab Better Placebo Q2W, every 2 weeks. Castro M, et al. New Engl J Med. 2018;378(26):2486-2496.

Relative Risk vs. Placebo (95% CI) Dupilumab Reduced Risk of Severe Exacerbation Independent of Baseline Blood Eosinophil Count Dupilumab, 300 mg Q2W vs. Matched Placebo Number of Patients Subgroup Placebo Dupilumab Relative Risk vs. Placebo (95% CI) Overall 321 633 .54 (.43-.68) Eosinophil count ≥300 cells/mm3 142 277 .33 (.23-.45) ≥150 to <300 cells/mm3 95 175 .56 (.35-.89) <150 cells/mm3 83 181 1.15 (.75-1.77) FeNO ≥50 ppb 75 124 .31 (.19-.49) ≥25 to <50 ppb 97 186 .44 (.28-.69) <25 ppb 144 317 .79 (.57-1.10) 0.1 0.25 0.5 0.75 1 1.5 2 Dupilumab Better Placebo Better Castro M, et al. New Engl J Med. 2018;378(26):2486-2496.

Change from Baseline FEV1 Over 52-week Treatment with Dupilumab Least-Squares Mean Change from Baseline in FEV1 (liters) 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 Week 0.4 0.3 0.2 0.1 0.0 Dupilumab, 300 mg Dupilumab, 200 mg Placebo, 2.00 mL Placebo, 1.14 mL Patients received dupilumab at a dose of 200 mg or 300 mg every 2 weeks, or a matched-volume placebo. For the lower dose of dupilumab, the matched placebo had a volume of 1.14 mL. For the higher dose of dupilumab, the matched placebo had a volume of 2.00 mL. Castro M, et al. New Engl J Med. 2018;378(26):2486-2496.

Percentage Reduction in Oral Dupilumab Reduces Oral Corticosteroid Use in Glucocorticoid-dependent Severe Asthma Percentage Reduction in Oral Glucocorticoid Dose 0 4 8 12 16 20 24 Week –20 –40 –60 –80 Placebo Dupilumab Primary endpoint P<.001 In the intention-to-treat population, the least-squares mean (±SE) percentage change in the oral glucocorticoid dose from baseline to week 24, while asthma control was maintained, was -70.1±4.9% in the dupilumab group vs. -41.9±4.6% in the placebo group. Rabe KF, et al. New Engl J Med. 2018;378(26):2475-2485.

Least-Squares Mean Difference P-value for Interaction Dupilumab Percent Reduction in Oral Steroid Use According to Blood Eosinophil Group Subgroup Placebo (n=107) Dupilumab (n=103) Least-Squares Mean Difference (95% CI) P-value for Interaction Number of Patients Percentage Points ≥300 or <300 cells/mm3 .24 ≥300 41 48 -36.8 (-54.7 to -18.9) <300 66 55 -21.3 (-38.8 to -3.9) ≥150 or <150 cells/mm3 .71 ≥150 69 81 -29.4 (-43.1 to -15.7) <150 38 22 -26.9 (-54.5 to -.7) 10 0 –10 –20 –30 –40 –50 Placebo Better Dupilumab Better Only the patients whose glucocorticoid dose was 30 mg per day or less at baseline were included in the analysis of the endpoint regarding the elimination of glucocorticoid use. Rabe KF, et al. New Engl J Med. 2018;378(26):2475-2485.

Case Evaluation: Discussion In addition to the currently available biologic therapies, what other treatment approaches may be appropriate for a patient like Kate?

Targeted Biologics for Severe Asthma: Overview of Efficacy Agent Exacerbations Asthma Control FEV1 QOL OCS Use Mepolizumab* ↓ ACQ-5 NS ↑ Reslizumab* ACQ-7  — Benralizumab* ACQ-6  Omalizumab ↑↓ Dupilumab* ACQ-5  Under Development Tezepelumab* ACQ-6 NS, not statistically significant; , statistically significant. *No strong safety signals for any biologic vs. placebo in clinical trials.

Other Therapies

Effect of Azithromycin on Exacerbations and QOL in Adults with Uncontrolled Asthma: Introduction Macrolide antibiotics have antibacterial, antiviral, and anti-inflammatory effects Reported benefit in eosinophilic and noneosinophilic subtypes Systematic reviews of randomized controlled trials report benefits of macrolides on asthma symptoms Unable to draw conclusions about the effects on other endpoints, including exacerbations, due to lack of data, heterogeneity of results, and inadequate study design and sample size Trial tested hypothesis that azithromycin reduces asthma exacerbations and improves QOL in patients with symptomatic asthma on inhaled maintenance therapy Gibson PG, et al. Lancet. 2017;390:659-668.

Add-on Azithromycin in Uncontrolled Asthma Despite ICS and Long-acting Bronchodilator Therapy AMAZES Study Exacerbations per Person Year Incidence Rate Placebo Azithromycin Ratio (95% CI) Noneosinophilic asthma 1.74 1.15 .66 (.47-.93) Eosinophilic asthma 1.98 .96 .52 (.29-.94) Inhaled corticosteroid 1.86 1.07 .58 (.46-.74) dose adjustment Frequent exacerbators 2.79 1.47 .55 (.41-.73) Cough and sputum VAS 1.72 .79 .49 (.26-.95) Bacteria–negative 1.85 1.18 .61 (.52-.72)* Bacteria–positive 2.64 1.11 .39 (.22-.69)* Add-on azithromycin reduces asthma exacerbations in adults with uncontrolled asthma despite maintenance ICS and a long-acting bronchodilator therapy 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 Favors Azithromycin Favors Placebo *P<.05 VAS, Visual Analog Scale. Gibson PG, et al. Lancet. 2017;390:659-668.

Impact of Bronchial Thermoplasty (BT) on Asthma Control Rates of Severe Exacerbations (Events/Subject/Year) 1.2 1 0.8 0.6 0.4 0.2 Rates of Emergency Room Visits 12 months before BT Year 1 Year 2 Year 3 Year 4 Year 5 Average over 5 years 12 months before BT Year 1 Year 2 Year 3 Year 4 Year 5 Average over 5 years At 5 years, BT was associated with durable improvements in asthma control (based on maintained reduction in severe exacerbations and ED visits for respiratory symptoms). Wechsler ME, et al. J Allergy Clin Immunol. 2013;132(6):1295-1302.

Approach to Treatment Selection

Step Therapy for Adult Patients with Asthma Consider low-dose ICS LTRA or low-dose theophylline Medium to high-dose ICS or low-dose ICS and LTRA or low-dose ICS and theophylline Add tiotropium* or high-dose ICS and LTRA or high-dose ICS and theophylline Add tiotropium*; add low-dose OCS Low-dose ICS Low-dose ICS/LABA Medium- or high-dose ICS/LABA Refer for add-on treatment (eg, anti-IgE, anti-IL-5) Step 1 Step 2 Step 3 Step 4 Step 5 Preferred Controller Other Controller Options Reliever As needed short-acting beta2-agonist or low-dose ICS/LABA† As needed short-acting beta2-agonist Step therapy for adult patients with asthma adapted from the 2015 Global Initiative for Asthma guidelines.1 *Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations; it is not indicated in children younger than 18 years old. **For patients prescribed beclomethasone/formoterol or budesonide/formoterol. IL indicates interleukin; LTRA, leukotriene receptor antagonist; OCS, oral corticosteroid. *Tiotropium by soft-mist inhaler is indicated as add-on treatment for patients with a history of exacerbations; it is not indicated in children younger than 18 years old; †For patients prescribed beclomethasone/formoterol or budesonide/formoterol. Chipps BE, et al. Ann Allergy Asthma Immunol. 2017;118:133-142.

Therapeutic Options for Severe Asthma by Inflammatory Phenotype IgE (allergic) Eosinophilic Preferred: 3-month trial of anti-IgE (omalizumab)  determine responsiveness Alternatives: newer targeted biologics, or BT Preferred: 3-month trial of anti-IL-5 (mepolizumab, reslizumab, or benralizumab)  Alternatives: BT or newer biologics*† (currently in development) Preferred: Either biologic type with observation  switch if non-responsive Alternatives: BT Noneosinophilic/Non-IgE (allergic) Preferred: BT Alternatives: theophylline or biologics in development* Note: Although chronic OCS is an accepted therapy in the National Asthma Education and Prevention Program (NAEPP) and GINA guidelines, the panel recommends that all other therapies be considered prior to employing maintenance OCS. *Dupilumab; †Benralizumab. Blaiss MS, et al. Allergy Asthma Immunol. 2017;119(6):533-540.

Considerations for Long-term Asthma Management

Patient Education Review the status of the patient’s asthma control regularly Teach and reinforce at every opportunity Basic facts about asthma What defines well-controlled asthma and patient’s current level of control Roles of medications Skills (eg, inhaler technique, use of a spacer, self-monitoring) When and how to handle signs and symptoms of worsening asthma When and where to seek care Measures to prevent or limit exposure to asthma triggers Develop an active partnership with the patient and provide a written action plan Jones MA. Respir Care. 2008;53(6):778-84;discussion 784-6.

Patient-reported Topics Discussed During Routine Visits Topics discussed during routine visits with managing healthcare providers in the past 12 months (as reported by patients with severe asthma): Topic Patients (%) Current medications 65% Symptoms 44% Steps to better control symptoms 28% Daily life limitations 27% Technique used to take medication 24% Personal asthma action plan 17% Fears or feelings associated with asthma 13% Adapted from: Allergy & Asthma Network. OPEN Asthma Survey: Observations of Patient Experience in the Nation. Available at: http://allergyasthmanetwork.org/research/open-asthma-survey.

Summary Despite increased understanding of asthma pathophysiology and a corresponding expansion of available therapies, a subset of affected patients continue to report severe uncontrolled disease Many clinically important phenotypes and endotypes have now been identified and can provide valuable guidance in personalizing treatment for patients with severe asthma A wide range of targeted therapies have demonstrated good efficacy in the treatment of patients demonstrating different severe asthma phenotypes Severe asthma management should include implementation of strategies for improving disease awareness, increasing collaborative decision-making, and promoting self-management among patients to ensure optimal health outcomes

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