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Improving Control in Severe Asthma

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

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Improving Control in Severe Asthma

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

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

  3. 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

  4. Overview of Severe Asthma

  5. 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.

  6. Epidemiology of Uncontrolled Asthma 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.

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

  8. Definition of Severe Asthma

  9. 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.

  10. ATS/ERS (2014): Severe Asthma STEP 5 • 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 STEP 4 Refer for add-on treatment (eg, anti-IgE, anti-IL-5) STEP 3 Medium- or high-dose ICS/LABA STEP 2 Low-dose ICS/LABA STEP 1 Low-dose ICS Preferred Controller Medium to high-dose ICS or low-dose ICS and LTRA or low-dose ICS and theophylline Add tiotropium*; add low-dose OCS Consider low-dose ICS LTRAor low-dose theophylline Add tiotropium* or high-dose ICS and LTRA or high-dose ICS and theophylline Other Controller Options ATS, American Thoracic Society; ERS, European Respiratory Society; GINA, Global Initiative on Asthma; IgE, immunoglobin E; IL, interleukin; OCS, oral corticosteroid. As needed short-acting beta2-agonist (SABA) As needed SABA or low-dose ICS/LABA† Reliever *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.

  11. Identification of Patients with Severe Asthma

  12. 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.

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

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

  15. 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.

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

  17. Differential Diagnosis More Common Less Common 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 • Chronic obstructive pulmonary disease (COPD) • Gastroesophageal reflux disease (GERD) • Heart failure • Cystic fibrosis (CF) • Vocal cord dysfunction (VCD) ACE, angiotensin-converting enzyme. Chung KF, et al. Eur Respir J. 2014;43(2):343-373.

  18. Severe Asthma Phenotypes and Endotypes

  19. Asthma Is Not One Disease

  20. 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.

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

  22. Asthma 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.

  23. Asthma Phenotypes Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.

  24. 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

  25. 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.

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

  27. 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 FeNO, forced exhaled nitric oxide; NO, nitric oxide. Kim H, et al. AllergyAsthma Clin Immunol. 2017;13:48.

  28. Clinical Indications of FeNO 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.

  29. 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.

  30. Additional Biomarkers of Severe Asthma †Not commercially available. DPP-4, dipeptidyl peptidase-4. Kim H, et al. AllergyAsthma Clin Immunol. 2017;13:48.

  31. Case Evaluation: Discussion • How might biomarkers guide therapy?

  32. 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.

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

  34. Current Treatment Options

  35. 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?

  36. 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 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.

  37. 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?

  38. Targeted Biologic Therapies for Severe Asthma

  39. 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.

  40. Reduction in Asthma Exacerbation Rates in Low- and High-biomarker Subgroups FeNOEosinophilsPeriostin 40 20 0 –20 –40 –60 –80 <19.5 ppb ≥19.5 ppb <260/µL ≥260/µL <50 ng/mL ≥50 ng/mL –32 –9 –30 –53 –16 –3 Percent Reduction in Protocol-Defined Asthma Exacerbation Rate (mean, 95% CI) n=193 n=201 n=383 n=414 n=279 n=255 P=.45* P=.001* P=.54* P=.005* P=.94* P=.07* *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.

  41. Exacerbation Rates and FEV1 After 32 Weeks ofTreatment with Mepolizumab FEV1 Asthma Exacerbations 250 200 150 100 50 0 75 70 65 60 • Placebo • Mepolizumab 75 mg, intravenously • Mepolizumab 100 mg, subcutaneously Placebo FEV1 (% of Predicted Value) Mepolizumab 75 mg, intravenously Cumulative Number of Exacerbations Mepolizumab 100 mg, subcutaneously 0 0 4 8 12 16 20 24 28 32 Week 0 4 8 12 16 20 24 28 32 Week P<.001 for both comparisons. 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.

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

  43. IL-5-targeted Treatment with Benralizumab Reduces Exacerbations in Patients with Elevated Eosinophils 51%* 45%* 28%‡ 36%† CALIMA SIROCCO *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.

  44. 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 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 * † * † * † * † † * † * † * † Change From Baseline Least-Squares Means (L) Change From Baseline Least-Squares Means (L) 0 4 8 16 24 32 40 48 56 0 4 8 16 24 32 40 48 56 • 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.

  45. 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.

  46. Dupilumab Reduced Risk of Severe Exacerbation Independent of Baseline Blood Eosinophil Count Dupilumab, 200 mg Q2W vs. Matched Placebo 0.1 0.25 0.5 0.75 1 1.5 2 Placebo Better Dupilumab Better Q2W, every 2 weeks. Castro M, et al. New Engl J Med. 2018;378(26):2486-2496.

  47. Dupilumab Reduced Risk of Severe Exacerbation Independent of Baseline Blood Eosinophil Count Dupilumab, 300 mg Q2W vs. Matched Placebo 0.1 0.25 0.5 0.75 1 1.5 2 Placebo Better Dupilumab Better Castro M, et al. New Engl J Med. 2018;378(26):2486-2496.

  48. Change from Baseline FEV1 Over 52-week Treatment with Dupilumab 0.4 0.3 0.2 0.1 0.0 Least-Squares Mean Change from Baseline in FEV1 (liters) Dupilumab, 300 mg Dupilumab, 200 mg Placebo, 2.00 mL Placebo, 1.14 mL 0 2 4 6 8 10 12 16 20 24 28 32 36 40 44 48 52 Week 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.

  49. Dupilumab Reduces Oral Corticosteroid Use in Glucocorticoid-dependent Severe Asthma 0 –20 –40 –60 –80 Primary endpoint Percentage Reduction in Oral Glucocorticoid Dose Placebo Dupilumab P<.001 0 4 8 12 16 20 24 Week 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.

  50. Dupilumab Percent Reduction in Oral Steroid Use According to Blood Eosinophil Group 10 0 –10 –20 –30 –40 –50 Dupilumab Better Placebo 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.

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