Faculty Jonathan Corren, MD Clinical Associate Professor of

Faculty Jonathan Corren, MD Clinical Associate Professor of

Faculty Jonathan Corren, MD Clinical Associate Professor of Medicine and Pediatrics Divisions of Clinical Immunology and Allergy David Geffen School of Medicine at UCLA Los Angeles, California Michael E. Wechsler, MD Professor of Medicine Director, NJH Cohen Family Asthma Institute Department of Medicine National Jewish Health Denver, Colorado Faculty Disclosures Jonathan Corren, MD

Research Support: Genentech, AstraZeneca, Regeneron, Sanofi, Stallergenes Greer Consultant: Genentech, Novartis, Regeneron, Sanofi Speakers Bureau: Genentech, Novartis, AstraZeneca Michael Wechsler, MD Research Support: AstraZeneca, Novartis, Sanofi Consultant: AstraZeneca, Novartis, Teva, Boehringer Ingelheim,GlaxoSmithKline, Sanofi, Regeneron Learning Objectives Explain how phenotypic, endotypic, and genetic characteristics factor into severe asthma Compare and contrast biologic agents that are currently available or emerging in the treatment of severe asthma Identify patients who may benefit from the use of a biologic agent for severe asthma Employ a stepwise approach to incorporating novel, personalized biologic-based treatment plans for severe asthma into the real-world clinical setting

Phenotypes and Biomarkers In this module we discuss how phenotypic, endotypic, and underlying pathogenic mechanisms factor into severe asthma. We review the clinical differentiation of asthma subgroups and the characterization of inflammatory pathways and biomarkers, as well as its application to clinical practice. Clinical Differentiation of Asthma Into Subgroups Back to Asthma Basics Definition Airway hyperresponsiveness Airflow limitation, which is spontaneously variable or reversible with bronchodilators Diagnosis Based on a combination of clinical symptoms and physiologic abnormalities Does not rely on pathologic markers

Asthma is Not a Clinically Homogeneous Condition Multiple areas of difference: Clinical presentations Physiological characteristics Responses to therapy Time of asthma development is a key factor: Childrenrelatively homogeneous with a strong personal and family allergic history of atopy Adultsvery mixed group of patients Heterogeneity in Asthma Not a New Concept Spector SL, Farr RS. J Allergy Clin Immunol. 1976 May;57(5):499-511. . Basis for Disease is Present Early and

Evolves Throughout Life Genetics , environment Proteins, biochemical pathways, cells Physiology, symptoms Fitting the Individual Into a Larger Group What is a phenotype? The outward manifestation of a disease state related to both genetics and environmental influences What is an endotype? A phenotype of a disease state that has been well-characterized with regard to pathophysiologic mechanisms Separation of Asthma Into Clinical Phenotypes Unbiased hierarchical cluster analysis Clinical characteristics (gender, age of onset, severity)

Physiology (lung function, airway hyperresponsiveness) Triggers (allergens, tobacco, occupation) Sputum inflammatory cells (eosinophils, neutrophils) Sum total of characteristics are segregated into groups, with no single feature playing a predominant role in the classification Phenotypic Clusters in Adults With Asthma Show Significant Differences Cluster Age/Obesity Allergy Severity 1

Early Yes Mild 2 Early Yes Moderate 3 Late, obese

No Severe 4 Early Yes Severe 5 Late No Severe

Moore WC, et al. J Allergy Clin Immunol. 2010; 181:31523. Phenotypic Clusters in Children With Asthma Are Similar 4 clusters, all associated with: Prior or current atopic dermatitis Elevated total and specific IgE Comprise, a continuum based on: Number of controller medications Lung function eNO concentrations eNO, exhaled nitric oxide; IgE, Immunoglobulin E Fiztpatrick AM, et al. J Allergy Clin Immunol. 2011;127:382-389.e1-13. Phenotypes/Endotypes of Severe Asthma Phenotype

Clinical/Physiologic Characteristics Early-onset allergic History of food allergy, atopic dermatitis and allergic rhinitis Late-onset minimally atopic eosinophilic Chronic rhinosinusitis/nasal polyps Severe airway obstruction Subset = AERD Late-onset non-eosinophilic Poorly characterized

May have significant LRT infection and/or GERD AERD, Aspirin-exacerbated respiratory disease; eNO, exhaled nitric oxide; IgE, Immunoglobulin E; LRT, lower respiratory tract Wenzel SE. Nat Med. 2012;18:716-725. Trejo Bittar HE, et al. Ann Rev Pathol Mech Dis. 2015.10:511-545. Corren J. Discov Med. 2013;15:243-249. Characterization of Inflammatory Pathways and Biomarkers Type 2 (T2)50% to 70% Non-type 230% to 50% Main cytokines = IL-4, IL-5, IL-13 Cytokines and cells not well-characterized; may involve IL-17, GM-CSF Frequently related to bronchial infection

Cell sources = Th2 cells, IL-C2 cells, mast cells Variable airway, tissue and blood eosinophilia and eNO; leukotrienes in AERD Large portion have elevated total IgE and specific IgE No increase in eosinophils, eNO; may have increase in sputum PMNs Typically do not have elevated IgE or relevant specific IgE eNO, exhaled nitric oxide; GM-CSF, Granulocyte-macrophage colony-stimulating factor; IgE, Immunoglobulin E; PMN, polymorphonuclear; Th2, T helper 2 Utilization of Inflammatory Markers Inflammatory markers have been shown to play an important role in predicting severity and responsiveness to therapies Inflammatory profile may be characterized by:

Genotyping Cytokines Cell populations (in airway, tissue and blood) Exhaled gases (nitric oxide) Serum proteins (periostin, DPP4) DPP4, dipeptidyl peptidase-4 What Makes an Ideal Biomarker? Reproducible Accurate Accessible Correlates with severity of disease at baseline and reflects responsiveness to therapy Reasonable cost Noninvasive Eosinophil as an Inflammatory Biomarker Variable numbers of blood and airway eosinophils are present in patients with type 2 cytokine profiles

Likely relates to level of type 2 activation Eosinophils in blood and airway are correlated with: Frequency of asthma exacerbations Degree of airflow limitation Presence and severity of chronic rhinosinusitis/nasal polyposis Sputum and Blood Eosinophils Correlate With Bronchial Type-2 Cytokine mRNA Parameter Threshold Value Sensitivity Specificity Sputum eosinophils

2% 54% 100% 0.8% 84% 100% 230 cells/mcl 76% 100% Blood eosinophils

Peters SP, et al. J Allergy Clin Immunol. 2014;2(6):650-2. Blood Eosinophil Counts Correlate With Risk of Asthma Exacerbations Claims database analysis examining eosinophil count and exacerbations requiring systemic CS or ER/hospital care Eosinophil Stratum Severe Exacerbations Relative Risk 201300 cells per L (n=25,882) .8 301400 cells per L (n=15,030) 1.1

401500 cells per L (n=8659) 1.2 501600 cells per L (n=4928) 1.4 601700 cells per L (n=2726) 1.6 701800 cells per L (n=1631) 1.5 801900 cells per L (n=947) 1.6

9011000 cells per L (n=1019) 2.1 >1000 cells per L (n=1019) 2.4 Adapted from Price DB, et al. Lancet Respir Med. 2015;3:849-858. Blood Eosinophil Counts Correlate With Risk of Asthma Exacerbations Claims database analysis examining eosinophil count and exacerbations requiring systemic CS or ER/hospital care Eosinophil Stratum Severe Exacerbations Relative Risk

201300 cells per L (n=25,882) .8 301400 cells per L (n=15,030) 1.1 401500 cells per L (n=8659) 1.2 501600 cells per L (n=4928) 1.4 601700 cells per L (n=2726) 1.6

701800 cells per L (n=1631) 1.5 801900 cells per L (n=947) 1.6 9011000 cells per L (n=1019) 2.1 >1000 cells per L (n=1019) 2.4 Adapted from Price DB, et al. Lancet Respir Med. 2015;3:849-858.

Sputum Eosinophils Identify Patients With Frequent Asthma Exacerbations Parameter Non-frequent exacerbators Frequent exacerbators ICS dose (mcg/day) OCS dose (mg/day) ACQ Sputum eosinophils (percent) 800 1.7 1.4

8.2 1700* 6.7* 2.3* 25.7* *P<0.05 ACQ, asthma control questionnaire; ICS, inhaled corticosteroid; OCS, oral corticosteroid Kupczyk M. et al. Clin Exp Allergy. 2014;44(2):212-21. Sputum Neutrophil as an Inflammatory Biomarker Sputum neutrophilia (>60% of total WBC) present in subgroup of asthmatics Most often in combination with eosinophils but may occur as isolated neutrophilia Factors that influence PMN count in sputum:

Use of inhaled corticosteroids Air pollution Lower respiratory tract infection Sensitization to fungi Gastroesophageal disease Found to correlate with higher levels of asthma severity PMN, polymorphonuclear; WBC, white blood cells Serum Proteins Cytokine protein measurements in blood and sputum are difficult and may not be accurate Preferable to identify surrogate markers to indicate predominant cytokine profile in lung Airway IL-13 found to correlate with epithelial proteins periostin and

dipeptidyl peptidase-4 (DPP4): Secreted by airway epithelium into blood Initial studies showed good correlation with IL-13 and predictive of response to anti-IL-13 agents Uncertain whether these tests will be employed as biomarkers in the future Exhaled Nitric Oxide as a Marker of Type 2 Pathway eNO is produced by NO synthase in respiratory epithelium under direct control of IL-13 and possibly other factors Often, but not always, correlated with sputum/blood eosinophil numbers Is a moderately reproducible marker of Th2 phenotype (coefficient of variation 20%) Type 2 biomarkers predictive of responsiveness to ICS NO >33 ppb positive response to ICS NO <22 ppb successful discontinuation of ICS ICS, inhaled corticosteroid; eNO, exhaled nitric oxide; ppb, parts per billion

Treatment difference vs placebo in FEV1 (L) Blood Eosinophils Predicted Response to IL-5 Inhibition Baseline eosinophils count strata (cells/L) 0.3 0.25 0.2 0.15 0.1 0.05 0 <100 >100

<200 >200 Placebo n=16 n=65 n=37 n=44 n=54 n=27 n=68 n=13 Reslizumab n=62 n=282n=158n=186n=239n=105n=275n=69 P value .6537 .1202 .5122 .2401 .2579 .2818 .5422 .0436 Adapted from Corren J, et al. Chest. 2016;150(4):799-810. <300 >300 <400 >400

Summary Recent research has attempted to better describe and understand heterogeneity in asthma Clinical characteristics that differentiate phenotypes of asthma include age, gender, age of asthma onset, atopic status, obesity, exacerbation frequency, and NSAID sensitivity Employment of biomarkers has facilitated the use of new targeted therapies for type 2 asthma Discovery of new biomarkers in non-type 2 asthma will help address an important unmet need Novel Treatment Options In this module we review the latest biologic-based targeted therapies. Our discussion will differentiate between biologic agents, focusing on mechanism of action, as well as the latest safety and efficacy data of targeted therapy. Stepwise-Approach: Assess Adequate Use of ICS

and Consider Nonbiologic Add-on Therapy When confirming diagnosis of severe asthma, critical to: Assess inhaler technique and adherence Issues with ICS account for 50% to 80% of uncontrolled asthma Assess coexisting conditions, risk factors, and triggers Review FeNO after ICS therapy Israel E, et al. N Engl J Med. 2017;377:965-976. Inhaled Corticosteroids: First-Line Therapy for All Patients Convenient, inexpensive, safe drugs Broad mechanism of actionaffect eosinophils, lymphocytes, mast cells and dendritic cells Efficacious in majority of asthmatics, less effective in more severe patients: Mild70% Moderate50% Severe33%

Addition of other agents (LABA, LAMA, LTRA)is often beneficial and adds bronchodilation to the anti-inflammatory effects of ICS, reducing exacerbations and improving lung function LABA, long-acting beta2 agonists; LAMA, long-acting muscarinic antagonists; LTRA, leukotriene receptor antagonists ICS Add-On Therapy Corticosteroids (inhaled and oral)with or without LABA may offer only partial control in severe asthma Consider nonbiologic add-ons: LABA, tiotropium, macrolide, leukotriene modifier and bronchial thermoplasty Tiotropiumlong-acting muscarinic antagonist Shown to increase lung function and time to first exacerbation Consider risk and benefits [lower cost than biologics] Bronchial thermoplasty Approved 2010; bronchoscopic treatment targeting airway smooth muscle with radio-frequent energy

Assess for targeted treatment with biologic agents Current Standard Treatments Poor response to ICS can lead to increased doses but there is a limited dose response; In those circumstances, many doctors still give oral corticosteroids such as prednisone Avoid daily OCS CS associated with systemic toxicity, including: Adrenal insufficiency Weight gain Hypertension Cataracts

Glaucoma Osteoporosis CS, corticosteroids; OCS, oral corticosteroids Wechsler ME. Respir Care. 2018;63:699-707; Bagnasco D, et al. Front Med. 2017;4:135; Cazzola M, et al. Expert Opin Drug Saf. 2018;17:429-435; Israel E, et al. N Engl J Med. 2017;377:965-976. Understanding Pathogenic Mechanism Study of pathophysiology of asthma, especially type 2 and eosinophilic inflammation led to latest targeted interventions Targeted therapies shown to reduce number of exacerbations 4 approved, type-2 targeted-biologic therapies that target IL-5 and IgE and one that is in development IL-4/-13 Importance of understanding Type 2 cytokines: IL-4, IL-5, IL-13 IL-5, Interleukin 5; IL-5Ra, Interleukin 5 receptor ; Th2, T helper 2 lymphocytes Bagnasco D, et al. Front Med. 2017;4:135; Farne HA, et al. Cochrane Database Syst Rev. 2017;9:CD010834. Targeted Pathways for Biologic Therapies

Targeted Pathways IgE IL-5 Inhaled allergens stimulate production of IgE by B lymphocytes and bind to mast cellsdegranualation Pro-eosinophilic cytokine; cytokine that regulates proliferation, maturation, migration, and effector functions of eosinophils IL-13 Cytokine found in increased levels in airways and sputum of asthma patients and involved in eosinophil trafficking and B cell production of IgE Cytokine associated with eosinophil trafficking and production of eNO from epithelial cells TSLP Novel target; epithelial-cell-derived cytokine; drives allergic inflammatory responses by activating dendritic cells and mast cells

IL-4 Non Type 2 Inflammatory Pathways IL-17 Cytokine produced by Th17 cells; plays important role in the immunologic responses seen in asthma CXCR2 Potent chemo-attractant for neutrophils; under investigation in asthma and COPD CSCR2, Chemokine receptor 2; IgE, Immunoglobulin E; Th2, T helper 2 cells; TSLP, Thymic stromal lymphopoietin Wechsler ME. Respir Care. 2018;63:699-707. Approved Biologics and Targets Target Antigen IL-5Ra

IL-5 Agent (FDA Approved) Mode of Delivery Benralizumab (Nov 2017) Injectable Reslizumab (April 2017) Intravenous (3 mg/kg)

monthly Safety and Adverse Events Safe and well tolerated. Most common AEs: nasopharyngitis; asthma worsening (CALIMA: 14% Q4W group, 11% Q8W, 15% placebo arm) (SIORCCO: 13% vs 19% of placebo-treated) Safe and well tolerated in patients exposed >2 yr 3 Clinical Data Trial Results Approved for use in eosinophilic asthma. For patients with blood

eosinophil count of at least 300/mL. CALIMA trial (n=1306): Q4W & Q8W regimens decreased exacerbations by 36% and 28%, respectively; lowered blood counts1 SIROCCO trial (n=1,205): 48 weeks 1 of 3 addon SQ; exacerbations reduced 45% & 51% in Q4W and Q8W; Exacerbations decreased 17%30% in patients with >300 blood eosinophils/LL2 Approved for maintenance treatment w/severe exacerbations, despite on Infusion-site reactions uncommon (<2%). current asthma Most common AEs: nasopharyngitis, upper medications. respiratory tract infections, sinusitis, influenza, For patients with blood

and headache. SAEs more frequent in placebo eosinophil count of at least grp. No helminthic infestations reported. 2 in 400/mL. reslizumab grp anaphylactic reactions, but negative for ADAs. Further research needed in special population. BREATH program: 4 studies (n=1656), serum eosinophil counts reduced (mean diff vs placebo: 476.83, 95% CI 499.32 to 454.34)3 Reduced number of eosinophils in the blood and lungs; decreased blood eosinophils.3 Asthma Control Questionnaire 5 (ACQ5); LABA, long-acting -agonists; LD, loading dose; mL, microliter; SQ, subcutaneous; QoL, quality of life 1. Fitzgerald JM, et al; Lancet. 2016;388:21282141. 2.Bleecker ER, et al. Lancet. 2016;388:21152127. 3. Cazzola M, et al. Expert Opin Drug Saf. 2018;17:429-435. Approved Biologics and Targets (continued)

Target Antigen Agent (FDA approved) Mode of Delivery Injectable IL-5 Mepolizumab (Nov 2015) anti-IgE Ab Omalizumab

(2003) Injectable Safety and Adverse Events Safe and well tolerated Most common AEs and SAEs: injection-site reactions (12%), infections (7%), systemic reactions (3%), serious cardiac, vascular, thromb events (3%); malignancies (2%), serious ischemic events (<1%) AEs (80.4% vs 79.5%) and SAEs (9.3% vs 10.5%) were similar in the omalizumab and placebo groups, respectively. Note concerns about anaphylaxis and cardiovascular risk and lack of efficacy in some patients

Anti-IL-4/ -13 Dupilumab Injectable (FDA approved for asthma indication October 19, 2018.) Safe and well tolerated. AEs similar across groups: injectionsite reactions (17% vs 8% placebo, respectively), back pain (4%, both groups), eosinophilia (4% vs 1%, respectively). Clinical Data

Trial Results First long-term safety data reported for IL-5; Approved for patients with blood eosinophil count of at least 150/mL. COLUMBA trial (n=347): Pts treated w/100 mg SQ every 3-4 wks for 3.54.5 yrs; 61% decrease in exacerbation rate, 78% reduction in blood eosinophils by wk 4, sustained; 1/3 experienced no exacerbations; ACQ5 improved.1 Dream study: reduced exacerbations by 40-60%; 50% reduction in CS. Blood eosinophil counts decline by 75% within a month, failure to achieve decrease raises questions about biologic efficacy in patient; FeNO minimally reduced. 2,3 Hanania et al. (n=850): 48 wks decreased exacerbations 25%; improved asthma QoL scores. Overall trial history: reduced asthma exacerbations, serum-free IgE, ICS dose; QOL improved.4

Approved for patients with total serum IgE level >30 IU/ mL; for moderate-to-severe persistent allergic asthma whose asthma symptoms are not controlled by ICS. MoA: Binds to free IgE; prevents IgE from binding to high-affinity receptors Approved for patients with asthma previously treated with medium-dose or high-dose ICS and LABAs. Consider for patients with allergies , elevated IgE, eosinophilia, or high eNO levels.

Quest trial (n=1902); 4 grps 200 mg (400 mg LD) and 300 mg (600 mg LD) every other week; 6080% reduction in exacerbations; Reduced FeNO and IgE levels;. Improved lung function and reduced dependence on OCS. 5,6 1. Ortega H, et al. Presented at ATS 2018. Abstract A1367; 2. Bel EH, et al. N Engl J Med. 2014;371:1189-97; 3. Pavord ID, et al. Lancet. 2012; 380:651-9; 4.Hanania NA, et al. Ann Intern Med. 2011;154:573-82; 5. Castro M, et al. N Engl J Med. 2018;378:2486-2496; 6. Wenzel S, et al. Lancet. 2016;388:31-44. Farne et al Cochrane Review 13 studies reviewed Cochrane database; n=6000 Compared agents targeting anti-IL-5 or anti-IL-5R (i.e., mepolizumab, reslizumab, and benralizumab) against placebo Showed all IL-5 therapies reduced rates of clinically significant asthma exacerbation by ~50% in group with severe eosinophilic asthma Supports use of anti-IL-5 treatments as an adjunct to standard of care in people with severe eosinophilic asthma and poor control Noted limited evidence for improved HRQoL scores and lung function Farne HA, et al. Cochrane Database Syst Rev. 2017;9:CD010834.

Bronchial Thermoplasty Method to decrease smooth muscle mass by applying excess heat in the airways with radio-frequent energy Note: little understood regarding appropriate patient selection Asthma Intervention Research2 (AIR2) Trial n=288 adults Safe therapy Study shown to improve asthma quality of life and reduce exacerbations 5 year long-term study showed sustained reduction in exacerbations, ER visits and hospitalizations Real world studies have shown sustained efficacy out to 3 years Goorsenberg AWM, et al. Respiration. 2018:1-7. Summary Asthma therapy has evolved More targeted therapies targeting specific pathways Importance of evaluating endotypes for asthma to identify: Type-2 inflammation or non-type-2 inflammation

Eosinophilic asthma or non-eosinophilic asthma IgE-mediated asthma or non-IgE-mediated asthma Use of biomarkers to identify appropriate therapies Treatment Strategies Discussion This module discusses select biological-based therapies for severe asthma based on phenotype and endotype. Dr. Corren and Dr. Wechsler also discuss optimal treatment regimen based on asthma severity. What are the strategies to maximize standard medical therapies in asthma management? Allergen avoidance Allergy immunotherapy Biologics (novel therapies) Bronchial Thermoplasty What is your approach to treating patients with severe asthma?

Treat with personalized approach Identify asthma type by phenotype or endotype Treat with the most appropriate therapeutic strategy based on underlying asthmatic mechanism of inflammation What can we achieve with biologics? Reduced exacerbation Reduced steroid dose and side effects Improved symptoms and quality of life Disease modification to prevent asthma over long term Which therapy is best for a specific patient? How do you choose between biologics? Biomarkers help predict therapeutic responses Phenotype patients and choose most appropriate therapy Goal of personalized or precision medicine Potential need to measure different biomarkers to determine endotype/phenotype

George L, et al. Ther Adv Chronic Dis. 2016;7:34-51. What are the long-term health risks with biologic therapy? Real, long-term consequences of eosinopenia are not known Do not know if biologics provides long-term safe control of severe refractory eosinophilic asthma Cazzola M, et al. Expert Opin Drug Saf. 2018;17(4):429-435. On the Horizon In this module we discuss specific therapies in development. We will address persistent questions in the treatment of severe asthma, such as long-term treatment of biologics and the potential of combination therapy. And well provide summary takeaways. Additional Nonbiologic Treatment Options Active against atypical bacteria and have anti-inflammatory activity Macrolide antibiotics, add-on therapy: azithromycin (oral)

Ketolide antibiotic: telithromycin Gibson PG, et al. Lancet. 2017;390(10095):659-668. AMAZES Study Effect of azithromycin on asthma exacerbations N=420 Randomly assigned (1:1) to receive azithromycin 500 mg or placebo 3 times per week for 48 weeks Azithromycin reduced asthma exacerbations; significantly improved asthma-related quality of life Reported beneficial in eosinophilic and noneosinophilic subtypes Gibson PG, et al. Lancet. 2017;390(10095):659-668. TezepelumabPhase 2b Clinical Trial Data Tezepelumab, TSLP inhibitor Study (n=584) showed reduced blood eosinophil counts, FeNO levels, and total

serum IgE levels Low dose (70 mg once every 4 weeks), medium dose (210 mg once every 4 weeks), or high dose (280 mg once every 2 weeks) Reduced exacerbations across all patient groups both type 2 and non-type asthma by ~70% More Patients in tezepelumab groups were demonstrated to achieve wellcontrolled (27.2% in tezepelumab overall vs 14.9% in placebo) or partially controlled (22.0% in tezepelumab overall vs 19.1% in placebo) asthma at 52 weeks vs placebo Recruiting patients for tezepelumab, phase 3 (ClinicalTrials.gov; NCT03347279) IgE, Immunoglobulin E; TSLP, thymic stromal lymphopoietin; AAAAI, American Academy of Allergy, Asthma & Immunology; WAO, World Allergy Organization Corren J, et al. N Engl J Med. 2017;377(10):936-946. Corren J, et al. J Allergy Clin Immunol. 2018;141(2):AB80. ClinicalTrials.gov; NCT02054130. Emerging Target-Specific Therapies CRTh2 oral inhibitors in development Fevipiprant, ARRY 502, BI-671800, OC000459 Promising results in cellular, functional, clinical outcomes; acceptable safety Shows decrease in PGD2-mediated eosinophil migration Improve lung function and symptoms in patients with eosinophilic asthma CxCR2 antagonist decreases IL-8 levels; shown promise in early trials

Navarixin reduced sputum and blood neutrophils; trend toward better asthma control based on ACQ, but no significant change in FEV1 IL-6potential biomarker of systemic inflammation along with C-reactive protein; shown to be increased in a subset of patients with severe asthma, particularly severe asthma associated with obesity IL-17 Brodalumab didnt achieve clinical benefit but perhaps not the right patients were selected IL-33no data yet, but in clinical development IL-25no data, yet ACQ, Asthma Control Questionnaire; CRTh2, chemoattractant receptor homologue expressed on Th2 cells (alternative name DP2); FEV 1 , forced expiratory volume in one second; PGD2, Prostaglandin D2 George L, et al. Ther Adv Chronic Dis. 2016;7:34-51; Santus P, et al. Expert Opin Investig Drugs. 2016;25(9):1083-92; Naik SP, et al. J Asthma. 2017;54(6):584-593. Persistent Questions How do we decide between biologics that target same pathways? How do we decide between biologics for patients that meet criteria for different therapies? How long should we treat? Should we be combining biologics? Should we be giving biologics earlier in treatment paradigm?

Future Research Needed Determine optimal duration of biologics Long-term safety effects of treatment Risk of relapse on withdrawal More research on biomarkers to assess treatment response and identification of newer biologics Effects of treatment on non-eosinophilic patients Comparing anti-IL-5 treatments Takeaways Today we have a better understanding of underlying disease mechanisms Use biomarkers and endotypes to personalize treatment approach Advances in treatment of severe asthma include: Evidence-based treatment guidelines Evidence about phenotypic patterns Increased understanding of biomarkers and use in treatment selection

Screen patients to choose the right therapy for the right patient Biomarkers are needed to identify most appropriate therapeutic strategy to a specific patient

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