Clearing the Air in Severe Asthma Management

Jonathan Corren, MD Associate Clinical Professor of Medicine and Pediatrics David Geffen School of Medicine at UCLA Director, Allergy Medical Clinic Los Angeles, California

John J. Oppenheimer, MD Clinical Professor of Medicine Rutgers New Jersey Medical School Newark, New Jersey Clinician, Atlantic Health System Morristown Medical Center Morristown, New Jersey

Reynold A. Panettieri, Jr, MD Professor of Medicine Robert Wood Johnson Medical School Vice Chancellor, Translational Medicine and Science Director, Rutgers Institute for Translational Medicine and Science New Brunswick, New Jersey Emeritus Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Dr. Corren completed a fellowship in allergy and immunology at the National Jewish Center for Immunology and Respiratory Medicine in 1990, where he also served as a faculty member and clinical investigator for 2 years. He subsequently joined the faculty at the University of California-Los Angeles (UCLA) School of Medicine and served as Director of Clinical Allergy Services at the UCLA Center for Health Sciences, the Nasal and Sinus Disease Center, and the Fellowship Training Program in Clinical Immunology and Allergy. He is currently a faculty member in the Departments of Medicine and Pediatrics at UCLA and has a private practice, where he performs clinical consultations and conducts clinical trials and transitional research primarily related to the role of cytokine inhibition in allergic diseases, new methods of allergy immunotherapy, and development of new provocational models for studying allergic rhinitis.

Dr. John Oppenheimer is the Director of Clinical Research at Pulmonary and Allergy Associates and Clinical Professor of Medicine at the Rutgers New Jersey Medical School. He is board certified in internal medicine and allergy and immunology. He trained and was on faculty at the National Jewish Center in Denver, Colorado.

Dr. Oppenheimer has participated in more than 100 clinical studies and more than 180 publications.

Dr. Panettieri is Professor of Medicine at Robert Wood Johnson Medical School and Vice Chancellor for Translational Medicine and Science and the Director of the Institute for Translational Medicine and Science at Rutgers University. Previously, he was the Robert L. Mayock and David A. Cooper Professor of Medicine in the Pulmonary, Allergy and Critical Care Division of the Department of Medicine and served as Deputy Director of the Center of Excellence in Environmental Toxicology at the University of Pennsylvania Perelman School of Medicine, where he is Professor Emeritus.

Dr. Panettieri’s basic science interests focus on airway smooth muscle function in asthma and the molecular and cellular mechanisms of airway smooth muscle function and growth. His lab also focuses on cytosolic signaling pathways that mediate gene expression and alter myocyte function. He is principal investigator on several National Institutes of Health (NIH)-sponsored grants and industry-sponsored clinical studies and is director of a program project grant examining novel approaches in modulating G-protein-coupled receptor function. He is the author of more than 475 peer-reviewed publications. Dr. Panettieri is the recipient of numerous honors and awards, including the Robert E. Cooke Memorial Lectureship at the American Academy of Allergy, Asthma and Immunology annual meeting, the Joseph R. Rodarte Award for Scientific Distinction, and the Recognition Award for Scientific Accomplishments from the American Thoracic Society (ATS). He is also an active member of national professional and scientific societies, including the American College of Chest Physicians and the ATS. In 2013, he was elected Chairman of the Respiratory Structure and Function Assembly of the ATS. In addition to his research and clinical interests, Dr. Panettieri served as chair of the NIH Lung Cellular, Molecular, and Immunobiology Study Section, is a member of the NIH Distinguished Editorial Panel, and is a member of the American Society for Clinical Investigation and the Association of American Physicians.

Sally E. Wenzel, MD Professor of Medicine and Immunology Chair, Department of Environmental and Occupational Health Graduate School of Public Health Director, University of Pittsburgh Asthma Institute at UPMC/UPSOM UPMC Chair of Translational Airway Biology Pittsburgh, Pennsylvania

Dr. Sally Wenzel completed her medical degree at the University of Florida. Following her residency in internal medicine at Wake Forest University and her fellowship in pulmonary and critical care medicine at Virginia Commonwealth University, she spent 19 years at National Jewish and the University of Colorado before moving to the University of Pittsburgh. She received the Elizabeth Rich Award for her role in promoting women in science, the American Thoracic Society (ATS) Award for Scientific Achievement, the ATS Foundation Breathing for Life Award, and the European Respiratory Society President’s Award. She is currently Director of the University of Pittsburgh Asthma Institute at the University of Pittsburgh Medical Center and Chair of the Department of Environmental and Occupational Health at the Graduate School of Public Health, University of Pittsburgh. Dr. Wenzel has served as Deputy Editor for the American Journal of Respiratory and Critical Care Medicine and is a frequent reviewer for The New England Journal of Medicine and other publications.

Dr. Wenzel has a passion for understanding and improving the treatment of asthma, in particular severe asthma. She has promoted severe asthma as a complex disease and her studies of asthma phenotypes have led the field in understanding these complexities. Dr. Wenzel has developed a strong translational program to study the pathobiology of severe asthma and its phenotypes, modeling ex vivo findings in vitro, using primary human airway cells from patients and controls.

TARGET AUDIENCE

The educational design of this activity addresses the needs of clinical immunologists, allergists, and other specialists involved in the management of patients with severe asthma.

EDUCATIONAL OBJECTIVES

Upon completion of this activity, participants will be better able to • Discuss asthma pathophysiology, including Th2-mediated processes and clinically relevant treatment targets • Implement guideline recommendations related to the identification, comprehensive assessment, and longitudinal management of patients with severe asthma • Describe the mechanistic rationale, published evidence, and prescribing considerations for biologic therapies in severe asthma • Tailor therapeutic regimens for patients with severe asthma based on disease phenotypes, ongoing symptoms and exacerbation risks, treatment-related toxicities, and comorbidities • Engage patients with severe asthma in long-term management planning to reflect treatment goals, clinical and laboratory findings, and potential benefits and risks of available therapeutic options

STATEMENT OF NEED/PROGRAM OVERVIEW

An outsized proportion of asthma-related morbidity and mortality is borne by the 5% to 15% of affected patients who have severe forms of the disease.1,2 These patients suffer from poorly controlled symptoms and frequent exacerbations, often despite daily treatment with high-dose inhaled corticosteroids and other long-acting controller medications.1,2 Ongoing research has elucidated key pathophysiologic processes and other clinical parameters related to asthma severity and persistence.2,3 In many cases, the patient’s medical history, clinical presentation, and results from biomarker testing can help classify severe asthma phenotypically.2,3 Increasingly, this can allow physicians to personalize maintenance regimens using targeted therapies that reflect identified endotypes—ie, asthma phenotypes linked to specific underlying disease mechanisms and proinflammatory signaling cascades.2,4,5 Several biologic medications are now available to treat certain cohorts with severe asthma, and other targeted agents are in late-stage development.5-8 Clinical immunologists, allergists, and other specialists who manage patients with severe asthma need to stay current on the latest published trial data for newer targeted therapies, approvals from the US Food and Drug Administration, and actionable best-practice recommendations on evaluating and treating patients with severe asthma. During this Interactive Exchange™ program, a panel of expert faculty will present updates on advances in our understanding of severe asthma pathophysiology and

comprehensively evaluating and longitudinally managing patients with severe asthma, including how the evolving evidence base and individual patient preferences should shape clinical decision making.

REFERENCES

1. Levy ML. The national review of asthma deaths: what did we learn and what needs to change? Breathe (Sheff). 2015;11(1):14-24.

2. Chung KF, Wenzel SE, Brozek JL, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43(2):343-373.

3. Wan XC, Woodruff PG. Biomarkers in severe asthma. Immunol Allergy Clin North Am. 2016;36(3):547-557.

4. Lötvall J, Akdis CA, Bacharier LB, et al. Asthma endotypes: a new approach to classification of disease entities within the asthma syndrome. J Allergy Clin Immunol. 2011;127(2):355-360.

5. Fajt ML, Wenzel SE. Asthma phenotypes and the use of biologic medications in asthma and allergic disease: the next steps toward personalized care. J Allergy Clin Immunol. 2015;135(2):299-310.

6. Chipps BE, Corren J, Israel E, et al. Asthma yardstick: practical recommendations for a sustained step-up in asthma therapy for poorly controlled asthma. Ann Allergy Asthma Immunol. 2017;118(2):133-142.

7. Wu AY, Sur S, Grant JA, Tripple JW. Interleukin-4/interleukin-13 versus interleukin-5: a comparison of molecular targets in biologic therapy for the treatment of severe asthma. Curr Opin Allergy Clin Immunol.

2019;19(1):30-37.

8. Corren J, Parnes JR, Wang L, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med. 2017;377(10):936-946.

DISCLOSURE OF CONFLICTS OF INTEREST

It is the policy of Integritas Communications that all faculty, instructors, and planners disclose any real or apparent conflicts of interest relating to the topics of this educational activity.

The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this activity: Jonathan Corren, MD Speakers Bureau: AstraZeneca; Genentech, Inc.; Regeneron Pharmaceuticals, Inc., sanofi-aventis U.S. LLC; Consultant/Advisor: AstraZeneca; Genentech, Inc.; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC; Pulmatrix; Research Grant: AstraZeneca; Genentech, Inc.; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC; Stallergenes Greer plc John J. Oppenheimer, MD Consultant/Independent Contractor: AstraZeneca; DBV Technologies; GlaxoSmithKline; Sanofi; Grant/Research Support: AstraZeneca; Novartis Reynold A. Panettieri, Jr, MD Nothing to disclose Sally E. Wenzel, MD Consultant/Advisor: AstraZeneca; sanofi-aventis U.S. LLC; Pieris; Research Grant: AstraZeneca; GlaxoSmithKline; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC

NON-FACULTY

Julia Muino; Rose O’Connor, PhD, CHCP; and Jim Kappler, PhD, hereby state that neither they nor their spouses/life partners have any financial relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months.

DISCLOSURE OF UNLABELED USE

This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Integritas Communications and Sanofi Genzyme and Regeneron Pharmaceuticals do not recommend the use of any agent outside of the labeled indications.

DISCLAIMER

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management.

Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

Disclosures • Jonathan Corren, MD – Speakers Bureau: AstraZeneca; Genentech, Inc.; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC – Consultant/Advisor: AstraZeneca; Genentech, Inc.; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC; Pulmatrix – Research Grant: AstraZeneca; Genentech, Inc.; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC; Stallergenes Greer

• John J. Oppenheimer, MD – Consultant/Independent Contractor: AstraZeneca; DBV Technologies; GlaxoSmithKline; sanofi-aventis U.S. LLC – Grant/Research Support: AstraZeneca; Novartis

• Reynold A. Panettieri, Jr, MD – Speakers Bureau: AstraZeneca; Boehringer-Ingelheim; Novartis Pharmaceuticals Corporation; Teva Pharmaceutical Industries Ltd. – Consultant/Advisor: AstraZeneca; MedImmune, LLC; Novartis Pharmaceuticals Corporation.

– Research Grant: AstraZeneca; Genentech, Inc.; MedImmune, LLC; NIH; OncoArendi Therapeutics SA; RFIM; sanofi-aventis U.S. LLC; Theratrophix, LLC.

• Sally E. Wenzel, MD – Consultant/Advisor: AstraZeneca; sanofi-aventis U.S. LLC; Pieris – Research Grant: AstraZeneca; GlaxoSmithKline; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC

Educational Objectives • Discuss asthma pathophysiology, including Th2-mediated processes and clinically relevant treatment targets • Implement guideline recommendations related to the identification, comprehensive assessment, and longitudinal management of patients with severe asthma • Describe the mechanistic rationale, published evidence, and prescribing considerations for biologic therapies in severe asthma • Tailor therapeutic regimens for patients with severe asthma based on disease phenotypes, ongoing symptoms and exacerbation risks, treatment-related toxicities, and comorbidities • Engage patients with severe asthma in long-term management planning to reflect treatment goals, clinical and laboratory findings, and potential benefits and risks of available therapeutic options Th2, T helper 2.

ADVANCES IN SEVERE ASTHMA PATHOPHYSIOLOGY Dr Wenzel

Normal Airway Smooth-muscle hyperresponsiveness

Hyperresponsiveness, remodeling, mucus production, and smooth-muscle constriction and hypertrophy

Smooth-muscle constriction Lumen

Lumen Smooth-muscle hypertrophy

Mucus production

Exacerbations Symptoms Airway narrowing

Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation.

Wheezing, shortness of breath, chest tightness, and cough can vary over the disease course.

Pathophysiologic Mechanisms of Severe Asthma Type 2 Inflammation

Non–Type 2 Inflammation

Irritants, pollutants, microbes, and viruses

Antigens

TSLP

CRTh2

IL-33

IL-13

Th2 cell

ILC2

IL-4, IL-5, IL-13

GATA3

B cell

IL-25

IL-4

GM-CSF Leukotrienes

GATA3 IL-5

CRTh2

Mast cell

Histamine IL-3, IL-4, IL-5, IL-9

CXCL8

TGF-β

GM-CSF

IL-23

Th17 cell

CRTh2

TNF

IL-17

CXCR2

IL-8 Lipoxin

Eosinophil

Th1 cell

IFN-γ

IL-6

PGD2

IgE

IL-6

Leukotrienes B4

BLT2 ALX

Neutrophil

ALX, lipoxin A4 receptor; BLT2, leukotriene B receptor 2; CRTh2, chemoattractant receptor homologue from Th2 cells; CXCL8, CXC motif chemokine ligand 8; CXCR2, CXC motif chemokine receptor 2; GATA3, GATA binding protein 3; GM-CSF, granulocyte–macrophage colony-stimulating factor; IFN-γ, interferon gamma; IgE, immunoglobulin E; IL, interleukin; ILC2, innate lymphoid cells; PGD2, prostaglandin D2; TSLP, thymic stromal lymphopoietin; TGF-β, transforming growth factor beta; Th, T helper; TNF, tumor necrosis factor.

Adapted from Israel E, Reddel HK. N Engl J Med. 2017;377(10):965-976.

Asthma Phenotype vs Endotype • Phenotype – Observable characteristics in an individual that result from interactions of a genotype with the environment

• Endotype – A specific biologic mechanism that explains an observable characteristic of an organism

Different asthma phenotypes and endotypes may respond differently to various targeted therapies.

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

Asthma Clinical Phenotypes Category

Phenotype

Trigger-induced asthma

1.

2.

3.

4.

5.

Clinical presentation of asthma

6. Preasthma wheezing in infants a. Episodic (viral) wheeze b. Multi-trigger wheezing 7. Exacerbation-prone asthma 8. Asthma associated with apparent irreversible airflow limitation

Inflammatory markers of asthma

9. Eosinophilic and neutrophilic asthma

AERD, aspirin-exacerbated respiratory disease.

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

Allergic Nonallergic AERD Infection Exercise-induced

Asthma Molecular Phenotypes Inflammatory Markers

• Type 2 asthma – Eosinophilic – High nitric oxide – High IgE – Mediated by IL-4, IL-5, and IL-13

• Non–type 2 asthma – Neutrophilic – Mediated by IL-1, IL-6, IL-17, and TNF

IgE, immunoglobulin E; IL, interleukin; TNF, tumor necrosis factor.

Chung KF, et al. Eur Respir J. 2014;43(2):343-373; Kim H, et al. Allergy Asthma Clin Immunol. 2017;13:48.

Severe Asthma

Clinical Heterogeneity • Clustering approaches applied to 112 clinical, physiologic, and inflammatory variables from 378 SARP patients yielded 6 subpopulationsa 1.

2.

3.

4.

Mild asthma, normal lung function, no symptoms Predominantly mild allergic asthma, early onset Early-onset atopic asthma, predominantly Hispanic women with high symptom burden Predominantly women with high body mass index, early onset, frequent symptoms, with possible genetic predisposition 5. Mostly severe asthma, later age at onset, with nasal polyposis, sinusitis, and high-dose inhaled corticosteroid (CS) use 6. Only severe asthma, early onset, high oral CS use, lowest lung function, most symptoms, sinusitis

Patients in distinct asthma subpopulations may respond differently to asthma treatment. aPatients

in the Severe Asthma Research Program (SARP) cohort (N=726) with persistent asthma.

Wu W, et al. J Allergy Clin Immunol. 2014;133:1280-1288.

40 20 0

FeNO, fractional exhaled nitric oxide; SARP, Severe Asthma Research Program.

Wu W, et al. J Allergy Clin Immunol. 2014;133:1280-1288.

2

3

4

5

6

Number of Skin Reactions to Allergens

60

1

12 8 4 0

Subject Clusters No

100 80 60 40 20 0 1

2

3

Yes

4

5

6

Subject Clusters

1

2

3

4

5

6

Subject Clusters Exhaled NO, Parts Per Billion

Asthma Symptoms Caused by Animal Exposure, %

• >350 patients from SARP with bronchoscopic data • Clusters included 5 with asthma and 1 healthy control • 3 distinct clusters of earlyonset allergic asthma (2-4) of worsening severity • Severe disease associated with marginally less atopy, but persistent FeNO increases

Age Asthma Onset

More Severe Allergic/Early-Onset Phenotypes Seen Across Clusters

250 200 150 100 50 0 1

2

3

4

5

6

Subject Clusters

Late-Onset Type 2 High Disease

20 0 1

2

3

4

5

6

Number of Skin Reactions to Allergens

40

12 8 4 0

Subject Clusters No

100 80 60 40 20 0 1

2

3

Yes

4

5

6

Subject Clusters AERD, aspirin-exacerbated respiratory disease; FeNO, fractional exhaled nitric oxide.

Wu W, et al. J Allergy Clin Immunol. 2014;133:1280-1288.

1

2

3

4

5

6

Subject Clusters Exhaled NO, Part Per Billion

– Nasal polyposis most common in adult-onset cluster – Associated with AERD, but not a necessary element – High eosinophil and FeNO levels, consistent with type 2 disease

60

Had Surgery to Remove Nasal Polyps, %

• Adult-onset cluster easily identified

Age Asthma Onset

Nasal Polyposis and Eosinophilia

250 200 150 100 50 0 1

2

3

4

5

6

Subject Clusters

Seeking Personalized Therapy

The Role of Biomarkers in Asthma Phenotyping Blood eosinophils

FeNO

IgE

FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E. Kim MA, et al. Curr Opin Allergy Clin Immunol. 2014;14(1):49-54; Chung KF, et al. Eur Respir J. 2014;43(2):343-373; Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. www.ginasthma.org. Accessed February 10, 2019.

Blood Eosinophils • Eosinophilic airway inflammation is often found in patients with asthma • Blood eosinophils can be a surrogate marker for eosinophilic inflammation in the airway • Studies suggest blood eosinophil counts as low as 150 cells/μL may predict positive treatment response to certain targeted therapies

IL-5

IL-4

Th2 cell

IL-5 IL-13 Eosinophil trafficking to tissues Eosinophil differentiation

IL, interleukin; Th, T helper.

Douwes J, et al. Thorax. 2002;57(7):643-648; Eltboli O, Brightling C. Expert Rev Respir Med. 2013;7(1):33-42; Ortega HG, et al. Lancet Respir Med. 2016;4(7):549-556; Wagener A, et al. Thorax. 2015;70(2):115-120.

FeNO • Nitric oxide is produced by the lung and present in exhaled breath • Patients with asthma can have high FeNO in their exhaled breath • ↑ FeNO in SA, especially patients on OCS, is a potential biomarker for refractory disease

FeNO Levels

High >50 ppb in adults >35 ppb in children

Medium 20-50 ppb in adults 20-35 ppb in children

Low <25 ppb in adults <20 ppb in children

Clinical Implications Likely eosinophilic inflammation and CS responsiveness Cautious interpretation necessary Less likely eosinophilic inflammation or corticosteroid responsiveness

CS, corticosteroid; FeNO, fractional exhaled nitric oxide; IL, interleukin; ppb, parts per billion; SA, severe asthma; OCS, oral corticosteroid; Th, T helper.

Alving K, et al. Eur Respir J. 1993;6(9):1368-1370; Dweik RA, et al. Am J Respir Crit Care Med. 2011;184(5):602-615; Kharitonov SA, et al. Lancet. 1994;343(8890):133-135; Medrek SK, et al. Curr Allergy Asthma Rep. 2017;17(10):69; Wysocki K, et al. J Allergy Clin Immunol. 2014;133(3):915-918.

Immunoglobulin E • Elevated IgE levels can predict asthma diagnosis in some patients1,2 • IgE levels are associated with higher blood eosinophil counts and FeNO concentrations1,2 • IgE levels are tested to determine eligibility for certain severe asthma therapies—eg, anti-IgE biologic agents1,2

Th2 cell

– Anti-IgE therapy may be more effective in patients with high levels of Th2-associated biomarkers3

B cell

IL-4

IgE

Mast cell

FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E; IL, interleukin; Th, T helper.

1. Ahmad Al Obaidi AH, et al. J Asthma. 2008;45(8):654-663; 2. Matsui EC, et al. Allergy. 2010;65(11):1414-1422; 3. Hanania NA, et al. Am J Respir Crit Care Med. 2013;187(8):804-811.

Emerging Biomarkers

The Role of Biomarkers in Asthma Phenotyping TARC/CCL17

Eotaxin

Serum periostin

TARC/CCL17, chemokine (C-C motif) ligand 17.

Kim MA, et al. Curr Opin Allergy Clin Immunol. 2014;14(1):49-54; Chung KF, et al. Eur Respir J. 2014;43(2):343-373; Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. www.ginasthma.org. Accessed February 10, 2019.

PATIENT EVALUATION Dr Corren

Severe Asthma

Estimated Prevalence, 2015 Approximately 25 Million Americans Have Asthma1

5%-10%

Severe Asthma2-4

Mild-to-Moderate Asthma

1. American Lung Association. Asthma in adults fact sheet. www.lung.org/lung-health-and-diseases/lung-disease-lookup/asthma/learn-about-asthma/asthma-adults-facts-sheet.html.

Accessed February 10, 2019; 2. Busse WW, et al. J Allergy Clin Immunol. 2000;106(6):1033-1042; 3. Lang DM. Allergy Asthma Proc. 2015;36(6):418-424; 4. Chung KF, et al. Eur Respir J. 2014;43(2):343-373.

Burdens of Severe Asthma I have struggled with depression personally when I have been so, so sick, and I probably struggle with it every day now….

When my kids were young, I really couldn’t play with them all that much.

I have lost in every facet of my life.

On some occasions the mind’s there and wants to do it but the body can’t keep up … and it sort of makes you feel worthless in a way.

Most housework I can’t do. Can’t vacuum. I can’t do the bathroom or anything like that.

Even though severe asthma represents a small percentage of all asthma cases, these patients experience an outsized proportion of morbidity and mortality associated with the disease.

Foster JM, et al. Eur Respir J. 2017;50(3):1700765.

Identification of Severe Asthma Definition From the ATS and ERS

• Asthma in patients aged ≥6 years that would be uncontrolled if not for – High-dose ICS plus a LABA or leukotriene modifier/theophylline for the previous year

OR – Systemic corticosteroids for ≥50% of the year

• Asthma that is uncontrolled despite these therapies It is important to confirm that ‘uncontrolled’ asthma symptoms are not caused by confounding factors.

ATS, American Thoracic Society; ERS, European Respiratory Society; ICS, inhaled corticosteroid; LABA, long-acting β2 agonist.

Chung KF, et al. Eur Respir J. 2014;43(2):343-373.

Determining Asthma Control Patients Aged ≥12 Years

Components of Control

Not Well Controlled

Very Poorly Controlled

>2 days/week

Throughout the day

1-3×/week

≥4×/week

Some limitation

Extremely limited

>2 days/week

Several times/day

FEV1/peak flow

60%-80% predicted/personal best

<60% predicted/personal best

Validated questionnaires • ATAQ • ACQ • ACT

• 1-2 • ≥1.5 • 16-19

Symptoms Nighttime awakenings Interference with normal activity Rescue inhaler use

aLevel

• 3-4 • N/A • ≤15

of control determined by most severe impairment or risk category.

ACQ, Asthma Control Questionnaire; ACT, Asthma Control Test; ATAQ, Asthma Therapy Assessment Questionnaire; FEV1, forced expiratory volume in 1 second; N/A, not applicable.

National Asthma Education and Prevention Program. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma – Full Report 2007. https://www.nhlbi.nih.gov/sites/default/files/media/docs/asthsumm.pdf.

Best Practices in Patient Evaluation Confirm asthma diagnosisa Assess disease severityb Evaluate triggers that affect asthma Evaluate comorbid states that affect asthma Assess treatment adherence and inhaler techniquec

a.Carefully consider other possible disorders in the differential diagnosis and confirm asthma diagnosis with physiologic testing b.Standardized questionnaires (including rescue inhaler use), exacerbation history, measurement of biomarkers c. Less than 50% of medication prescribed for asthma is taken by patients; poor inhaler technique in up to 75% of patients

Aaron SD, et al. Respir Crit Care Med. 2018;198(8):1012-1020. Bender B, et al. Ann Allergy Asthma Immunol. 1997;79(3):177-185.

Conditions Commonly Misdiagnosed as Asthma in Adults • COPD • Hyperventilation with panic attacks • Bronchiolitis – (constrictive/proliferative)

• Congestive heart failure • Adverse drug reaction – (eg, ACE inhibitors, β-blockers)

• Bronchiectasis, cystic fibrosis • Hypersensitivity pneumonitis

ACE, angiotensin-converting enzyme; COPD, chronic obstructive pulmonary disease.

• • • •

Hypereosinophilic syndromes Pulmonary embolus Herpetic tracheobronchitis Endobronchial lesion or foreign body – (eg, amyloid, carcinoid, tracheal stricture)

• Allergic bronchopulmonary aspergillosis • Acquired tracheobronchomalacia • Churg-Strauss syndrome

Always Consider Potential Asthma Triggers • Irritants – Tobacco and wood smoke – Particulates, pollution – Gas or diesel fumes

• Occupational factors – Chemicals – Fumes

• Allergens – Pollens – Mold – Animal dander – Insects

• Concomitant medications – NSAIDs, beta-blockers

NSAID, nonsteroidal anti-inflammatory drug.

Centers for Disease Control and Prevention. Environmental triggers of asthma. https://www.atsdr.cdc.gov/csem/csem.asp?csem=32&po=6. Accessed February 10, 2019; Wechsler ME. Am J Med. 2014;127(11):1049-1059; Morales DR, et al. BMC Medicine. 2017;15:18; American Academy of Allergy, Asthma, and Immunology. Medications may trigger asthma symptoms. https://www.aaaai.org/conditions-and-treatments/library/asthma-library/medications-that-can-trigger-asthma-symptoms. Accessed February 10, 2019.

Clinical Considerations for Asthma Comorbidities Comorbidities

Clinical Considerations

Atopic dermatitis

• Increases risk for asthma, especially in patients with childhood atopic dermatitis1,2 • Treating comorbid asthma and atopic dermatitis with anti-IgE biologic therapy can improve symptoms of both disorders and patient QoL3-5 • IL-4/-13 receptor blockade is effective for both moderate-to-severe atopic dermatitis and moderate-to-severe asthma6

Gastroesophageal reflux disease

• Associated with increased asthma exacerbations7 • Proton pump inhibitors have produced inconsistent results related to asthma symptoms and lung function8,9

IgE, immunoglobulin E; IL, interleukin; QoL, quality of life.

1. Ballardini N, et al. J Allergy Clin Immunol. 2014;133(2):594-596; 2. Burgess JA, et al. J Allergy Clin Immunol. 2008;122(2):280-285; 3. Velling P, et al. Eur J Med Res. 2011;16(9):407-410; 4. Kim DH, et al. Clin Exp Dermatol. 2013;38(5):496-500; 5. Toledo F, et al. J Eur Acad Dermatol Venereol. 2012;26(10):1325-1327; 6. Drugs@FDA. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/761055s007lbl.pdf; 7. Denlinger LC, et al. Am J Respir Crit Care Med. 2017;195(3):302-313; 8. Holbrook JT, et al. JAMA. 2012;307(4):373-381; 9. Kiljander TO, et al. Am J Respir Crit Care Med. 2010;181(10):1042-1048.

Clinical Considerations for Asthma Comorbidities (cont’d) Comorbidities

Clinical Considerations • ICS may be less effective in obese individuals1 Obesity

• Weight reduction can improve symptom control and lung function2-4 • Associated with increased risk for severe asthma exacerbations and decreased lung function5,6

Obstructive sleep apnea

• Comorbid sleep disturbances may increase asthma-related mortality7 • CPAP treatment can improve asthma symptoms and ameliorate declines in lung function6,8

CPAP, continuous positive airway pressure; ICS, inhaled corticosteroid.

1. Sutherland ER, et al. Am J Respir Crit Care Med. 2008;178(7):682-687; 2. Dias-Junior SA, et al. Eur Respir J. 2014;43(5):1368-1377; 3. Dixon AE, et al. J Allergy Clin Immunol.

2011;128(3):508-515; 4. Ulrik CS. Curr Opin Pulm Med. 2016;22(1):69-73; 5. Wang Y, et al. Sleep Med. 2016;26:1-5; 6. Wang TY, et al. BMC Pulm Med. 2017;17(1):55; 7. Han KT, et al.

BMC Pulm Med. 2016;16(1):154; 8. Abdul Razak MR, Chirakalwasan N. Asian Pac J Allergy Immunol. 2016;34(4):265-271.

Clinical Considerations for Asthma Comorbidities (cont’d) Comorbidities

Clinical Considerations Rhinosinusitis/ Nasal polyposis

Vocal cord dysfunction

• Patients with adult-onset asthma may be more likely to have comorbid nasal polyposis1 • Associated with increased asthma exacerbations2 • Surgical removal of nasal polyps has produced inconsistent results for asthma symptoms and lung function3,4 • Treatment of comorbid rhinosinusitis/nasal polyposis with targeted therapies against IgE, IL-5/IL-5Rα, or IL-4Rα may be effective5-7 • Associated with poor asthma control8 • Nasal steroids can improve VCD in patients with chronic rhinitis9 • Speech therapy and trigger avoidance can help improve VCD10

IgE, immunoglobulin E; IL, interleukin; IL-4Rα, interleukin-4 receptor α; IL-5Rα, interleukin-5 receptor α 1. Staniorski JC, et al. Int Forum Allergy Rhinol. 2018;8(4):495-503; 2. Denlinger LC, et al. Am J Respir Crit Care Med. 2017;195(3):302-313; 3. Adelman J, et al. Otolaryngol Head Neck Surg. 2016;155(2):220-237; 4. Vashista R, et al. Int Forum Allergy Rhinol. 2013;3(10):788-794; 5. Rivero A, Liang J. Ann Otol Rhinol Laryngol. 2017;126(11):739-747; 6. Bachert C, et al. JAMA. 2016;315(5):469-479; 7. Weinstein SF, et al. J Allergy Clin Immunol. 2018;142(1):171-177; 8. Newman KB, et al. Am J Respir Crit Care Med. 1995;152(4 Pt 1):1382-1386; 9.

Bucca C, et al. J Allergy Clin Immunol. 1995;95(1 Pt 1):52-59; 10. Patel RR, et al. Am J Speech Lang Pathol. 2015;24(3):566-584.

Assessment Tools to Evaluate Asthma Symptom Control Asthma Control Test (ACT)1

Asthma Control Questionnaire (ACQ)2

Asthma Therapy Assessment Questionnaire (ATAQ)3 For links to these assessment tools and other resources, please visit: www.ExchangeCME.com/AsthmaResources19.

1. Nathan RA, et al. J Allergy Clin Immunol. 2004;113(1):59-65; 2. Juniper EF, et al. Eur Respir J. 1999;14(4):902-907; 3. Vollmer WM, et al. Am J Respir Crit Care Med. 1999;160(5 Pt 1):1647-1652.

Asthma Action Plan

US Department of Health and Human Services. Asthma action plan. www.nhlbi.nih.gov/files/docs/public/lung/asthma_actplan.pdf. Accessed February 10, 2019.

Adherence • Assess for adherence – Inspect medication dose counters – Breath-actuated devices are more accurate – Check pharmacy refill records

• Reasons for nonadherence – Inadequate access to medication – Dissatisfaction with medication delivery – Perceived adverse effects – Lack of improvement with medication noted by patient

Seek to understand and address reasons for low adherence, particularly defining the purpose of the medication and why it is essential to their care.

PERSONALIZING THERAPY IN SEVERE ASTHMA Dr Panettieri

Unmet Needs in Patients With Asthma â&#x20AC;˘ Careful assessment of current adherence to asthma guideline recommendations is an important first step when considering an asthma biologic â&#x20AC;&#x201C; 28% of patients who had uncontrolled asthma did not improve after 1 year of dose escalation of ICS/LABA and guideline-recommended care1

Prescribers of asthma biologics should consider how best to assess and improve medication adherence to ICS/LABA before considering the use of a biologic agent.2 LABA, long-acting beta agonist; ICS, inhaled corticosteroid.

1. Bateman ED, et al. Am J Respir Crit Care Med. 2004;170(8):836-844; 2. Rank MA, et al. Ann Allergy Asthma Immunol. 2018 Dec 19. pii: S1081-1206(18)31536-9.

FDA-Approved Biologic Agents for Severe Asthma Anti-IgE Therapy

Anti-IL-5/IL-5Rα Therapies

IgE

Mepolizumab Reslizumab

IL-5

B cell

Benralizumab

Omalizumab

IL-5Rα

Anti-IL-4Rα Therapy

c

IL-4

Dupilumab

Mast cell

OR

IL-13

Dupilumab

IL-4Rα

IL-5 regulates eosinophil proliferation, differentiation, migration, and survival

IL-4

γc

IL-4Rα

IL-13Rα1

IL-4 mediates IgE production, Th2-cell differentiation, B-cell growth, and eosinophil recruitment

FDA, US Food and Drug Administration; IgE, immunoglobulin E; IL, interleukin; IL-4Rα, interleukin-4 receptor α; IL-5Rα, interleukin-5 receptor α; IL-13Rα1, interleukin-13 receptor α1; Th, T helper.

Adapted from Darveaux J, Busse WW. J Allergy Clin Immunol Pract. 2015;3(2):152-161 and Gandhi NA, et al. Nat Rev Drug Discov. 2016;15(1):35-50.

Omalizumab • Approved for patients aged ≥6 years with1 – Moderate-to-severe persistent asthma – A positive skin test or in vitro reactivity to a perennial aeroallergen – Inadequate control with ICS

• SQ administration1 – Based on pretreatment serum IgE level and body weight1

Annual Exacerbation Rate2

Anti-IgE mAb 1.6

1.47

38.3%

Percent RR vs placebo

1.4 1.2 1.0

0.91a

0.8 0.6 0.4 0.2 0.0 Control

Omalizumab

Pooled Clinical Study Data aP<0.0001.

ICS, inhaled corticosteroid; IgE, immunoglobulin E; mAb, monoclonal antibody; Q2W, every 2 weeks; Q4W, every 4 weeks; RR, relative reduction; SQ, subcutaneous.

1. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/daf/; 2. D’Amato G, et al. Ther Clin Risk Manag. 2007;3(4):613-619.

Mepolizumab

MENSA Trial of an Anti-IL-5 mAb

– ≥150 cells/μL at screening OR ≥300 cells/μL during the prior year

• Treated with high-dose ICS plus another controller

2.0

Annual Exacerbation Rate1

• ≥2 exacerbations within the last year • High blood eosinophils

53%

1.74

Percent RR vs placebo

1.5 1.0

0.83a

0.5 0.0 Placebo (n=191)

Mepolizumab (n=194)

Approved as add-on maintenance therapy for patients aged ≥12 years with severe eosinophilic asthma; SQ administration.2 aP<0.001

versus placebo.

Patients with severe asthma aged 12 to 82 years were randomly assigned to receive SQ mepolizumab 100 mg or placebo Q4W for 32 weeks.

ICS, inhaled corticosteroid; IL, interleukin; mAb, monoclonal antibody; Q4W, every 4 weeks; RR, relative reduction; SQ, subcutaneous.

1. Ortega HG, et al. N Engl J Med. 2014;371(13):1198-1207; 2. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2017/125526s004lbl.pdf.

Reslizumab

• ≥1 exacerbation within the last year • High blood eosinophils – ≥400 cells/μL at screening

• Treated with medium- to high-dose ICS

Annual Exacerbation Rate1

2 Pooled Phase 3 Trials of an Anti-IL-5 mAb 2.0

1.81

50%-59% Percent RR vs placebo

1.5 1.0

0.84a

0.5 0.0 Placebo (n=476)

Reslizumab (n=477)

Approved as add-on maintenance therapy for patients aged ≥18 years with severe eosinophilic asthma; IV administration.2 aP<0.0001

versus placebo.

Patients with severe asthma aged 12 to 75 years were randomly assigned to IV reslizumab 3 mg/kg or placebo Q4W for 52 weeks.

ICS, inhaled corticosteroid; IL, interleukin IV, intravenous; mAb, monoclonal antibody; Q4W, every 4 weeks; RR, relative reduction.

1. Castro M, et al. Lancet Respir Med. 2015;3(5):355-366; 2. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2019/0761033s010lbl.pdf.

Benralizumab 51%

2.0 1.5

Percent RR vs placebo

28%

Percent RR vs placebo

1.33 0.93

1.0 0.65a

0.66b

0.5 0.0 SIROCCO

CALIMA

≥300 Eosinophils/μL Placebo

Benralizumab

Annual Exacerbation Rate1,2

• ≥2 exacerbations within the last year • Treated with medium- to highdose ICS plus LABA

Annual Exacerbation Rate1,2

SIROCCO and CALIMA Trials of an Anti-IL-5Rα mAb 17%

2.0 1.5 1.0

Percent RR vs placebo

1.21

40%

Percent RR vs placebo

1.21 1.00 0.73c

0.5 0.0 SIROCCO

CALIMA

<300 Eosinophils/μL Placebo

Benralizumab

Approved as add-on maintenance therapy for patients aged ≥12 years with severe eosinophilic asthma; SQ administration.3 aP<0.0001

versus placebo; bP<0.02 versus placebo; cP<0.005 versus placebo.

N=1205 (SIROCCO) or 1306 (CALIMA) patients aged 12 to 75 years with severe asthma randomly assigned to SQ benralizumab 30 mg Q8W (first 3 doses Q4W) or placebo.

ICS, inhaled corticosteroid; IL-5Rα, interleukin-5 receptor α; LABA, long-acting beta agonist; mAb, monoclonal antibody; Q4W, every 4 weeks; Q8W, every 8 weeks; RR, relative reduction; SQ, subcutaneous.

1. Bleecker ER, et al. Lancet. 2016;388(10056):2115-2127; 2. FitzGerald JM, et al. Lancet. 2016;388(10056):2128-2141; 3. Drugs@FDA. www.accessdata.fda.gov/scripts/cder/daf/.

Dupilumab

-48%

1.2 1.0

-46% 0.97

0.87

0.8 0.6

0.52a

0.46a

0.4 0.2 0.0 Placebo

Dupilumab 200 mg

Placebo

Dupilumab 300 mg

Annual Exacerbation Rate

Annual Exacerbation Rate

LIBERTY ASTHMA QUEST Trial With an Anti-IL-4Rα mAb 1.5 1.0 0.5 0.0

-36%

0.87

0.56

Placebo

Dupilumab 200 mg

0.84

Placebo

-44% 0.47 Dupilumab 300 mg

≥150 to <300 Eosinophils/μL 1.5 1.0 0.5 0.0

1.08

-66%

1.24

0.40a

0.37 Placebo

Dupilumab 200 mg

-67%

Placebo

≥300 Eosinophils/μL

Dupilumab 300 mg

Approved as add-on maintenance therapy for patients ≥12 years with moderate-to-severe eosinophilic or OCS-dependent asthma; SQ administration.2 aP<0.001

versus placebo.

N=1902 patients aged ≥12 years with moderate-to-severe asthma uncontrolled with medium- to-high-dose ICS plus 1 or 2 other controllers received SQ dupilumab or placebo Q2W for 52 weeks.

Castro M, et al. N Engl J Med. 2018;378(26):2486-2496. Drugs@FDA. www.accessdata.fda.gov/drugsatfda_docs/label/2018/761055s007lbl.pdf

Emerging Agent: Tezepelumab

Phase 2b Dose-Ranging Trial With an Anti-TSLP mAb TSLP

TSLPR

Tezepelumab

IL-7Rα

TSLP regulates type 2 immune responses by activating dendritic cells, ILC2 cells, T cells, and B cells aP≤0.001

61% 71% 66%

1.0

Annual Exacerbation Rate

Anti-TSLP Therapy

Percent RR vs placebo

0.8

Percent RR Percent RR vs placebo vs placebo

1.0

0.8

Placebo Tezepelumab 70 mg Q4W Tezepelumab 210 mg Q4W Tezepelumab 280 mg Q2W

0.67 0.6

0.6

0.4

0.4 0.26a 0.19a

0.2

0.22a

b

b

0.2

b

b

a

a

0.0

0.0 Placebo

Tezepelumab Tezepelumab Tezepelumab 70 mg Q4W 210 mg Q4W 280 mg Q2W

<250 cells/μL ≥250 cells/μL

Blood Eosinophil Count

versus placebo; bP<0.05 versus placebo.

N=584 patients aged 18 to 75 years with ≥2 exacerbations or 1 severe exacerbation requiring hospitalization in the last year despite medium- to high-dose ICS plus LABA were randomly assigned to receive SQ tezepelumab for 52 weeks.

ICS, inhaled corticosteroid; IL-7Rα, interleukin-7 receptor α; ILC2, type 2 innate lymphoid cell; LABA, long-acting beta agonist; mAb, monoclonal antibody; Q2W, every 2 weeks; Q4W, every 4 weeks; RR, relative reduction; SQ, subcutaneous; TSLP, thymic stromal lymphopoietin.

Corren J, et al. N Engl J Med. 2017;377(10):936-946.

Safety of Biologics in Asthma Biologic Agent

Most Commonly Reported Adverse Reactions in Clinical Trials

Benralizumab

Headache, pharyngitis

None

Dupilumab

Injection site reactions

None

Mepolizumab

Headache, injection site reaction, back pain, fatigue

None

Omalizumab

Arthralgia, pain (general)

Anaphylaxis

Reslizumab

Oropharyngeal pain

Anaphylaxis

Drugs@FDA: FDA Approved Drug Products. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm.

Black Box Warning

Biomarkers Predicting Response to Biologics Biologic Agent

Sputum Eosinophil

Blood Eosinophil

FeNO

Benralizumab

●

●

Dupilumab

●

●

●

●

●

●

Mepolizumab

●

Omalizumab Reslizumab FeNO, fractional exhaled nitric oxide; IgE, immunoglobulin E. Medrek SK, et al. Curr Allergy Asthma Rep. 2017;17(10):69.

●

●

IgE

●

WHATâ&#x20AC;&#x2122;S NEW IN BIOLOGICS? Dr Panettieri

Atopic Dermatitis â&#x20AC;˘ Dupilumab now approved by the FDA for the treatment of adult patients with moderate-to-severe atopic dermatitis1 â&#x20AC;˘ Evidence suggests omalizumab may improve symptoms and quality of life in people with asthma and comorbid atopic dermatitis2,3 FDA, US Food and Drug Administration.

1 www.accessdata.fda.gov/drugsatfda_docs/label/2018/761055s007lbl.pdf; 2. Velling P, et al. Eur J Med Res. 2011;16(9):407-410; 3. Kim DH, et al. Clin Exp Dermatol. 2013;38(5):496-500.

Rhinosinusitis and Nasal Polyposis • Benralizumab – Phase 2 study for severe chronic rhinosinusitis with eosinophilic polyposis underway1

• Dupilumab – Reduces polyp size and symptoms; improves QoL in people with CSwNP2 – Improves allergic rhinitis–associated symptoms in people with perennial allergic rhinitis and uncontrolled persistent asthma3

• Omalizumab – Reduces polyp size and symptoms in people with nasal polyps and comorbid asthma5 – Improves symptoms and QoL in patients with CSwNP and comorbid severe allergic asthma6

• Reslizumab – Decreases polyp size in people with massive bilateral nasal polyps or recurrent nasal polyps postsurgery7

• Mepolizumab – Decreases polyp size in people with severe nasal polyposis4 CSwNP, chronic sinusitis with nasal polyposis; QoL, quality of life.

1. ClinicalTrials.gov NCT03450083; 2. Bachert C, et al. JAMA. 2016;315(5):469-479; 3. Weinstein SF, et al. J Allergy Clin Immunol. 2018;142(1):171-177; 4. Gevaert P, et al. J Allergy Clin Immunol. 2011;128(5):989-995; 5. Gevaert P, et al. J Allergy Clin Immunol. 2013;131(1):110-116; 6. Bidder T, et al. Rhinology. 2018;56(1):42-45; 7. Gevaert P, et al. J Allergy Clin Immunol. 2006;118(5):1133-1141.

Biologic Therapies

Clinical Trials Underway for Other Conditions and Comorbidities • Omalizumab – Chronic spontaneous urticaria

• Dupilumab – Active eosinophilic esophagitis – Eosinophilic gastritis – Chronic spontaneous urticaria – Nasal polyposis and chronic symptoms of sinusitis

ClinicalTrials.gov.

• Benralizumab – Atopic dermatitis – Eosinophilic gastritis – Severe nasal polyposis – Aspirin-exacerbated respiratory disease

• Reslizumab – Chronic rhinosinusitis

OTHER ADVANCED TREATMENT MODALITIES Dr Panettieri

Bronchial Thermoplasty Patient Selection

• Bronchial thermoplasty: – Involves the delivery of radio frequency energy to reduce airway smooth muscle mass – Indicated for a highly select group of patients aged ≥18 years with uncontrolled, severe, persistent asthma – In clinical trials, bronchial thermoplasty reduced the rate of severe exacerbations and improved patient quality of life, with durable responses up to 5 years, to date

Clinicians must determine which patients are appropriate candidates for bronchial thermoplasty.

Castro M, et al. Am J Respir Crit Care Med. 2010;181(2):116-124; Chung KF, et al. Eur Respir J. 2014;43(2):343-373; Wechsler ME, et al. J Allergy Clin Immunol. 2013;132(6):1295-1302; Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. Available from: www.ginasthma.org. Accessed February 10, 2019.

Allergen Immunotherapy • Desensitizes patients with allergies to specific antigens • Subcutaneous and sublingual preparations available • Benefits can include: – Fewer asthma symptoms – Improvements in FEV1 – Fewer exacerbations, depending on the measure – Reduced asthma medication usage – May act as disease-modifying strategy

• May cause asthma exacerbations • Lacking randomized, controlled clinical trials in severe asthma FEV1, forced expiratory volume in 1 second.

Mosbech H, et al. J Allergy Clin Immunol. 2014;134(3):568-575; Passalacqua G, et al. Asthma Res Pract. 2015;1:6; Virchow JC, et al. JAMA. 2016;315(16):1715-1725; Zielen S, et al. J Allergy Clin Immunol. 2010;126(5):942-949.

Fevipiprant

Change in Sputum Postbronchodilator Eosinophils, FEV1, L Fold Reduction

Oral D2 (CRTh2) Receptor Antagonist 0.5 1 2 4 8 16

PGD2 Fevipiprant Fevipiprant Placebo 0

0.2

a

a

6

12

Weeks Fevipiprant Placebo

0.1

a

0

-0.1 -0.2

aP<0.05

CRTh2

0

6

Weeks

12

Phase 3 trials underway with total daily fevipiprant dose of 150 mg

versus placebo.

N=117 patients with persistent eosinophilic asthma inadequately controlled with ICS randomly assigned to fevipiprant 225 mg or placebo orally BID for 12 weeks.

BID, twice daily; CRTh2, chemoattractant receptor homologue from Th2 cells; FEV1, forced expiratory volume in 1 second; ICS, inhaled corticosteroid; PGD2, prostaglandin D2; Th, T helper.

Gonem S, et al. Lancet Respir Med. 2016;4(9):699-707; ClinicalTrials.gov. NCT NCT03215758.

SHARED DECISION MAKING Dr Panettieri

Shared Decision Making

Focus on Choice Rather Than Change “Healthcare professionals have a duty to inform people about the benefits and harms of proposed interventions…

Shared decision making is defined by extending this duty to supporting people to arrive at informed preferences, eliciting and respecting those preferences by integrating them as decisions are made.”

• Patients should be engaged in decisions to the extent that they wish • A shared decision-making process is not limited to the use of patient decision aids

Elwyn G, et al. Implement Sci. 2016;11:114.

Step-Up Therapy for Poorly Controlled Asthma Stepping Up From GINA Step 4 to Step 5: Patient Profile Difficult-to-treat asthma: Symptomatic ≥ 2 months or 2 or more exacerbations requiring OCS in past year, despite using high doses of anti-inflammatory and bronchodilator medications and optimal adherence

Patient Profile: IgE (allergic)

Patient Profile: Eosinophilic

Difficult-to-treat characteristics and moderate-to-severe allergic asthma (with total serum IgE = 30-700 IU/mL) and demonstrated IgE-mediated hypersensitivity to a perennial allergen

Difficult-to-treat asthma and eosinophilic phenotype (current or history of blood eosinophils >300 cells/μL and 2 or more exacerbations requiring OCS in past year OR current or history of ≥150 cells/μL and 3 or more exacerbations requiring OCS in past year

Add omalizumab

Consider treatment targeted to the patient’s phenotype or characteristics

Patient Profile: Nonatopic, Noneosinophilic Difficult-to-treat asthma and sputum neutrophils in patients who do not respond to high doses of corticosteroids and do not have other type 2 markers

Add an anti-IL-5, anti-IL-5Rαa, or anti-IL-4Rαb biologic 3-month therapeutic trial with interval reassessment

aBenralizumab,

Asthma specialist care required

Patient Profile: Noninflammatory Patient with difficult-to-treat asthma profile who doesn’t qualify for other targeted therapies, and/or has tried and failed targeted therapies for which s/he might be eligible, and demonstration of variable airflow obstruction by bronchodilator reversibility

Consider adding a macrolide antibiotic Consider bronchial thermoplasty in addition to regular treatment

an anti-IL-5Rα mAb, currently FDA-approved for severe eosinophilic asthma, had not yet received approval by the FDA at the time the original treatment algorithm was published; bdupilumab, an anti-IL-4Rα mAb, currently FDA-approved for moderate-to-severe eosinophilic or OCS-dependent asthma, had not yet received approval by the FDA at the time the original treatment algorithm was published.

Adapted from Chipps BE, et al. Ann Allergy Asthma Immunol. 2018;S1081-1206; Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018.

Available at: www.ginasthma.org. Accessed February 10, 2019.

Step-Up Therapy for Poorly Controlled Asthma Stepping Up From GINA Step 4 to Step 5: Patient Profile

Asthma specialist care required

Difficult-to-treat asthma: Symptomatic ≥2 months or 2 or more exacerbations requiring OCS in past year, despite using high doses of anti-inflammatory and bronchodilator medications and optimal adherence

Consider treatment targeted to the patient’s phenotype or characteristics

Patient Profile: IgEwhether (allergic) Consider

Profile: Eosinophilic Patient Profile: Patient Airway Smooth toPatient start first with anti-IgE, anti-IL-5/-5Rα, orProfile: anti-IL-4Rα.

Neutrophilic Muscle Hypertrophy Difficult-to-treat characteristics and Difficult-to-treat asthmaavailable and eosinophilic When choosing among therapies, consider the following: moderate-to-severe allergic asthma (with phenotype (current or history of blood

• • • • •

Difficult-to-treat asthma and sputum neutrophils in patients who do not respond to high doses of corticosteroids and do not have other type 2 markers

Patient eligibility criteria satisfied Predictors of response Dosing frequency Add an anti-IL-5, anti-IL-5Rαa, Add omalizumab Route of delivery (SQ or IV)or anti-IL-4Rα b biologic Patient preference3-month therapeutic trial with interval reassessment

total serum IgE = 30-700 IU/mL) and demonstrated IgE-mediated hypersensitivity to a perennial allergen

eosinophils >300 cells/μL and 2 or more exacerbations requiring OCS in past year OR current or history of ≥150 cells/μL and 3 or more exacerbations requiring OCS in past year

Patient with difficult-to-treat asthma profile who doesn’t qualify for other targeted therapies and/or has tried and failed targeted therapies for which s/he might be eligible and demonstration of variable airflow obstruction by bronchodilator reversibility

Consider adding a macrolide antibiotic Consider bronchial thermoplasty in addition to regular treatment

aBenralizumab, an anti-IL-5Rα mAb, currently FDA-approved for severe eosinophilic asthma, had not yet received approval by the FDA at the time the original treatment algorithm was published; bdupilumab, an anti-IL-4Rα mAb, currently FDA-approved for moderate-to-severe eosinophilic or OCS-dependent asthma, had not yet received approval by the FDA at the time the original treatment algorithm was published.

IgE, immunoglobulin E; FDA, US Food and Drug Administration; GINA, Global Initiative for Asthma; IL, interleukin; IL-4Rα, interleukin-4 receptor α; IL-5Rα, interleukin-5 receptor α; IV, intravenous; mAb, monoclonal antibody; OCS, oral corticosteroid; SC, subcutaneous.

Adapted from Chipps BE, et al. Ann Allergy Asthma Immunol. 2018;S1081-1206; Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2018. Available at: www.ginasthma.org. Accessed February 10, 2019.

Helping Patients Understand Biologic Therapy for Poorly Controlled Asthma A Handout

Adult-Onset Asthma

Management Considerations â&#x20AC;˘ Compared with early-onset asthma, late-onset disease responded to reslizumab treatment, with larger increases in FEV1 and reductions in exacerbations1

â&#x20AC;˘ Dupilumab treatment resulted in improvements in FEV1 and reductions in severe exacerbation rates in both earlyonset and late-onset asthma cohorts2

FEV1, forced expiratory volume in 1 second.

1. Brusselle G, et al. Pulm Pharmacol Ther. 2017;43:39-45; 2. Weinstein SF, et al. Am J Respir Crit Care. 2016;193:A6486.

Oral Corticosteroid-Dependent Asthma Clinical Characteristics

% % 32 –45 of patients with severe asthma require frequent, and often daily, OCS1,2

% 93

of asthma registry patients with severe disease had ≥1 condition linked to OCS exposure3-5

• T2DM • Osteoporosis • Cataracts • Dyspeptic disorders

• Weight gain • Osteopenia • Hypertension • Obstructive sleep apnea

Management strategies that minimize OCS use—and the associated risks of adverse events—are preferred.6 OCS, oral corticosteroid; T2DM, type 2 diabetes mellitus.

1. Moore WC, et al. J Allergy Clin Immunol. 2007;119(1):405-413; 2. Shaw DE, et al. Eur Respir J. 2015;46(5):1308-1321; 3. Sweeney J, et al. Thorax. 2016;71(4):339-346; 4. Luskin AT, et al. Clinicoecon Outcomes Res. 2016;8:641-648; 5. Sullivan PW, et al. J Allergy Clin Immunol. 2018;141(1):110-116; 6. Chung KF, et al. Eur Respir J. 2014;43(2):343-373.

Conclusions • It is critical to identify patients with poorly controlled, severe asthma • Targeted biologic therapies can improve symptoms, decrease exacerbation risks, and improve QoL in various severe asthma cohorts – An anti-IgE biologic is FDA-approved for patients with moderate-to-severe, persistent allergic asthma, a positive skin test or in vitro reactivity to a perennial aeroallergen, and age/body weight serum IgE levels – Three biologic therapies targeting IL-5 signaling are now FDA-approved for patients with severe eosinophilic asthma – A biologic agent targeting IL-4Rα was approved for patients with moderate-to-severe asthma ≥aged 12 years who have an eosinophilic phenotype or OCS–dependent asthma – A biologic agent targeting TSLP is in mid- to late-stage clinical development

• Some biomarkers can be useful in classifying asthma phenotypes or predicting treatment responses • Precision management for patients with asthma and potentially pathologically related or other complicating comorbidities will likely improve outcomes

CLINICAL PRACTICE GUIDELINES Difficult-to-treat & severe asthma in adolescent and adult patients: diagnosis and management.

Global Strategy for Asthma Management and Prevention. https://ginasthma.org/wp-content/uploads/2018/11/GINA-SA-FINAL-wms.pdf

International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma.

Chung KF, et al. Eur Respir J. 2014;43(2):343-373. http://erj.ersjournals.com/content/erj/43/2/343.full.pdf

An official ATS clinical practice guideline: interpretation of exhaled nitric oxide levels (FeNO) for clinical applications.

Dweik RA, et al. Am J Respir Crit Care Med. 2011;184(5):602-615. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408724/pdf/rccm.9120-11ST.pdf

PATIENT RESOURCES

American Thoracic Society (ATS)

The mission of the ATS is to improve health worldwide by advancing research, clinical care, and public health in respiratory disease, critical illness, and sleep disorders. https://www.thoracic.org/patients/patient-resources/

Asthma Action Plan

This printable reference tool is designed to help patients know when to use their different asthma medications and when to call their health care providers. http://www.aafa.org/media/asthma-action-plan-aafa.pdf

Chest Foundation

The CHEST Foundation creates trusted patient education resources and disease awareness campaigns that empower patients to engage in better managing their health. foundation.chestnet.org/patient-education-resources/asthma/

CLINICAL ASSESSMENT TOOLS Asthma Control Test (ACT)

Asthma and Allergy Foundation of America (AAFA)

AAFA is dedicated to improving the quality of life for people with asthma and allergic diseases through education, advocacy, and research. http://www.aafa.org/page/asthma.aspx

This 5-question test evaluates asthma control over the past 4 weeks on a 5-point Likert scale. A score of <20 on the ACT suggests asthma that is uncontrolled.

Nathan RA, et al. J Allergy Clin Immunol. 2004;113(1):59-65. http://www.pamf.org/asthma/education/handouts/adults/ACT_Eng.pdf

American College of Allergy, Asthma & Immunology (ACAAI)

Asthma Control Questionnaire (ACQ)

The ACAAI fosters a culture of collaboration and congeniality in which members work toward the common goals of patient care, education, advocacy, and research. http://acaai.org/

American Lung Association

The American Lung Association is the leading organization working to save lives by improving lung health and preventing lung disease through education, advocacy, and research. http://www.lung.org/lung-health-and-diseases/lung-disease-lookup/asthma/

This 7-question assessment tool measures asthma control over the past 7 days.

Six questions are self-administered by the patient, and 1 question requires a clinicianâ&#x20AC;&#x2122;s input. Scores range from 1 (totally controlled) to 6 (severely uncontrolled).

Juniper EF, et al. Eur Respir J. 1999;14(4):902-907. http://www.qoltech.co.uk/acq.html

Asthma Therapy Assessment Questionnaire (ATAQ)

This 4-question test assesses asthma control over the past 4 weeks. Each question has a possible score of 0 or 1; if the sum of the 4 question scores is >1, the patientâ&#x20AC;&#x2122;s asthma may be uncontrolled.

Vollmer WM, et al. Am J Respir Crit Care Med. 1999;160(5 Pt 1):1647-1652. http://getasthmahelp.org/documents/2007Guidelines_ValidatedQuestionnaires.pdf

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