Clinical Issues in Severe Asthma

This activity is jointly provided by The Elsevier Office of Continuing Medical Education (EOCME) and Integritas Communications.

This activity is supported by an independent educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals.

An Educational Symposium at the ATS 2017 International Conference. All ATS 2017 International Conference attendees are invited to attend this educational program.

MEDICAL COMMUNICATIONS INQUIRIES info@integritasgrp.com integritasgrp.com

FACULTY FACULTY

EUGENE R. Bleecker, MD

Professor and Co-Chief Division of Genetics, Genomics and Precision Medicine Department of Medicine Co-Director, Division of Pharmacogenomics Center for Applied Genetics and Genomic Medicine University of Arizona College of Medicine Tucson, Arizona

Dr. Eugene R. Bleecker is Co-chief of and Professor in the Division of Genetics, Genomics and Precision Medicine, and Co-Director of the Division of Pharmacogenomics in the Center for Applied Genetics and Genomic Medicine of the University of Arizona College of Medicine. He has major scientific interest and expertise in translational approaches in allergy, asthma, and chronic obstructive pulmonary disease (COPD), including defining clinical disease heterogeneity and biomarker endotypes, genetics of disease susceptibility and severity, pharmacogenetics of response to therapy and clinical trials. He has been Principal Investigator for the Wake Forest site for the National Heart, Lung, and Blood Institute (NHLBI) Severe Asthma Research Program (SARP1, 2, and 3) grants, co-investigator on NHLBI AsthmaNet, and has led the Wake Forest portion of the National Institutes of Health (NIH) Pharmacogenomics Network grant as well as being principal or co-investigator on multiple grants throughout his career. He has published over 325 manuscripts, 120 book chapters, editorials, and reviews as well as over 560 abstracts.

Dr. Bleecker was one of the first to publish on the genetic basis of asthma, identifying susceptibility and severity genes. He published the largest study showing that common gene variants do not modulate responsiveness to long-acting beta-agonists (LABA) (Bleecker et al, Lancet. 2007) and has shown that a rare variation in the ADRB2 gene is associated with severe exacerbations in asthmatics on LABA therapy (Ortega et al, Lancet Respir Med. 2014).

Throughout his career, he has had an active role in designing and performing clinical trials that provide an evidence basis for therapeutic interventions in asthma, including the NHLBI Asthma Clinical Research Network (ACRN) and AsthmaNet networks as well as industry studies. He is senior author on the TALC ACRN study that showed the therapeutic value of anticholinergics in asthma and triggered industry studies leading to the recent approval by the US Food and Drug Administration of tiotropium for asthma (a therapy previously reserved for COPD) (Peters et al, N Engl J Med. 2010). He led the recent studies on the efficacy of an anti-IL-5r (benralizumab) biologic therapy in severe asthma (Bleecker et al, Lancet. 2016).

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REYNOLD A. FACULTY

Panettieri, Jr., MD

Professor of Medicine Robert Wood Johnson Medical School Vice Chancellor, Clinical & Translational Science Director, Rutgers Institute for Translational Medicine & Science Emeritus Professor of Medicine University of Pennsylvania Philadelphia, Pennsylvania

Dr. Reynold A. Panettieri, Jr., is the Director of the Institute for Translational Medicine and Science and Vice Chancellor for Translational Medicine and Science at Rutgers University and the former Director of the Airways Biology Initiative at the University of Pennsylvania. His interests are in the cellular and molecular mechanisms that regulate airway smooth muscle cell growth and the immunobiology of airway smooth muscle. Consequences of increases in airway smooth muscle growth promote the development of irreversible airflow obstruction and airway remodeling seen in patients with chronic severe asthma. Dr. Panettieri’s lab also focuses on cytosolic signaling pathways that mediate gene expression and alter myocyte function.

Dr. Panettieri also served as the Deputy Director of the Center of Excellence in Environmental Toxicology at the University of Pennsylvania. He directed the human exposure chamber that defines the molecular mechanisms regulating ozone- and particulate matter–induced airway hyperresponsiveness. In parallel with his basic science interests, Dr. Panettieri managed the comprehensive clinical program for the care of patients with asthma and is actively involved in clinical investigations focused on the management of asthma and COPD. In addition to his research and clinical interests, Dr. Panettieri served as chairperson 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.

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Wenzel, MD

Professor of Medicine Director, University of Pittsburgh Asthma Institute at UPMC/UPSOM UPMC Chair of Translational Airway Biology Subsection Chief of Allergy Pulmonary, Allergy and Critical Care Medicine Pittsburgh, Pennsylvania

Dr. Sally E. 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, and the ATS Foundation Breathing for Life Award.

She is currently Director of the University of Pittsburgh Asthma Institute at University of Pittsburgh Medical Center (UPMC), holds the UPMC chair in Translational Airway Biology, and is Subsection Chief of Allergy. 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.

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FACULTY

SALLY E.

TARGET AUDIENCE The educational design of this activity addresses the needs of allergists/clinical immunologists, pulmonologists, and other clinicians involved in the management of patients with severe asthma.

PREAMBLE

EDUCATIONAL OBJECTIVES After completing this activity, the participant should be better able to do the following: • Describe pathophysiology of severe asthma with a focus on helper T cell type 2 (Th2)– mediated processes, biomarkers of disease phenotypes, and treatment targets • Evaluate patients with severe asthma for symptom severity, exacerbation history, comorbidities, disease phenotypes, and prior treatment responses • Discuss the clinical profiles of cytokine-targeting biologic medications for the treatment of severe asthma • Individualize therapeutic regimens for severe asthma based on identified disease phenotypes, ongoing evaluations of symptoms, exacerbation risks, and comorbid conditions

STATEMENT of NEED/PROGRAM OVERVIEW Up to 15% of the more than 25 million Americans with asthma have a severe form of the disease.1 Even with therapy, many of these patients continue to suffer from uncontrolled symptoms. The consequences are dire, including increased morbidity and mortality.1,2 Evolving insights into the pathophysiologic underpinnings of various asthma phenotypes have paved the way for new targeted biologic therapies, with significant implications for best-practices management of severe disease.3 With several biologics now available and many additional options in late developmental stages, pulmonologists and clinical immunologists will be increasingly tasked with personalizing the choice of treatment with the identified disease endotypes. In this Clinical Issues™ program, faculty with expertise in clinical immunology and pulmonology will discuss and debate a series of topics related to the evaluation and long-term treatment of patients with severe asthma. The faculty panel will provide their insights into severe asthma classification, biomarkers, comorbidity management, and current and emerging targeted biologic therapies, all shaped by the latest evidence presented at the American Thoracic Society’s 113th Annual International Conference. Attendees are sure to leave this lively and engaging program with new information and a fresh perspective on the evolving management paradigms in severe asthma.

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

3. Walsh GM. Biologics targeting IL-5, IL-4 or IL-13 for the treatment of asthma—an update. Expert Rev Clin Immunol. 2017;13(2):143-149.

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PROGRAM AGENDA 6:30 pm –7:00 pm Registration and Dinner 7:00 pm –7:05 pm Introduction and Preassessment 7:05 pm –7:30 pm Pathophysiology and Burdens of Severe Asthma 7:30 pm –7:55 pm Patient Evaluations, Monitoring, and Treatment Goals 7:55 pm –8:20 pm T ailoring Long-term Management Plans for Patients With Severe Asthma

DISCLOSURE of CONFLICTS of INTEREST It is the policy of the Elsevier Office of Continuing Medical Education 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 CME activity: Eugene R. Bleecker, MD Consultant/Advisor: AstraZeneca; BoehringerIngelheim Pharmaceuticals, Inc; GlaxoSmithKline plc; Knopp Biosciences LLC; MedImmune, LLC; Novartis Pharmaceuticals Corporation; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC; Grant/Research Support: AstraZeneca; Boehringer-Ingelheim Pharmaceuticals, Inc.; Genentech, Inc.; GlaxoSmithKline plc.; Janssen Global Services, LLC; Johnson & Johnson; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Regeneron Pharmaceuticals, Inc.; sanofi-aventis U.S. LLC; Teva Pharmaceutical Industries Ltd. Reynold A. Panettieri, Jr., MD Consultant/Advisor: AstraZeneca; MedImmune, LLC; Novartis Pharmaceuticals Corporation; Grant/Research Support: Amgen Inc.; AstraZeneca; Bristol-Myers Squibb Company; Novartis Pharmaceuticals Corporation; OncoArendi Therapeutics SA; RFIM; Theratrophix, LLC.; Vertex Pharmaceuticals Incorporated; Speakers Bureau: Boston Scientific Corporation; Teva Pharmaceutical Industries Ltd. Sally E. Wenzel, MD Consultant/Advisor: AstraZeneca; BoehringerIngelheim Pharmaceuticals, Inc; Genentech, Inc.; Novartis Pharmaceuticals Corporation; sanofi-aventis U.S. LLC.; Grant/Research Support: AstraZeneca; Boehringer-Ingelheim Pharmaceuticals, Inc.; Genentech, Inc.; GlaxoSmithKline plc.; Novartis Pharmaceuticals Corporation; sanofi-aventis U.S. LLC.

NON-FACULTY Rose O’Connor, PhD; Jim Kappler, PhD; Sandy Breslow; Alison Kemp; and Bernard M. Abrams, MD, 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.

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PREAMBLE

8:20 pm –8:30 pm Postassessment and Question and Answer Session

PROVIDER INFORMATION This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Elsevier Office of Continuing Medical Education and Integritas Communications.

FINANCIAL SUPPORT

PREAMBLE

This activity is supported by an independent educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals.

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. The Elsevier Office of Continuing Medical Education, 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 patient’s conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

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GUIDELINES »» Global Strategy for Asthma Management and Prevention Global Initiative for Asthma (GINA) 2017. http://ginasthma.org/gina-reports/

»» 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 College of Allergy, Asthma & Immunology (ACAAI) 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-diseaselookup/asthma/

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RESOURCE CENTER

»» 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

»» 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

CLINICAL ASSESSMENT TOOLS »» Asthma Control Test (ACT) 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. https://www.nhp.org/provider/asthma/Survey_ACT_adult_EN.pdf

RESOURCE CENTER

»» Asthma Control Questionnaire (ACQ) 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 clinician’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 patient’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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SUGGESTED READING »» Efficacy and safety of tralokinumab in patients with severe uncontrolled asthma: a randomised, double-blind, placebo-controlled, phase 2b trial.

Brightling CE, et al. Lancet Respir Med. 2015;3(9):692-701. www.pubmed.gov/26231288 »» Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial.

Bleecker ER, et al. Lancet. 2016;388(10056):2115-2127. https://www.ncbi.nlm.nih.gov/pubmed/27609408 »» Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebocontrolled, phase 3 trials.

Castro M, et al. Lancet Respir Med. 2015;3(5):355-366. www.pubmed.gov/25736990 »» A review of anti-IgE monoclonal antibody (omalizumab) as add on therapy for severe allergic (IgE-mediated) asthma.

D’Amato G, et al. Ther Clin Risk Manag. 2007;3(4):613-619. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2374942/pdf/tcrm-0304-613.pdf »» Biologics in asthma—the next step towards personalized treatment.

Darveaux J, Busse WW. J Allergy Clin Immunol Pract. 2015;3(2):152-161. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774509/pdf/nihms-759179.pdf

RESOURCE CENTER

»» Inflammatory and comorbid features of patients with severe asthma and frequent exacerbations.

Denlinger LC, et al. Am J Respir Crit Care Med. 2017;195(3):302-313. https://www.ncbi.nlm.nih.gov/pubmed/?term=27556234 »» Cluster analysis and clinical asthma phenotypes.

Haldar P, et al. Am J Respir Crit Care Med. 2008;178(3):218-224. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3992366/pdf/emss-29902.pdf »» Targeting key proximal drivers of type 2 inflammation in disease.

Gandhi NA, et al. Nat Rev Drug Discov. 2016;15(1):35-50. https://www.ncbi.nlm.nih.gov/pubmed/26471366

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»» Benralizumab, an anti-interleukin-5 receptor α monoclonal antibody, as add-on treatment for patients with severe, uncontrolled, eosinophilic asthma (CALIMA): a randomised, double-blind, placebo-controlled phase 3 trial.

FitzGerald JM, et al. Lancet. 2016;388(10056):2128-2141. https://www.ncbi.nlm.nih.gov/pubmed/27609406 »» Adult asthma biomarkers.

Kim MA, et al. Curr Opin Allergy Clin Immunol. 2014;14(1):49-54. www.pubmed.gov/24300416 »» Mepolizumab treatment in patients with severe eosinophilic asthma.

Ortega HG, et al. N Engl J Med. 2014;371(13):1198-1207. http://www.nejm.org/doi/pdf/10.1056/NEJMoa1403290 »» Severe eosinophilic asthma treated with mepolizumab stratified by baseline eosinophil thresholds: a secondary analysis of the DREAM and MENSA studies.

Ortega HG, et al. Lancet Respir Med. 2016;4(7):549-556. https://www.ncbi.nlm.nih.gov/pubmed/?term=27177493 »» Allergen immunotherapy in asthma; what is new?

Passalacqua G, et al. Asthma Res Pract. 2015;1:6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4970380/pdf/40733_2015_ Article_6.pdf

RESOURCE CENTER

»» Co-morbidities in severe asthma: clinical impact and management.

Porsbjerg C, Menzies-Gow, A. Respirology. 2017;22(4):651-661. http://onlinelibrary.wiley.com/doi/10.1111/resp.13026/epdf »» Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b doseranging trial.

Wenzel S, et al. Lancet. 2016;388(10039):31-44. https://www.ncbi.nlm.nih.gov/pubmed/27130691

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