Faculty Tara Carr, MD Nicola Hanania, MD Linda Rogers, MD The - PowerPoint PPT Presentation

Faculty Tara Carr, MD Nicola Hanania, MD Linda Rogers, MD The University of Arizona Baylor College Icahn School of Medicine Health Sciences of Medicine at Mount Sinai

This activity was made possible by an educational grant supported by Sanofi Genzyme and Regeneron Pharmaceuticals

Disclosure of Relevant Financial Relationships In accordance with the ACCME Standards for Commercial Support, The France Foundation (TFF) requires that individuals in a position to control the content of an educational activity disclose all relevant financial relationships with any commercial interest. TFF resolves all conflicts of interest to ensure independence, objectivity, balance, and scientific rigor in all its educational programs. Furthermore, TFF seeks to verify that all scientific research referred to, reported, or used in a CME/CE activity conforms to the generally accepted standards of experimental design, data collection, and analysis. TFF is committed to providing learners with high-quality CME/CE activities that promote improvements in healthcare and not those of a commercial interest.

Faculty Disclosures • Tara Carr, MD, has served as a consultant for AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., and Sanofi Genzyme and Regeneron Pharmaceuticals. She has also received research grant support from Aimmune Therapeutics, DBV Technologies, and Roche/Genentech. • Nicola Hanania, MD, has received honoraria for serving on advisory boards and as a consultant for AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novartis, Roche, and Sanofi Genzyme and Regeneron Pharmaceuticals. He has also received research grant support from AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Glaxo SmithKline, and Roche. • Linda Rogers, MD, has received honoraria for serving as a consultant for AstraZeneca, Sanofi US, and Teva Pharmaceutical Industries, and for serving on advisory boards for AstraZeneca. She has received research grant support from Sanofi.

Learning Objectives Explain how phenotypes and endotypes can help guide a precision medicine 1 approach to severe asthma Summarize mechanisms of action and key efficacy and safety data pertaining to 2 biologics used in severe asthma Apply information on phenotypes and endotypes and biologics to precision 3 therapy, as part of a personalized treatment selection process

Historical Perspectives on Severe Asthma “It must be admitted that the remedies for asthma are of very irregular and uncertain operation; that probably there is no single remedy that is not inoperative in a large number of cases; that that which is useful in one is valueless in another while there are many cases that resist all remedies . If this intractability of asthma were doubtful the large number of remedies that have been suggested would be a sufficient proof of it.” “The success of a remedy given on certain principles proves the correctness of the principles on which it was given, and the known action of a medicine directly implies the nature of the pathological state.” -Henry Hyde Salter, MD, 1860

Historical Approaches to Asthma Treatment

Asthma Definition Today Chronic inflammatory disorder of the airways Airway inflammation Episodic (reversible) Recurring episodes of wheezing, airway limitation — breathlessness, chest tightness, and coughing, obstructive especially at night or early morning symptoms Chronically inflamed airways are hyperresponsive; airflow becomes limited (by bronchoconstriction, mucus, increased Airway inflammation) when airways are hyperresponsiveness exposed to various triggers WHO/NHLBI Workshop Report. 1995. Global strategy for asthma management and prevention. National Institutes of Health, National Heart, Lung, and Blood Institute, Bethesda, MD. Publication No. 95-3659.

Asthma: More Than Just Allergy Persistent asthma threshold Environmental Lung tissue structure-function Episodic airway triggers inflammation relationships Steady-state respiratory Tissue damage function Tissue repair & Transient Persistent remodeling symptoms pathological changes Time (y) Holt PD, Sly PG. Nature Medicine 2012; 18(5),726-35.

Asthma in the US Today • National data 1 • Costs: $81.9 billion in 2013 2 – 20.4 million adults (8.3%) – Medical – 6.1 million children (8.3%) – Missed work and – 12.4 million acute attacks school days – 1.7 million ED visits – Asthma-related – 3,518 deaths annually mortality (rate: 10/million) 1. CDC. https://www.cdc.gov/asthma/most_recent_data.htm. 2015, 2016. 2. Nurmagambetov T, et al. Ann Am Thorac Soc . 2018;15(3):348-356.

Economic Burden of Asthma in the US Cost analysis of medically treated asthma* using 2008 – 2012 MEPS data Absenteeism Medical Costs for All Payers † • Work/school days missed per person per year: • 1.6 days (for all ages) • 2.2 days (for children) • Total annual number of work/school days missed: • 22,360 – 1,492,060 days • Represents indirect costs of $4 million – $345 million • Combined medical and absenteeism costs • $65 million – $3,718 million Per person for all ages • From 2015 to 2020, costs are expected to increase by ~24% *Medically treated asthma = diagnosis of asthma and at least one of the following: hospitalization, ED visit, office-based provider visit, outpatient hospital visit, or prescription drug. † Sum of all payments for hospitalizations, ED visits, office-based visits, outpatient visits, and prescription medications made by all payers (Medicare + Medicaid +private insurance). All costs reported in 2014 dollars. MEPS = Medical Expenditure Panel Survey Nurmagambetov T, et al. J Asthma . 2017;54(4):357-370.

ERS/ATS Definition of Uncontrolled Asthma Defined as at least one of the following • Poor symptom control: ACQ consistently > 1.5, ACT < 20 (or “not well controlled” by NAEPP/GINA guidelines) • Frequent severe exacerbations: ≥ 2 bursts of systemic CS (> 3 days each) in the previous year • Serious exacerbations: at least one hospitalization, ICU stay, or mechanical ventilation in the previous year • Airflow limitation: after appropriate bronchodilator withhold FEV1 <80% predicted (in the face of reduced FEV1/FVC defined as less than the lower limit of normal) Many patients with severe asthma are not well-controlled with standard therapy Abbreviations: ACQ: Asthma Control Questionnaire; ACT: Asthma Control Test; NAEPP: National Asthma Education and Prevention Program. Chung KF, et al. Eur Respir J. 2014;43:343-373 .

14 Factors That Can Contribute to Uncontrolled Asthma Disease-Related Factors Patient-Related Factors • Cyclical nature of disease • Comorbidities (eg, GERD, • Increased disease severity rhinosinusitis, depression) • Differing asthma phenotypes Environmental Factors • Smoking • Obesity • Passive smoking • Age • Frequent exposure to • Psychosocial issues (eg, lower Uncontrolled Asthma traffic or air pollution income, poor health literacy) • Outdoor and indoor • Poor treatment adherence allergens • Inadequate inhaler technique Physician-Related Factors • Heterogeneity of treatment response • Medication underprescribing • Failure to follow self-management • Failure to assess adherence plan • Failure to assess inhaler technique • Side effects of other medications • Misdiagnosis (eg, NSAIDs) • Lack of asthma action plan • Absence of specialty care GERD = gastroesophageal reflux disease Adapted from Wechsler ME. Am J Med . 2014;127(11):1049-1059.

Gaining Optimal Asthma Control Study (GOAL) ICS ICS + LABA * 75 80 62 * 60 Percent of Subjects 60 47 40 20 0  <500 mcg >500 - 1000 mcg Daily BDP (or Equivalent) Use in the Past 6 months 25% – 38% were unable to achieve well-controlled asthma despite high-dose ICS, LABA, and oral steroids * P <0.001 BDP = beclomethasone dipropionate; ICS = inhaled corticosteroid; LABA = long-acting beta agonist. Bateman ED, et al. Am J Respir Crit Care Med . 2004;15;170(8):836-844.

ERS/ATS Definition of Severe Asthma Asthma requiring treatment with • Guideline-suggested medications for GINA steps 4 – 5 asthma (high-dose ICS *,† and LABA or leukotriene modifier/theophylline) for the previous year OR • Systemic CS for ≥ 50% of the previous year to prevent it from becoming “ uncontrolled ” or which remains “ uncontrolled ” despite this therapy *For patients ages ≥ 6 years. † Definitions of high-dose ICS vary for patients ages 6-12 years vs those ages > 12 years. ERS = European Respiratory Society; ATS = American Thoracic Society; GINA: Global Initiative for Asthma; ICS = inhaled corticosteroids; LABA: long acting β 2 -agonists; CS = corticosteroids Chung KF, et al. Eur Respir J. 2014;43:343-373.

Focus Is Shifting Toward Disease Mechanisms What can be observed What are the potential and measured clinically? drivers of disease? Observable Characteristics Pathophysiological Mechanism (Phenotype) (Endotype) Lotvall J, et al. J Allergy Clin Immunol . 2011;127(2):355 – 360.