10/24/2016. Precision Management of Severe Asthma How, When and Where. The Goals of Today s Presentation

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1 1/24/216 Precision Management of Severe Asthma How, When and Where. Reynold A. Panettieri, Jr., MD Vice Chancellor for Clinical & Translational Science Director, Rutgers Institute for Translational and Medical Sciences The Goals of Today s Presentation Discuss severe asthma and how our understanding of disease mechanisms is evolving Introduce the phenotyping / endotyping paradigm Understand the role of biomarkers as a tool for identifying endotypes in clinical practice Explore the targets to manage an asthma endotype Doctors have always recognized that every patient is unique, and doctors have always tried to tailor their treatments as best they can to individuals. You can match a blood transfusion to a blood type that was an important discovery. What if matching a cancer cure to our genetic code was just as easy, just as standard? What if figuring out the right dose of medicine was as simple as taking our temperature? - President Obama, January 3,

2 1/24/216 Precision Medicine Mission Statement To enable a new era of medicine through research, technology, and policies that empower patients, researchers, and providers to work together toward development of individualized care. 4 Heterogeneity in Disease and Response to Therapy Jameson JL. N Engl J Med. 215;372(23): Heterogeneity in Disease and Response to Therapy Jamison JL et al NEJM

3 1/24/216 Examples of Precision Medicine Use Medical Field Disease Biomarker Intervention Cancer Chronic BCR-ABL Imatinib Myeloid Leukemia Hematology Thrombosis Factor V Avoid prothrombotics Leiden Infectious disease HIV/AIDS CD4+ T cells Antiretroviral therapy Highly active viral load Cardiovascular disease CAD CYP2C19 Clopidogrel Neurology Autoimmune CXCL13 Immunotherapy encephalitis Psychiatry Alcohol-use GRIK1 Topiramate disorder Pharmacogenomics Smoking CYP2A6 Varenicline cessation 7 Asthma as an Umbrella Term Based on Clinical Features Asthma Early onset Symptoms Late onset Exacerbations FEV 1 Adapted from Wenzel S. Nat Med. 212;18(5): Understanding of the Disease Is Changing Previous Understanding Patients with similar clinical characteristics have been grouped and treated similarly The Challenge Many patients may not respond to therapy considered to be the standard of care One size does not fit all Evolving Understanding Clinical differences in treatment response are related to underlying variations in multiple mechanisms: - genetic - pharmacologic - physiologic - biologic - immunologic Muraro A, et al. J Allergy Clin Immunol. 216;137:

4 1/24/216 Proposed Definitions Phenotype 1 The set of observable characteristics of an individual resulting from the interaction of his or her genotype with the environment (eg, atopy, obesity) Endotype 1,2 Subtype of a condition, which is defined by a distinct functional or pathobiological mechanism (eg, eosinophilic, Th2 high) 1. Wenzel SE. Nat Med. 212;18(5): Lang DM. Allergy Asthma Proc. 215;36: Importance of Biomarkers Barriers to Care in Uncontrolled Asthma 1 3 Utility of Biomarkers 4 Inadequate treatment response with standard of care Incomplete understanding of inflammatory mechanisms Phenotype and endotypes are not well established Need for targeted therapies Disease heterogeneity Define populations that will derive most benefit from a drug Predict disease course Monitor the effects of therapy Monitor adverse events Identify new biological pathways Facilitate identification of new drug targets Lang DM. Allergy Asthma Proc. 215;36: Drazen JM, et al. J Allergy Clin Immunol. 212;129: De Groot JC, et al. ERJ Open Res. 215;1:24 215; doi: / Cazzola M, et al. Pulm Pharmacol Ther. 21;23: Emerging Multidimensional Biomarker Approaches for Asthma Clinical value established Clinical value disputed Research level Sputum Inflammatory phenotypes Eosinophils/neutrophil s ECP Signaling proteins BAL and biopsy Remodeling Eosinophilia Cytokines Peripheral blood Periostin Genetics (also see: saliva) Granulocyte phenotypes Eosinophilia IgE Cytokines and chemokines ECP Exhaled air FeNO Volatile organic compounds: Patterns Exhaled Breath Condensate: Cytokines and chemokines ph Markers of oxidative stress Saliva Leukotrienes Genetics Susceptibility genes Pharmacogenetics Cytokines Urine Leukotriene Metabolites ulte4 There are numerous emerging biomarkers for asthma under investigation for their value in clinical research and practice 1,2 Single biomarker approaches remain important in the process of biomarker discovery, as newly identified biomarkers can be integrated into a multidimensional approach, strengthening their clinical value for different asthma phenotypes 2 1. Varricchi G, et al. Curr Opin Allergy Clin Immunol. 216;16(2): Vijverberg SJ, et al. Biologics. 213;7:

5 1/24/216 Characteristics of An Ideal Biomarker for Use in Clinical Practice Bronchoscopy with biopsies and bronchoalveolar lavage (BAL) considered the gold standard to assess airway inflammation, but are too cumbersome for application in clinical practice 1 An Ideal Biomarker 2 Easy to collect and measure Not invasive or expensive Confirms diagnosis Identifies either clinical or treatment response to phenotypes Evaluates changes in disease activity 1. Vijverberg SJ, et al. Biologics. 213;7: Chiappori A, et al. Clin Mol Allergy. 215;13:2. Asthma Outcomes Expert Panel: Recommendations Characterization of Study Prospective Clinical Trial Population for Prospective Clinical Trials Efficacy/ Effectiveness Outcomes Observational Study Outcomes Core Outcome Multiallergen screen (IgE) to define None None atopy Supplemental FeNO FeNO FeNO Sputum eosinophils Sputum eosinophils Sputum eosinophils CBC (total eosinophils) Total IgE CBC (total eosinophils) Total IgE CBC (total eosinophils) Total IgE Allergen-specific IgE Allergen-specific IgE Allergen-specific IgE Urinary LTE 4 Urinary LTE 4 Urinary LTE 4 Emerging Allergen skin testing Allergen skin testing Sputum PMNs and analytes Sputum PMNs and analytes Sputum PMNs and analytes Airway imaging Airway imaging Exhaled breath markers Airway imaging Cortisol measures Discovery by genetics and genomics Discovery by genetics and Exhaled breath markers genomics Discovery by genetics and genomics Szefler SJ. J Allergy Clin Immunol. 212;129(3 Suppl):S9 S23. Multiallergen Screen (IgE) A single, semiquantitative serologic measure of immunoglobulin E (IgE) against major allergens 1 Th2-high asthma patients often have high allergen-specific IgE as well as elevated levels of IL-4, IL-5, IL-13 2 A core biomarker for atopic asthma 1 Characterizes an individual as atopic, but does not specify which allergen(s) the person is sensitized to 1 In adults, the Phadiatop assay is recommended 1 In children under 15 years of age, addition of fx5 food allergen mix to the adult Phadiatop is recommended 1 1. Szefler SJ. J Allergy Clin Immunol. 212;129(3 Suppl):S9 S Vijverberg SJ, et al. Biologics. 213;7:

6 Lung Function (FEV1) Lung Function (FEV1) 1/24/216 Exhaled Nitric Oxide (FeNO) Quantitative measurement of airway NO, produced in cells by NO synthase; considered an indirect marker for airway inflammation 1 Considered a marker of Th2 inflammation and atopy, but not an effective biomarker useful in severe asthma 2 - Levels correlate with lung eosinophilia and inflammation, but are independent of IL-5 3 Recommended as a supplemental biomarker in asthma clinical trials 1 Benefits 1 Disadvantages 1 Methodology well standardized and normal ranges moderately well defined Reproducible and responsive to treatment Easy to perform and no risk Can be high in atopic individuals without asthma Equipment can be expensive The inflammatory factors that drive FeNO during an asthma episode remain unclear Unclear relationship to asthma control, phenotypes, and airway remodeling 1. Szefler SJ. J Allergy Clin Immunol. 212;129:S9 S Chiappori A, et al. Clin Mol Allergy. 215;13:2. 3. Fajt ML, Wenzel SE. 2. J Allergy Clin Immunol. 215;135: NATURE v NURTURE? ABERRANT INJURY-REPAIR RESPONSES PROMOTE AIRFLOW OBSTRUCTION IN ASTHMA Epigeneti c Epigeneti c Lazaar and Panettieri, Am J Med, 23 ASTHMA: A CHRONIC ACUTE DISEASE? Conventional Thought New Hypotheses Age (years) Age (years) Lazaar and Panettieri, 23 6

7 1/24/216 Loss of Lung Function in Asthma 6 Height-Age Adjusted Median FEV A B C Age (years) Damera, G and Panettieri R, 214 Stepwise Approach for Managing Asthma High-dose ICS + LABA + 6 Oral Corticosteroids Alternatives and Consider Omalizumab Needed 4 5 High-dose ICS + LABA and Consider Omalizumab Medium-dose ICS + LABA Low-dose ICS + Long-acting Beta 2-agonists (LABA) or Medium-dose ICS Low-dose Inhaled Corticosteroids (ICS) Short-acting Beta 2-agonists Adapted from National Asthma Education and Prevention Program (NAEPP) Guidelines. Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma. National Heart, Lung, and Blood Institute, NIH Publication No , Revised August 27. Immunobiology of Asthma Pelaia G et al. Nature Rev Drug Discov 212; 11:

8 Severe exacerbations (cumulative number) EG2-positive cells (%) 1/24/216 Eosinophils and Asthma Elevated Eosinophils in Airways of Patients With Atopic Asthma 1 Mean Cell Counts/mm Basement Membrane (SEM) Marker Asthma Nonasthmatic Nonatopic (atopic) Atopics Controls Airway level 1 CD (29.9) 48. (9.9) 48. (11.6) CD3 44. (11.9) 21. (5.) 18. (3.5) CD4 26. (6.7) 11.5 (3.8) 1. (3.7) CD8 1. (3.4) 4.7 (1.4) 4.5 (2.4) CD (.9)*.2 (.1).6 (.6) Elevated Eosinophils and Eosinophil Progenitors in Hyperresponse (HR) and Normoresponse (NR) Patients 1 6 Atopic asthmatic (grey circles), nonasthmatic atopic 5 (maroon triangles), and nonatopic healthy subjects (open circles) EG2 9.3 (2.7)* 2.7 (1.3)*.1 (.1) Eosinophil 4.3 (1.8)*.9 (.5).17 (.1) Neutrophil elastase 5. (1.2) 3.8 (.8) 7.5 (1.4) SEM, standard error of the mean. 1 HR p <.1 NR Increased eosinophils now known to be present in sputum, airways, and airway mucosal wall in 4% 6% of patients with asthma and contribute to airway dysfunction and tissue remodeling 2 5 *P<.5 compared with nonatopic asthmatics. Comparison with nonasthmatic atopic subjects. 1. Azzawi M, et al. Am Rev Respir Dis. 199;142: Zhang JY, et al. Immunol Clin North Am. 27;27: Douwes J, et al. Thorax. 22; 57: ; 4. Schleich FN, et al. BMC Pulmonary Med. 213;13:1. 5. Rosenberg HF, et al. Nat Rev Immunol. 213;13(1):9 22. The Impact of Managing Eosinophilic Inflammation in Moderate to Severe Asthma Cumulative Asthma Exacerbations in the BTS vs Sputum Management Group a1 (n=34) 6 asthma admissions BTS group Sputum group (n=34) 2 1 asthma admission Time (months) Elevated sputum eosinophil concentrations can persist in patients receiving standard of care 2,3 a Data from a randomized control trial in 74 patients aged years with moderate to severe asthma from specialist clinics at Glenfield Hospital, Leicester, UK between March and October Green RH, et al. Lancet. 22;36: Chung KF, et al. Eur Respir J. 214;43: Zhang JY, et al. Immunol Clin North Am. 27;27: Driven By a Tailored Approach to Therapy for Uncontrolled Asthma Personalized approach to asthma Diagnosis Refractory asthma? Phenotype Characterize subtype Genotype Gender Age Obesity Ethnicity Smoking Hx Blood biomarkers Endotypes Sputum biomarkers Other lge Eosinophils Periostin Cytokines Eosinophils Neutrophils Cytokines FeNO Tailored therapy Dunn RM, Wechsler ME. Clin Pharmacol Ther. 215;97(1):

9 Total number of clinically significant exacerbations 1/24/216 New Therapeutics in Severe Asthma that Impact Eosinophil Biology Investigational products IL-5/Rα IL-13/4R Mepolizumab Anti-IL-5 Reslizumab EOS Lebrikizumab Anti-IL-13 Tralokinumab Periostin/DPP-IV/ IL-13/eosinophils Linkage exists between mechanisms and potential for efficacy in patients with elevated eosinophils in IL-5 and IL-13/4R classes Mepolizumab, reslizumab and benralizumab (all with elevated EOS in blood or sputum) Lebrikizumab (MILLY)(when using the Th2 definition) Dupilumab (EOS >3 population) Anti-IL-5 Benralizumab Anti-IL-5Rα Anti-IL-13 Dupilumab Anti-IL-4Rα Mepolizumab for Severe Eosinophilic Asthma (DREAM) Reduced exacerbations and improved efficacy with increasing eosinophilia 3 25 Placebo 75 mg mepolizumab 25 mg mepolizumab 75 mg mepolizumab Time from start of treatment (months) Pavord I et al. Lancet 212; 38: Asthma Exacerbations and FEV 1 at 32 Weeks Ortega HG et al. N Engl J Med 214;371:

10 Probability of not experiencing CAE (%) Probability of not experiencing CAE (%) 1/24/216 Reslizumab Increased Time to First Exacerbation Description of planned arm Placeb o Reslizumab 2 Study 1 Study 2 Placebo: N=244 Reslizumab: N= Time to first CAE (weeks) Censored observations: Description of planned arm Placeb o Reslizumab Placebo: N=232 Reslizumab: N= Time to first CAE (weeks) Censored observations: 7 8 TTF: Kaplan Meier probability of not having an exacerbation by week 52 (95% CI) p value Placebo Study (37.7, 5.5) Study (45., 58.3) Reslizumab 61.3 (54.7, 67.2) 73.2 (66.8, 78.6) p<.1 p<.1 Castro et al, Lancet Respir Med 215;3: Biologic Rationale for Anti-IgE Therapy IgE plays a central role in the inflammatory cascade in asthma and represents a key target for therapeutic intervention Targeting IgE with omalizumab, impacts multiple layers of the inflammatory response via effects on: Dendritic cells Mast cells Basophils Th2 cytokines (IL-4/-5/-13) Eosinophils Exacerbations: Pooled analysis of exacerbation rates across seven studies Study Treatment difference versus control Relative reduction versus control (%) P-value INNOVATE ETOPA <.1 SOLAR Study <.1 Study <.1 Study ALTO Pooled <.1 Analysis of asthma exacerbations using Poisson regression for individual studies and pooled data (intent-to-treat population). *Rate adjusted for exacerbations at baseline; INNOVATE data therefore vary slightly from those published in Humbert, et al. 1 due to different methods of grouping centers. The pooled analysis includes unadjusted INNOVATE data. 7 1 Humbert M, et al. Allergy 25;6:39 16; 2 Ayres JG, et al. Allergy 24;59:71 8; 3 Vignola AM, et al. Allergy 24;59:79 17; 4 Busse W, et al. J Allergy Clin Immunol 21;18:184 9; 5 Solèr M, et al. Eur Respir J 21;18:254 61; 6 Holgate ST, et al. Clin Exp Allergy 24;34:632 8; 7 Bousquet J, et al. Allergy 25;6:

11 Eosinophils (% of inflammatory cells) 1/24/216 Eosinophils Omalizumab significantly reduces sputum eosinophil counts in mild-to-moderate asthma 4 p=.5 p= p< Baseline Post-treatment Baseline Post-treatment Omalizumab (n=19) Placebo (n=22) Horizontal bars are median values Adapted from: Djukanović R, et al. Am J Respir Crit Care Med 24;17: Predicted Response to Omalizumab from EXTRA Study: eno, EOS and Periostin Hanania NA, AJRCCM 213;187:84 11 Summary and Conclusions Asthma is a complex and heterogeneous disease Our understanding of disease mechanisms is evolving; however, there is much more to learn Biomarkers will be important for identifying disease mechanisms in both the laboratory and the clinic Eosinophils represent a potential asthma endotype that are actively being studied in the context of severe asthma A goal is to better correlate phenotypes with endotypes and prescribe therapies that specifically address underlying disease mechanisms 11

12 1/24/216 Biomarkers for Practitioners The Right Diagnosis The Right Patient At the Right Time The Right Therapy Paving the Way For Personalized Medicine. Food and Drug Administration (FDA) Report. October Accessed June 27,