Precision Asthma Therapy: Picking the Right Biologic for the Right Patient. The Asthma Umbrella. Asthma. Late onset. Early onset.

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1 recision Asthma Therapy: icking the Right Biologic for the Right atient The Asthma Umbrella Asthma arly onset Late onset Symptoms xacerbations FV1 T H 2 inflammation No or less T H 2 inflammation henotype A henotype B henotype C henotype D Wenzel S. Nature Medicine 18, (2012) recision Asthma Therapy: The ath Forward Clinical phenotypes Treatable traits Molecular endotypes recision medicines Remissions and cures

2 henotypes to ndotypes Wenzel S. ulm harmacol Ther. 2013;26: Journal of Allergy and Clinical Immunology , DOI: ( /j.jaci ) Copyright 2015 American Academy of Allergy, Asthma & Immunology JACI, May 2016

3 JACI, May 2016 Neutrophilic inflammation Type 2 Low Asthma aucigranulocytic inflammation ILC1/3? pithelium Neutrophil Th1 Th17 IL-8 IL-23 Barrier dysfunction roteases ROS IFN- TNF- Airway hyperreactivity and remodeling IL-17 IL-22 IL-23 CXCR2 H N O T Y N D O T Y Approved Under investigation otential Neutrophilic Asthma: A otential Biomarker for Disease Maes et al, JACI, May, 2016

4 fficacy Of A CXCR2 (IL-8) Antagonist In Severe Asthma With Sputum Neutrophils Blood Sputum Nair, et al. Clin xp Allergy Jul;42(7): osinophilic inflammation IL-5 Type 2 Hi Asthma Ag-specific Ig Airway hyperreactivity and remodeling ILC2 pithelium Mast cell NKT Th2 IL-13 IL-9 CRTH2/GD2 TSL IL-33 Barrier dysfunction IL-4 IL-13 IL-9 CRTH2/GD2 IL-4 IL-13 IL-4 IL-13 IL-5 CRTH2/GD2 H N O T Y N D O T Y JACI, May 2016 Approved Under investigation otential osinophil Specific Ig Biomarker BLOOD eriostin Dipeptidyl peptidase-4 (D-4) INDUCD SUTUM osinophils Treatment expected to produce a response Anti-IL5 Anti -Ig Anti- IL-4/IL-13 Corticosteroids (CS) CRTH2 antagonists Anti-Ig AIT Anti-IL-13 Anti IL-5 ICS Associations xacerbations LF decline Fixed airway obstruction xacerbations AHR (AIT) LF decline xacerbations xacerbations Comments (point of care, variability/fluctuation) asily available Significant fluctuation Research type Assay dependent Research type Significant fluctuation IL-13 Anti IL-13? Research type XHALD BRATH FeNO Anti IL-5 Anti Ig Anti IL-13 ICS xacerbations, LF decline asily available oint of care Significant fluctuation Metabolomics (VOC) ICS? Research type

5 Novel Ways to Measure osinophils in Clinical ractice Inexpensive, point-of-care diagnostic tools being developed to improve management of patients with respiratory diseases Bioactive paper 1 Bio-inks on paper strip measures quantity of eosinophil peroxidase (X) in sputum Throat or nasal swabs 2 Strong association between nasal and pharyngeal X levels and percentage of induced sputum eosinophils otentially clinically relevant diagnostic metric; simplicity of use provides potential novel point-of-care assay for management of poorly controlled patients Nasal X levels (ng/mg of total protein) Nasal X 2 r s = Induced sputum eosinophilia (% Non-Squamous Cells) haryngeal X levels (ng/mg of total protein) haryngeal X 2 r s = Induced sputum eosinophilia (% Non-Squamous Cells) 1. Bioactive aper Will Revolutionize oint-of-care Diagnostics. March 7, Rank MA et al. Allergy. 2016;71(4): otential for application in doctor s offices, outpatient clinics, and by patients themselves for self-management 1 Subgroup Analysis Of 177 atients With Blood osinophils 80% reduction in exacerbation Source: Ortega et al. N ngl J Med 2014; 371: Reslizumab ffects on FV1 and ACQ Based On Bld os: 16-Week Studies Corren et al, Chest, 2016, In ress

6 Benralizumab s ffects on Annual xacerbation Rate By osinophil Level 0.9 lacebo Benralizumab 2 mg Benralizumab 20 mg Benralizumab 100 mg 0.8 Annual exacerbation rate RR= -30% p=0.327 RR=24% p=0.362 RR=30% p=0.131 RR=-7% p=0.822 RR=43% p=0.049 RR=57% p=0.015 RR=6% p=0.844 RR=57% p=0.024 RR=70% p= cells/l 300 cells/l 400 cells/l RR, rate ratio Castro et al. Lancet Resp Med 2014; 2: Dupilumab-Induced Changes From Baseline in Absolute FV 1 By osinophils Hos ul) population Los (< 300 cells/ul) population lacebo q2w Dup 300q4w Dup 300q2w Dup 200q4w Dup 200q2w LS Mean Change ± S Baseline Week LS Mean Change ± S lacebo 200 mg q2w 300 mg q2w 200 mg q4w 300 mg q4w Week Wenzel, et al, Lancet, 2016 Asthma xacerbation Reductions in Omalizumab Clinical Trials by osinophil Strata 10% Asthma xacerbation Reduction 0% -10% -20% -30% -40% -50% -60% -70% <300 <300 <300 <300 <300 osinophils per L Sources: Hanania et al. AJRCCM 2013; Busse et al. JACI 2013; Genentech and Novartis Data on File

7 Heightened Response Of osinophilic Asthmatics To CRTH2 Antagonist OC os>250 os<250 ettipher R, et al. Allergy Sep;69(9): ndotype-driven Treatment In T2 Asthma JACI, May Week Replicate Lebrikizumab Trials in Adults with Asthma Hanania NA, et al. Thorax Aug;70(8):748.

8 Changes In FV 1 In Subgroups Treated With Tralokinumab for 52 Weeks 2 Why recision Medicine is Important