Dupilumab Efficacy and Safety in Adult Patients With Active Eosinophilic Esophagitis: a Randomized Double-Blind Placebo-Controlled Phase 2 Trial

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1 Dupilumab Efficacy and Safety in Adult Patients With Active Eosinophilic Esophagitis: a Randomized Double-Blind -Controlled Phase 2 Trial Ikuo Hirano, Evan S. Dellon, Jennifer D. Hamilton, Margaret H. Collins, Kathryn Peterson, Mirna Chehade, Alain M. Schoepfer, Ekaterina Safroneeva, Marc E. Rothenberg, Gary W. Falk, Yehudith Assouline-Dayan, Zhizhi Qing, Brian N. Swanson, Gianluca Pirozzi, Leda Mannent, Neil M.H. Graham, Bolanle Akinlade, Allen Radin

2 Background EoE is a chronic, type 2 immune-mediated disease characterized by esophageal dysfunction and eosinophil-predominant inflammation in the esophagus There are currently no US FDA-approved treatments for EoE Swallowed corticosteroids are being used off-label with limited studies on long-term efficacy and safety Previous studies of targeted biologic therapies have shown significant histological improvement but not symptom response in EoE EoE, eosinophilic esophagitis; FDA, US Food and Drug Administration.

3 Background Dupilumab, a fully human anti-interleukin (IL)-4 receptor α monoclonal antibody, inhibits signaling of IL-4 and IL-13, key drivers of type 2-mediated inflammation, and is approved in the USA and in the EU for the treatment of adults with moderate-tosevere atopic dermatitis Dupilumab has also shown efficacy and an acceptable safety profile in patients with other type 2 immune diseases including uncontrolled persistent asthma and severe chronic sinusitis with nasal polyps 1. Gandhi N, et al. Expert Rev Clin Immunol Simpson E, et al. N Engl J Med Wenzel S, et al. Lancet Bachert C, et al. JAMA

4 Objective To assess the efficacy and safety of dupilumab in adults with active EoE

5 Study Design: Dupilumab EoE Phase 2 Trial Phase 2, multicenter, double-blind, randomized, placebo-controlled study in patients with active EoE Screening period (1 35 days) Randomization (1:1) N = 47 Dupilumab SC 300 mg every week with 600 mg loading dose n = 23 n = week treatment period 16-week follow-up period PRO endpoints changed from 12 to 10 weeks prior to unblinding due to data capture issues PRO, patient-reported outcome; SC, subcutaneous. ClinicalTrials.gov Identifier: NCT

6 Key Inclusion and Exclusion Criteria Inclusion criteria Age years with prior EoE diagnosis per consensus guidelines Active inflammation with 15 eos/hpf in at least 2 of 3 esophageal regions at screening Patient-reported history of 2 episodes of dysphagia per week in the 4 weeks prior to screening and 2 episodes of dysphagia per week between screening and baseline Straumann Dysphagia Instrument (SDI) PRO score 5 at screening and baseline Presence of a coexisting allergic condition, peripheral eosinophil count 0.25 GI/L, or serum IgE 100 ku/l Exclusion criteria Esophageal stricture unable to be passed with a standard adult upper endoscope Dilation required at screening Use of systemic corticosteroids < 3 months or swallowed topical corticosteroids (TCS) < 6 weeks prior to screening

7 Primary Endpoint Change in SDI PRO total score from baseline to Week 10 Dysphagia frequency (0 4) None = 0 Once per week = 1 Several times per week = 2 Once per day = 3 Several times per day = 4 Dysphagia severity (0 5) Swallowing unhindered = 0 Slight sensation of resistance = 1 Slight retching with delayed passage = 2 Short period of obstruction necessitating intervention = 3 Longer-lasting period of obstruction, only removable by regurgitation = 4 Long-lasting complete obstruction, requiring endoscopic intervention = 5 Straumann A, et al. Gastroenterology 2010.

8 Secondary Endpoints % change in weekly Eosinophilic Esophagitis symptom Activity Index (EEsAI) PRO score from baseline to Week 10 Scale 0 100; higher scores = worse symptoms % change in overall peak esophageal eosinophil count (eos/hpf) at Week 12 Change in EoE endoscopy EREFS score from baseline to Week 12 Scale 0 8; higher scores = more severe endoscopic findings Incidence of treatment-emergent adverse events EREFS, edema, rings, exudates, furrows, strictures. 1. Schoepfer AM, et al. Gastroenterology Hirano I, et al. Gastroenterol Clin North Am

9 Exploratory Endpoints Change in EoE-Histological Scoring System (HSS) from baseline to Week 12 7 findings assessed; scale 0 63; higher scores = more severe histologic findings Change in esophageal distensibility plateau from baseline to Week 12 Measured using the Functional Lumen Imaging Probe (FLIP) FLIP simultaneously measures the diameter of the esophageal lumen and pressure (e.g. esophageal rigidity). Collins MH, et al. Dis Esophagus

10 Baseline Demographics and Clinical Characteristics Characteristic a Calculated using peak count from each esophageal region (mid, proximal, and distal). (n = 24) Dupilumab 300 mg every week (n = 23) Age, mean (SD), years 36.1 (12.8) 33.1 (8.7) Male sex, n (%) 10 (41.7) 13 (56.5) White race, n (%) 21 (87.5) 23 (100) Prior dilation, n (%) 10 (41.7) 11 (47.8) Number of prior esophageal dilations, mean (SD) 3.9 (3.3) 5.7 (8.0) 1 prior use of a corticosteroid for EoE, n (%) 9 (37.5) 7 (30.4) > 1 comorbid atopic disease, n (%) 19 (79.2) 20 (87.0) Blood eosinophil count, mean (SD), GI/L 0.4 (0.3) 0.3 (0.2) Serum total IgE, mean (SD), IU/mL (900.7) (288.8) SDI PRO score, mean (SD), scale (1.0) 6.4 (1.0) EREFS score, mean (SD), scale (1.5) 3.9 (1.9) Overall peak eosinophil count, mean (SD), eos/hpf a (57.1) (53.5)

11 Primary Endpoint Dupilumab significantly reduced SDI PRO score at Week 10 0 LS mean (± SE) change from baseline in SDI score P = (n/n = 14/24) Dupilumab 300 mg every week (n/n = 17/23) LS, least-squares.

12 Secondary Endpoint Dupilumab numerically reduced weekly EEsAI PRO score at Week 10 LS mean (± SE) % change from baseline in EEsAI score P = (n/n = 13/24) Dupilumab 300 mg every week (n/n = 17/23)

13 Secondary Endpoint Dupilumab significantly reduced overall peak esophageal intraepithelial eosinophil count at Week LS mean (± SE) % change from baseline in peak eosinophil count P < (n/n = 22/24) Dupilumab 300 mg every week (n/n = 23/23)

14 Secondary Endpoint Dupilumab significantly reduced overall peak esophageal intraepithelial eosinophil count at Week LS mean (± SE) % change from baseline in peak eosinophil count P < Peak eos (eos/hpf) at Week 12 Proportion of patients with response at Week 12, n (%) Dupilumab 300 mg qw P value vs placebo 6 0 (0) 15 (65.2) < < 15 0 (0) 19 (82.6) < (n/n = 22/24) Dupilumab 300 mg every week (n/n = 23/23) qw, every week.

15 Secondary Endpoint Dupilumab significantly decreased EREFS score at Week LS mean (± SE) change from baseline in EREFS score P = (n/n = 22/24) Dupilumab 300 mg every week (n/n = 23/23)

16 Exploratory Endpoint Dupilumab significantly improved total EoE-HSS grade and stage scores at Week 12 LS mean (± SE) % change from baseline in EoE-HSS grade score Total grade (n/n = 20/24) P < Dupilumab 300 mg every week (n/n = 21/23) LS mean (± SE) % change from baseline in EoE-HSS stage score Total stage (n/n = 20/24) P < Dupilumab 300 mg every week (n/n = 23/23)

17 Exploratory Endpoint Dupilumab significantly improved esophageal distensibility plateau at Week 12 LS mean (± SE) % change from baseline in distensibility plateau P < (n/n = 12/24) Dupilumab 300 mg every week (n/n = 12/23)

18 Dupilumab Was Generally Well Tolerated During the Study Period 12-week end of treatment period 28-week end of study period n (%) Dupilumab Dupilumab 300 mg qw 300 mg qw (n = 24) (n = 24) (n = 23) (n = 23) 1 treatment-emergent adverse events 15 (62.5) 18 (78.3) 16 (66.7) 21 (91.3) 1 serious adverse event a (13.0) Adverse events leading to treatment discontinuation 0 1 (4.3) 0 1 (4.3) Deaths Malignancies Terms with the difference of number of patients between two groups 3 Injection-site reactions (HLT) 7 (29.2) 13 (56.5) 7 (29.2) 13 (56.5) Injection-site erythema (PT) 2 (8.3) 8 (34.8) 2 (8.3) 8 (34.8) Injection-site inflammation (PT) 0 3 (13.0) 0 3 (13.0) Injection-site rash (PT) 0 3 (13.0) 0 3 (13.0) Upper respiratory tract infections (HLT) 3 (12.5) 7 (30.4) 6 (25.0) 9 (39.1) Nasopharyngitis (PT) 1 (4.2) 4 (17.4) 2 (8.3) 5 (21.7) Musculoskeletal, connective tissue pain and discomfort (HLT) 0 3 (13.0) 0 4 (17.4) a Serious adverse events were considered to not be related to the investigational medicinal product. There were no cases of conjunctivitis during the study period in dupilumab or placebo treated patients despite a prior history of conjunctivitis of 3 patients in each group. HLT, high level Term; PT, preferred term.

19 Conclusions Dupilumab significantly improved dysphagia, esophageal eosinophil counts, endoscopic features, histology, and esophageal distensibility in adults with active EoE compared with placebo Dupilumab was generally well tolerated, although nonserious injection-site erythema and nasopharyngitis occurred more frequently in the dupilumab group versus placebo These results confirm the critical role of IL-4 and IL-13 in EoE and support further evaluation of dupilumab

20 Acknowledgments Study investigators Alpan, Oral Hardi, Robert Leung, John Wo, John Barish, Charles Gordon, Glen Garber, John Mitlyng, Benjamin Whitlock, Tom Hendrix, Paul Regeneron Pharmaceuticals, Inc. Williams, Linda Chaudhry, Usman Sanofi Barry, Dianne Research sponsored by Sanofi and Regeneron Pharmaceuticals, Inc. ClinicalTrials.gov identifier: NCT Medical writing/editorial assistance provided by Xiomara V. Thomas, PhD, of Excerpta Medica, funded by Sanofi Genzyme and Regeneron Pharmaceuticals, Inc.