![]() Safety and efficacy of dupilumab for moderate-to-severe atopic dermatitis in patients using topical corticosteroids (TCS): Greater efficacy observed with combination therapy compared to TCS alone Diamant Thaçi, 1 Margitta Worm, 2 Haobo Ren, 3 Steven Weinstein, 3 Neil Graham, 3 Gianluca Pirozzi, 4 Franck Skobieranda, 4 Marius Ardeleanu 3 1 Universität zu Lübeck, Lübeck, Germany; 2 Charite-Universitätsmedzin Berlin, Berlin, Germany; 3 Regeneron Pharmaceuticals, Inc., Tarrytown, USA; 4 Sanofi, Bridgewater, USA Exhibit 99.1 |
![]() Disclosures Disclosures D Thaçi is a consultant for Astellas, Novartis, D Thaçi is a consultant for Astellas, Novartis, Regeneron, Celgene, Abbott, Pfizer, Janssen-Cilag, Regeneron, Celgene, Abbott, Pfizer, Janssen-Cilag, MSD, Leo-Pharma MSD, Leo-Pharma M Worm has nothing to disclose M Worm has nothing to disclose H Ren, S Weinstein, N Graham, and M Ardeleanu are H Ren, S Weinstein, N Graham, and M Ardeleanu are employees and shareholders of Regeneron employees and shareholders of Regeneron G Pirozzi is an employee and shareholder of Sanofi G Pirozzi is an employee and shareholder of Sanofi F Skobieranda was an employee of Sanofi when the F Skobieranda was an employee of Sanofi when the study was conducted study was conducted Study (NCT01639040) funded by Regeneron Study (NCT01639040) funded by Regeneron Pharmaceuticals, Inc. and Sanofi Pharmaceuticals, Inc. and Sanofi |
![]() Introduction Introduction Moderate-to-severe atopic dermatitis (AD) is characterized by Moderate-to-severe atopic dermatitis (AD) is characterized by eczematous dermatitis with intractable pruritus associated with sleep eczematous dermatitis with intractable pruritus associated with sleep disturbance and lower quality-of-life disturbance and lower quality-of-life For many patients, current therapies are inadequate and can be For many patients, current therapies are inadequate and can be associated with unwanted side effects associated with unwanted side effects IL-4 and IL-13 are thought to be central to T-helper 2 (Th2) IL-4 and IL-13 are thought to be central to T-helper 2 (Th2) inflammation, which mediates many features of AD inflammation, which mediates many features of AD Dupilumab is a fully human monoclonal antibody targeting the IL-4 Dupilumab is a fully human monoclonal antibody targeting the IL-4 receptor alpha subunit (IL-4R ), thus blocking the intracellular signaling receptor alpha subunit (IL-4R ), thus blocking the intracellular signaling of both IL-4 and IL-13 of both IL-4 and IL-13 Earlier clinical trials indicated that dupilumab monotherapy had Earlier clinical trials indicated that dupilumab monotherapy had an an acceptable safety profile and was efficacious in patients with moderate acceptable safety profile and was efficacious in patients with moderate to severe AD who cannot be adequately controlled with topical to severe AD who cannot be adequately controlled with topical medications medications Since topical corticosteroids (TCS) are commonly used in AD, we Since topical corticosteroids (TCS) are commonly used in AD, we assessed the safety and efficacy of dupilumab co-administered with assessed the safety and efficacy of dupilumab co-administered with TCS TCS |
![]() TGF- IL-10 T cells in immune mediated diseases T cells in immune mediated diseases IFN- IL-2 (IL-10) TNF- LT-a IL-4 IL-5 IL-10 IL-13 (TNF- ) IL-17A IL-17F IL-21 IL-22 (IL-10) (TNF- ) RORc2 Foxp3 GATA-3 IL-22 IL-13 (IL-10) FGF´s (TNF- ) ? ALLERGY INFLAMMATION, INFECTION EPITHELIAL INTEGRITY LIMITATION INFLAMMATION Th1 Th2 Th17 Th22 iTreg T naive |
![]() Atopic dermatitis: a disease of altered skin barrier and immune dysregulation Boguniewicz M, Leung DM. Immunol Rev. 2011 Jul;242(1):233-46. |
![]() Dupilumab blocks the Dupilumab blocks the IL-4/IL-13 receptor/ligand system IL-4/IL-13 receptor/ligand system Type I Receptor B cells, T cells, Monocytes, Eosinophils, Fibroblasts Type II Receptor Epithelial cells, Smooth muscle cells, Fibroblasts, Monocytes, Activated B cells |
![]() Study treatment (weekly SC injection for 4 wks) Dupilumab 300 mg + TCS (n=21) Screening Safety follow-up (7 wks) n=31 Randomized, double-blind, parallel- group, placebo-controlled study (NCT01639040) conducted in EU (NCT01639040) conducted in EU Placebo + TCS (n=10) Adult moderate-to- severe AD patients All patients received concomitant treatment with a potent TCS product on a standardized regimen: daily applications to active lesions, followed by applications two days per week once lesions were under control Topical treatment of any residual active AD lesions continues at the discretion of the investigator Study endpoints: • Primary endpoint was incidence and severity of adverse events (AEs) • Exploratory efficacy endpoints included EASI-50, IGA 1, SCORAD score |
![]() Key inclusion/exclusion criteria Key inclusion/exclusion criteria Inclusion • Male or female 18 yrs • Chronic AD > 2 yrs • IGA 3 • SCORAD > 20 • 10% BSA of AD involvement • Active AD lesion(s) for which treatment with potent TCS is indicated Exclusion • Hypersensitivity to TCS • 50% of the cumulative lesional surface located on face, flexural, or genital areas (generally unsuitable for treatment with potent TCS) • Acute or chronic infections • Recent treatment with immuno- suppressive/immunomodulating drugs • Significant co-morbidities or lab abnormalities |
![]() Baseline demographics Baseline demographics Placebo + TCS (n=10) Dupilumab SC 300 mg +TCS (n=21) Mean age, yrs (SD) 37.8 (16.7) 36.0 (11.3) Race, n (%) Caucasian 10 (100%) 20 (95.2%) Non-Caucasian 0 1 (4.8%) Gender, n (%) Male 5 (50.0%) 8 (38.1%) Female 5 (50.0%) 13 (61.9%) Mean BMI, kg/m 2 (SD) 23.92 (3.47) 25.26 (3.26) |
![]() Baseline disease characteristics Baseline disease characteristics [mean (SD)] [mean (SD)] Placebo + TCS (n=10) Dupilumab SC 300 mg +TCS (n=21) AD duration, yrs 32.4 (16.8) 30.9 (13.0) EASI score (0-72) 24.10 (12.70) 23.12 (12.35) IGA score (0-5) 3.35 (0.47) 3.43 (0.60) SCORAD score (0-103) 58.20 (13.83) 66.31 (13.01) % BSA of AD 38.85 (24.05) 40.43 (20.91) Pruritus Numeric Rating Scale (NRS) score (0-10) 5.00 (1.40) 6.43 (2.00) EASI=Eczema Area Severity Index; IGA=Investigator’s Global Assessment; SCORAD=scoring of atopic dermatitis; BSA = baseline body surface area; NRS=numeric rating scale |
![]() Treatment emergent adverse events Treatment emergent adverse events Placebo + TCS (n = 10) Dupilumab + TCS (n = 21) Total number of AEs 14 41 Total number of serious AEs 1 0 Deaths 0 0 Number (%) of patients discontinued from study due to AE 1 (10.0%) 0 Number (%) of patients with: Any AE 7 (70.0) 12 (57.1) Any serious AE 1 (10.0) 0 Most common AEs ( 5% in dupilumab groups) • Nasopharyngitis 2 (20.0) 5 (23.8) • Headache 1 (10.0) 3 (14.3) • Oropharyngeal pain 1 (10.0) 3 (14.3) • Rhinitis 0 2 (9.5) • Cough 0 2 (9.5) • Influenza 0 2 (9.5) • Somnolence 0 2 (9.5) |
![]() Dupilumab+TCS significantly improved Dupilumab+TCS significantly improved measures of efficacy vs TCS alone measures of efficacy vs TCS alone Placebo+TCS 300 mg DPL+TCS Placebo+TCS 300 mg DPL+TCS EASI-50 Responders (Patients achieving 50% Reduction in EASI) Pruritus Numeric Rating Scale 0 10 20 30 40 50 60 70 80 90 100 0 5 10 15 20 25 30 Study Day -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 0 5 10 15 20 25 30 Study Day *p=0.0015 **p=0.0051 DPL=dupilumab TCS=topical corticosteroids |
![]() Placebo+TCS 300 mg DPL+TCS Placebo+TCS 300 mg DPL+TCS SCORAD EASI -50 -40 -30 -20 -10 0 0 5 10 15 20 25 30 Study Day -20 -10 0 0 5 10 15 20 25 30 Study Day Dupilumab+TCS significantly improved Dupilumab+TCS significantly improved measures of efficacy vs TCS alone measures of efficacy vs TCS alone *p=0.0191 **p=0.0042 DPL=dupilumab TCS=topical corticosteroids |
![]() Dupilumab+TCS achieved superior Dupilumab+TCS achieved superior clinical outcomes vs TCS alone clinical outcomes vs TCS alone DPL=dupilumab TCS=topical corticosteroids Placebo+TCS 300 mg DPL+TCS TCS Used Weekly (g) 0 5 15 25 35 45 Wk 1 Wk 2 Wk 3 Wk 4 10 20 30 40 * *p=0.1413 Placebo+TCS 300 mg DPL+TCS IGA Score -3.0 -2.0 -1.0 0 0 5 10 15 20 25 30 Study Day **p=0.0281 |
![]() Summary Summary In this study of adults with moderate-to-severe AD, concomitant treatment with SC dupilumab+TCS exhibited an acceptable safety profile (primary endpoint) – – Most common treatment-emergent AEs were nasopharyngitis (23.8% vs Most common treatment-emergent AEs were nasopharyngitis (23.8% vs 20% for placebo), headache and oropharyngeal pain (both14.3% vs 10% 20% for placebo), headache and oropharyngeal pain (both14.3% vs 10% for placebo) for placebo) At 4 weeks, dupilumab+TCS group achieved superior clinical At 4 weeks, dupilumab+TCS group achieved superior clinical outcomes compared to TCS alone (exploratory efficacy endpoints) outcomes compared to TCS alone (exploratory efficacy endpoints) – – EASI-50: 100% responder rate for dupilumab +TCS, compared to 50% for EASI-50: 100% responder rate for dupilumab +TCS, compared to 50% for placebo+TCS placebo+TCS – – Significantly better improvement from baseline in EASI, SCORAD, IGA, Significantly better improvement from baseline in EASI, SCORAD, IGA, and pruritus NRS for dupilumab + TCS vs. Placebo + TCS and pruritus NRS for dupilumab + TCS vs. Placebo + TCS Patients on dupilumab + TCS used approximately 50% less TCS Patients on dupilumab + TCS used approximately 50% less TCS during the treatment period compared with patients on placebo + TCS during the treatment period compared with patients on placebo + TCS (48.7g vs 99.4g), associated with faster clearing of active AD lesions (48.7g vs 99.4g), associated with faster clearing of active AD lesions |
![]() Acknowledgements Acknowledgements Marius Ardeleanu Marius Ardeleanu Elisa Babilonia Elisa Babilonia Nancee Basinger Nancee Basinger Warren Brooks Warren Brooks Josh Cantor Josh Cantor Linda Williams Linda Williams Diamant Thaci Diamant Thaci Margitta Worm Margitta Worm Martin Kaatz Martin Kaatz Rolf Dominicus Rolf Dominicus Beatrice Gerlach Beatrice Gerlach All participating patients All participating patients Investigators Investigators Beate Schwarz Beate Schwarz Noemi Bakos Noemi Bakos Lajos Kemeny Lajos Kemeny Marcin Ambroziak Marcin Ambroziak Maria Czubek Maria Czubek Sanofi Sanofi Tara Coughlan Tara Coughlan Judy Cusick Judy Cusick Evelyn Dorsey Evelyn Dorsey Kristen Dougherty Kristen Dougherty Chad Fish Chad Fish Usman Chaudhry Usman Chaudhry Melissa Hager Melissa Hager Jennifer Hamilton Jennifer Hamilton Rebecca Indibi Rebecca Indibi Richard Kao Richard Kao Dan Kropas Dan Kropas Jacquie Kuritzky Jacquie Kuritzky Vicky Lai Vicky Lai Haobo Ren Haobo Ren Dawn Rich Dawn Rich Tara Seeliger Tara Seeliger Regeneron Regeneron Jennifer Cairns Jeffrey Ming Susan Slaytylak-Cheeks Maris Juszkiewicz-Borowiec Andrzej Kaszuba Dorota Bystrzanowska Athanasios Tsianakas |
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![]() The march of atopic eczema The march of atopic eczema T naive Th2 Th1 Th17 APC Eosinophil (Aero)allergen acute eczema: allergen-specific immune response (Th2, IgE, eosinophils) microbial products/ auto-antigens Th2 B cell IFN- IL-13 IL-4 local lymph node dermal vessel chronic eczema: microorganisms, auto-allergy, remodelling (Th1, Th2, Th17/Th22) IL-22 IL-17 IDEC TSLP IgE filaggrin filaggrin |