Dupilumab Monotherapy in Adults with Moderate-to-Severe Atopic Dermatitis: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Study Thomas Bieber, Diamant Thaçi, Neil Graham, Gianluca Pirozzi, 4 Ariel Teper, 4 Haobo Ren, Neil Stahl, George Yancopoulos, Allen Radin 1 Department of Dermatology and Allergy, Friedrich-Wilhelms University of Bonn, Bonn, Germany; 2 Comprehensive Center Inflammation Medicine, University of Lübeck, Lübeck, Germany; 3 Regeneron Pharmaceuticals, Inc., Tarrytown, United States; 4 Sanofi, Bridgewater, United States Exhibit 99.1 3 3 3 3 1 2 3 |
Disclosures • D Thaçi is a consultant for Astellas, Novartis, Regeneron, Celgene, Abbott, Pfizer, Janssen-Cilag, MSD, Leo-Pharma • T Bieber is a consultant for Regeneron, Basilea, L’Oréal, Oxagen, Bioalliance, Stern Biologics and a speaker for Astellas • N Graham, H Ren, N Stahl, G Yancopoulos, and A Radin are employees and shareholders of Regeneron • G Pirozzi and A Teper are employees and shareholders of Sanofi • Study (NCT01548404) funded by Regeneron Pharmaceuticals, Inc. and Sanofi 2 |
Introduction • Moderate-to-severe atopic dermatitis (AD) is characterized by eczematous dermatitis with intractable pruritus associated with sleep disturbance and lower quality-of-life • For many patients, current therapies are inadequate and can be associated with unwanted side effects • IL-4 and IL-13 are thought to be central to T- helper 2 (Th2) inflammation, which mediates many features of AD 3 |
Introduction 4 • Dupilumab is a fully human monoclonal antibody targeting the IL-4 receptor alpha subunit (IL-4R ), thus blocking the intracellular signaling of both IL-4 and IL-13 • Earlier clinical trials indicated that dupilumab monotherapy had an acceptable safety profile and was efficacious in patients with moderate-to- severe AD who cannot be adequately controlled with topical medications • We assessed the clinical efficacy of repeated subcutaneous doses of dupilumab monotherapy for 12 weeks in adult patients with moderate-to- severe AD poorly controlled by topical agents |
Dupilumab (anti-IL-4R ) blocks the 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 IL-4 IL-13 IL-4R IL-13R 1 c IL-4R 5 |
Study treatment (weekly SC injection for 12 wks) Screening (adult patients with moderate-to- severe AD) Safety follow-up (16 wks) Dupilumab Monotherapy in Adults with Moderate-to-Severe Atopic Dermatitis: A European 12-Week, Randomized, Double-Blind, Placebo-Controlled Phase 2a Study (NCT01548404) Dupilumab 300 mg (n=55) n=109 Placebo (n=54) Primary endpoint: Percent change in EASI from baseline to week 12 Secondary endpoints: Changes from baseline to week 12 in EASI, SCORAD, %BSA, pruritus NRS, 5-D pruritus scale, proportion of patients achieving EASI-50/75, IGA 0-1; and safety EASI=Eczema Area Severity Index; SCORAD=scoring of atopic dermatitis; BSA = baseline body surface area; NRS=numeric rating scale; EASI-50 50% reduction in EASI score; EASI-75 75% reduction in EASI score IGA 0-1=Investigator’s Global Assessment score of 0 (“clear”) or 1 (“almost clear”) 6 |
Key inclusion/exclusion criteria Inclusion • Male or female 18 yrs • Chronic AD 3 yrs • EASI 16 • IGA 3 • 10% BSA of AD involvement • History of inadequate response to a stable ( 1 month) regimen of topical corticosteroids or calcineurin inhibitors within 3 months prior to screening visit Exclusion • Prior treatment with dupilumab • Acute or chronic infections • Recent treatment with topical corticosteroids, calcineurin inhibitors, immunosuppressive/ immunomodulating drugs • Significant co-morbidities or lab abnormalities 7 |
Baseline demographics and disease characteristics* Placebo (n=54) Dupilumab 300 mg (n=55) Age, yrs 39.4 (12.3) 33.7 (10.4) Caucasian, n (%) 54 (100) 55 (100) Men, n (%) 27 (50.0) 31 (56.4) BMI, kg/m 24.51 (4.64) 25.89 (4.84) AD diagnosis age, yrs 14.4 (18.35) 6.6 (10.52) EASI score (0-72) 30.8 (13.63) 28.4 (13.57) IGA score (0-5) 4.0 (0.69) 3.9 (0.67) SCORAD score (0-103) 69.1 (13.38) 66.7 (13.82) %BSA of AD 50.8 (24.14) 46.8 (24.55) Pruritus (NRS) score (0-10) 5.00 (1.40) 6.43 (2.00) 5-D Pruritus Scale (5-25) 18.7 (3.50) 18.4 (3.04) EASI=Eczema Area Severity Index (range 0-72); IGA=Investigator’s Global Assessment (range 0-5); SCORAD=scoring of atopic dermatitis (range 0-103); BSA = baseline body surface area; NRS=numeric rating scale (range 0-10); 5-D Pruritus Scale (range 5-25) 8 *Values shown are mean (SD) or n (%). 2 |
9 -80 -70 -60 -50 -40 -30 -20 -10 10 Study Day Placebo 300 mg dupilumab Study drug administration Study Day 300 mg dupilumab 10 20 30 40 50 60 70 80 90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 0 10 20 30 40 50 60 70 80 90 Study drug administration † p<0.002, **P<0.0001 *p<0.001, **P<0.0001 -23.3% -74.0% -53.6% *, †**(LOCF) Percent change in EASI and SCORAD scores over 12 weeks Placebo -14.3% |
Proportion of patients who achieve EASI-50 and EASI-75 over 12 weeks 10 Placebo 300 mg dupilumab 0 80 60 40 30 20 10 100 70 50 90 Study Day 0 10 20 30 40 50 60 70 80 90 0 80 60 40 30 20 10 100 70 50 90 Study Day 0 10 20 30 40 50 60 70 80 90 Placebo 300 mg dupilumab † p<0.01, *p<0.001, **P<0.0001 Study drug administration Study drug administration † p<0.01, *p<0.001, **P<0.0001 EASI-50 50% reduction in EASI score; EASI-75 75% reduction in EASI score 35.2% 85.5% 61.8% 14.8% *, †**(LOCF) ** ** ** ** ** ** ** * ** ** ** ** ** ** ** ** ** * |
Percent patients achieving IGA 0-1 and mean BSA(%) at day 85 11 ** ** p<0.0001; LOCF ** 7.4 40.0 41.8 19.4 50.8 46.8 Placebo 300 mg dupilumab Placebo 300 mg dupilumab Baseline Day 85 |
10 20 30 40 50 60 70 80 90 0 Percent change in NRS and 5-D pruritus scores over 12 weeks 12 Study drug administration Study drug administration Placebo 300 mg dupilumab -10 -30 -40 -50 -60 -70 10 -20 0 Study Day 10 20 30 40 50 60 70 80 90 Placebo 300 mg dupilumab -10 -20 -30 -40 -45 -50 0 -15 -5 Study Day -25 -35 ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** ** **P<0.0001 **P<0.0001 NRS=numeric rating scale -15.1% -55.7% -9.9% -39.7% **(LOCF) |
Treatment emergent adverse events over 28 weeks Placebo (n = 54) Dupilumab 300 mg (n = 55) Total number of AEs 159 163 Total number of AEs related to study drug 45 49 Total number of serious AEs 11 1 Deaths 0 0 Number (%) of patients discontinued from study Due to AE 3 (5.6) 1 (1.8) Due to Lack of Efficacy 23 (42.6) 7 (12.7) Infections and infestations* 31 (57.4) 31 (56.4) Most common AEs ( 10%) Nasopharyngitis 10 (18.5) 22 (40.0) Headache 7 (13.0) 9 (16.4) Conjunctivitis 2 (3.7) 7 (12.7) 13 * System Organ Class |
Skin infections were less frequent with dupilumab treatment compared to placebo 14 *based on Standardized MedDRA Query; **one occurrence considered both severe and serious Placebo (n = 54) Dupilumab 300 mg (n = 55) Total number of patients (%) with skin infections 13 (24.1%) 3 (5.5%) Total number of skin infections* 14 3 Impetigo 3 1 Skin bacterial infection 3** 0 Eczema herpeticum 2** 0 Skin infection 2 0 Anorectal cellulitis 1 0 Cellulitis 1** 0 Infected dermatitis 1 0 Folliculitis 1 0 Infected blister 0 1 Pustular rash 0 1 |
Serious Adverse Events Placebo (n = 54) Dupilumab 300 mg (n = 55) Number of SAEs 11 1 Patients with SAE*, n (%) 7 (13.0%) 1 (1.8%) Facial bones fracture [traumatic] 0 1 (1.8%) Angina pectoris 1 (1.9%) 0 Cellulitis 1 (1.9%) 0 Eczema herpeticum 1 (1.9%) 0 Skin bacterial infection 1 (1.9%) 0 Renal failure 1 (1.9%) 0 Asthmatic crisis 1 (1.9%) 0 Lung disorder [pneumopathy] 1 (1.9%) 0 Dermatitis Atopic 4 (7.4%) 0 15 * MedDRA Preferred Term; all SAEs were classified as such due to hospitalization |
Summary • In this Phase 2a study of 109 European adults with moderate-to- severe AD, dupilumab (anti-IL-4R ) 300 mg SC weekly was associated with rapid and marked sustained improvement in EASI, SCORAD, IGA, and BSA%, and pruritus • At 12 weeks, the dupilumab group achieved statistically superior clinical outcomes compared to the placebo group in all measures of disease activity and pruritus • There were notably fewer patients with skin infections associated with dupilumab (5.5%) treatment compared with placebo (24.1%) • There were no infection related SAEs or eczema herpeticum in the dupilumab group • In the placebo group, 3 patients with skin infections and 4 patients with AD exacerbations required hospitalization • The most common TEAEs were nasopharyngitis, headache, and conjunctivitis 16 |
Acknowledgements Marius Ardeleanu Elisa Babilonia Warren Brooks Josh Cantor Usman Chaudhry Olga Filipovska Romana Machackova Petr Trestik Catherine Goujon Jean-Paul Ortonne Carle Paul Alain Taieb Jennifer Cairns Jeffrey Ming Susan Slaytylak-Cheeks All participating patients Investigators Jens Ulrich Thomas Werfel Margitta Worm Klara Bajor Noemi Bakos Zita Battyani Sanofi Judy Cusick Kristen Dougherty Chad Fish Melissa Hager Jennifer Hamilton Richard Kao Jacquie Kuritzky Linda Williams Regeneron Lajos Kemeny Marcin Ambroziak Dorota Bystrzanowska Maris Czubek Maria Juszkiewicz-Borowiec Andrzej Kaszuba Thomas Bieber Regina Foelster-Holst Martin Kaatz Knut Schaekel Margrit Simon Diamant Thaçi Athanasios Tsianakas 17 |
BACK-UP 18 |
The 5-D itch scale: a new measure of pruritus • 5-D Pruritus Scale: Duration, Degree, Direction, Disability, Distribution – Single-item domain scores (duration, degree and direction) are equal to the value of the response choice – The disability domain includes four items that assess the impact of itching on daily activities: sleep, leisure social activities, housework errands and work school – For the distribution domain, the number of affected body parts is tallied • 5-D scores can potentially range between 5 (no pruritus) and 25 (most severe pruritus) 19 Elman S et al. Brit J Dermat 2010;162:587-93. |