Diamant Thaçi1, Eric L Simpson2, Lisa A Beck3, Thomas Bieber4, Andrew Blauvelt5, Kim Papp6, Weily Soong7, Margitta Worm8, Jacek C Szepietowski9, Howard Sofen10, Makoto Kawashima11, Richard Wu12, Steven P Weinstein12, Neil M H Graham12, Gianluca Pirozzi13, Ariel Teper13, E Rand Sutherland14, Vera Mastey12, Neil Stahl12, George D Yancopoulos12, Marius Ardeleanu12. 1. Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. Electronic address: diamant.thaci@uksh.de. 2. Department of Dermatology, Oregon Health and Science University, Portland, OR, USA. 3. Department of Dermatology, University of Rochester Medical Center, Rochester, NY, USA. 4. Department of Dermatology and Allergy, University of Bonn, Bonn, Germany. 5. Oregon Medical Research Center, Portland, OR, USA. 6. K Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada. 7. Alabama Allergy & Asthma Center, Birmingham, AL, USA. 8. Department of Dermatology and Allergy, Charité University, Berlin, Germany. 9. Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland. 10. UCLA School of Medicine, Los Angeles, CA, USA. 11. Tokyo Women's Medical University, School of Medicine, Tokyo, Japan. 12. Regeneron Pharmaceuticals, Tarrytown, NY, USA. 13. Sanofi, Bridgewater, NJ, USA. 14. Sanofi, Cambridge, MA, USA.
Abstract
BACKGROUND: Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. METHODS: In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. FINDINGS:Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). INTERPRETATION:Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. FUNDING: Sanofi and Regeneron Pharmaceuticals.
RCT Entities:
BACKGROUND: Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments. METHODS: In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988. FINDINGS: Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively). INTERPRETATION:Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis. FUNDING: Sanofi and Regeneron Pharmaceuticals.
Authors: Sjors A Koppes; Richard Brans; Suzana Ljubojevic Hadzavdic; Monique H W Frings-Dresen; Thomas Rustemeyer; Sanja Kezic Journal: Int Arch Allergy Immunol Date: 2016-09-02 Impact factor: 2.749
Authors: Madison R Mack; Jonathan R Brestoff; Melissa M Berrien-Elliott; Anna M Trier; Ting-Lin B Yang; Matthew McCullen; Patrick L Collins; Haixia Niu; Nancy D Bodet; Julia A Wagner; Eugene Park; Amy Z Xu; Fang Wang; Rebecca Chibnall; M Laurin Council; Carrie Heffington; Friederike Kreisel; David J Margolis; David Sheinbein; Paola Lovato; Eric Vivier; Marina Cella; Marco Colonna; Wayne M Yokoyama; Eugene M Oltz; Todd A Fehniger; Brian S Kim Journal: Sci Transl Med Date: 2020-02-26 Impact factor: 17.956