title: Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.
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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Sanofi and Regeneron Pharmaceuticals.
authors.affiliation: Comprehensive Center for Inflammation Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany. Electronic address: diamant.thaci@uksh.de.
authors.forename: Diamant
authors.initials: D
authors.lastname: Thaçi
authors.affiliation: Department of Dermatology, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Eric L
authors.initials: EL
authors.lastname: Simpson
authors.affiliation: Department of Dermatology, University of Rochester Medical Center, Rochester, NY, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Beck
authors.affiliation: Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bieber
authors.affiliation: Oregon Medical Research Center, Portland, OR, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Blauvelt
authors.affiliation: K Papp Clinical Research and Probity Medical Research, Waterloo, ON, Canada.
authors.forename: Kim
authors.initials: K
authors.lastname: Papp
authors.affiliation: Alabama Allergy & Asthma Center, Birmingham, AL, USA.
authors.forename: Weily
authors.initials: W
authors.lastname: Soong
authors.affiliation: Department of Dermatology and Allergy, Charité University, Berlin, Germany.
authors.forename: Margitta
authors.initials: M
authors.lastname: Worm
authors.affiliation: Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland.
authors.forename: Jacek C
authors.initials: JC
authors.lastname: Szepietowski
authors.affiliation: UCLA School of Medicine, Los Angeles, CA, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Sofen
authors.affiliation: Tokyo Women's Medical University, School of Medicine, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Kawashima
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Wu
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Weinstein
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Neil M H
authors.initials: NM
authors.lastname: Graham
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Pirozzi
authors.affiliation: Sanofi, Bridgewater, NJ, USA.
authors.forename: Ariel
authors.initials: A
authors.lastname: Teper
authors.affiliation: Sanofi, Cambridge, MA, USA.
authors.forename: E Rand
authors.initials: ER
authors.lastname: Sutherland
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Vera
authors.initials: V
authors.lastname: Mastey
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Stahl
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.affiliation: Regeneron Pharmaceuticals, Tarrytown, NY, USA.
authors.forename: Marius
authors.initials: M
authors.lastname: Ardeleanu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D002170:Canada; D018153:Czech Republic; D003876:Dermatitis, Atopic / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005858:Germany; D006801:Humans; D006814:Hungary; D007279:Injections, Subcutaneous; D053662:Interleukin-4 Receptor alpha Subunit / Q000037:antagonists & inhibitors*; D007564:Japan; D008297:Male; D008875:Middle Aged; D011044:Poland; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014481:United States; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C504000:IL4R protein, human; D053662:Interleukin-4 Receptor alpha Subunit; C582203:dupilumab