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
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.
The Lancet