Elsevier

The Lancet

Volume 387, Issue 10013, 2–8 January 2016, Pages 40-52
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(15)00388-8Get rights and content

Summary

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.

Introduction

Atopic dermatitis is a chronic skin disorder characterised by intense pruritus, disruption of skin-barrier function, and type 2 inflammation.1, 2 Atopic dermatitis typically features intermittent flares, but moderate-to-severe disease rarely clears without effective treatment. Topical corticosteroids have been the foundation of pharmacological treatments for atopic dermatitis, but for many patients with moderate-to-severe atopic dermatitis, the efficacy of topical treatments is limited, and long-term application of topical corticosteroids carries the risk of side-effects.2, 3 Systemic immunosuppressant drugs for atopic dermatitis are generally more effective than topical treatments, but they also have substantial potential for more severe toxic effects.4, 5, 6, 7 Furthermore, systemic corticosteroids and ciclosporin have been associated with marked rebound effects after treatment discontinuation.4, 5, 6, 7 Except for ciclosporin, which is approved in some countries, systemic immunosuppressant treatments are not approved for atopic dermatitis, which suggests substantial unmet need.4, 5, 6, 7

Research in context

Evidence before this study

Findings of previous phase 1 and 2a studies showed preliminary efficacy and a favourable safety profile of dupilumab in patients with atopic dermatitis, asthma, and chronic sinusitis with nasal polyposis. To obtain information about the unmet need for systemic treatment of atopic dermatitis, we searched PubMed and Embase on Feb 27, 2015, for randomised, controlled, blinded clinical trials of systemic immunosuppressant treatments and oral glucocorticoids for treatment of moderate-to-severe atopic dermatitis published in English language. Additionally, we searched the reference lists of recent treatment guidelines and a recent systematic review of systemic treatments in patients with atopic dermatitis. We used the following search terms: “atopic dermatitis”, “eczema”, “cyclosporine”, “ciclosporin”, “methotrexate”, “azathioprine”, “mycophenolate”, “interferon-γ”, “intravenous immunoglobulin”, “prednisone”, “prednisolone”, “dexamethasone”, “beclomethasone”, and “methylprednisolone”. Overall, we identified 22 randomised, controlled, blinded studies. Systemic immunosuppressant treatments were effective in moderate-to-severe atopic dermatitis, but were associated with toxic effects, especially with long-term treatment, and systemic corticosteroids were associated with rebound effects. As noted in current guidelines, with the exception of ciclosporin, which is approved in some countries, most systemic immunosuppressant treatments are not approved for moderate-to-severe atopic dermatitis, except in cases of refractory disease, indicating a substantial unmet need.

Added value of this study

Our results showed the clinical efficacy of dupilumab at five different dose regimens in patients with moderate-to-severe atopic dermatitis, with the most consistent benefits recorded with dose regimens of 300 mg once a week and 300 mg every 2 weeks. Consistent with findings of previous phase 1 and 2a studies, dupilumab had a favourable safety profile with no dose-limiting toxic effects. Our findings confirmed the efficacy reported in the previous early-phase studies. Our study used the longest duration of treatment reported up to now for this drug; was the first study of dupilumab in atopic dermatitis assessing several dose regimens given less frequently than weekly, including less-frequent doses lower than 300 mg, which provided data to optimise treatment regimens; and was the largest study of dupilumab so far and, therefore, provides important safety information.

Implications of all the available evidence

There is an unmet need for a safe and effective systemic treatment for patients with moderate-to-severe atopic dermatitis (especially those with an inadequate response or who cannot tolerate current treatment) because approved treatments are often ineffective or associated with adverse effects and, therefore, are unsuitable for the long-term management of atopic dermatitis. Our findings showed a positive benefit–risk ratio for dupilumab, which specifically targets the Th2-mediated inflammation driving atopic dermatitis. Phase 3 confirmatory studies are underway investigating dupilumab as monotherapy, and in combination with topical corticosteroids; these studies are larger and of longer duration than the present study, and will further evaluate the efficacy and safety of dupilumab at doses of 300 mg once a week and every 2 weeks, the two dose regimens selected from the present study, in patients with moderate-to-severe atopic dermatitis.

The prevalence of atopic dermatitis is about 3–10% in adults and up to 20% in children, and has a substantial effect on quality of life.8, 9, 10, 11 Patients with atopic dermatitis have increased risk of other atopic disorders, including asthma, allergic rhinitis, and chronic sinusitis with nasal polyposis.10, 12, 13, 14 Atopic dermatitis is also associated with increased risk of mental health disorders related to the psychological and social burden of disease.15, 16 As with other atopic disorders, Th2 cytokines and their downstream effects are prominent in atopic dermatitis, although other inflammatory pathways, including Th1-mediated and Th22-mediated processes, might also contribute to the pathogenesis of atopic dermatitis.17, 18, 19

Dupilumab is a fully-human monoclonal antibody directed against the interleukin (IL)-4 receptor α (IL-4Rα) subunit that blocks signalling of both IL-4 and IL-13, key Th2 cytokines.20 In early-stage clinical trials, dupilumab showed significant improvements in atopic dermatitis,20 asthma,21 and chronic sinusitis with nasal polyposis,22 suggesting that the IL-4 and IL-13 pathways are requisite drivers of these atopic diseases. In these studies, dupilumab was well-tolerated with a favourable safety profile.20, 21, 22 The present phase 2b study assessed the efficacy and safety of several dupilumab dose regimens compared with placebo in adults with moderate-to-severe atopic dermatitis.

Section snippets

Study design

This randomised, placebo-controlled, double-blind, parallel-group, dose-ranging phase 2b study was undertaken at 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Study drug (dupilumab or placebo) was given once a week for 16 weeks (baseline [week 0] to week 15), followed by a 16-week follow-up period. Rescue treatment for atopic dermatitis (drug or phototherapy or both) was given at the

Results

From May 15, 2013, to Jan 27, 2014, 452 patients were assessed for eligibility; 72 were ineligible for the study, and 380 were randomly assigned. 379 patients (61 in the placebo group and 318 in the dupilumab group) received one or more doses of study treatment (figure 1) and 347 (53 [87%] given placebo and 294 [92%] given dupilumab) completed the 16 weeks of treatment. Treatment groups had similar baseline characteristics (table 1). The mean duration of atopic dermatitis at baseline was

Discussion

Our results show that treatment with dupilumab provides significant improvement in the clinical signs and symptoms of atopic dermatitis in adult patients with moderate-to-severe atopic dermatitis. Importantly, these patients had previously had inadequate control of their atopic dermatitis by standard-of-care topical treatment. The robustness of these findings was supported by substantial improvements from baseline with dupilumab treatment compared with placebo in all major primary and secondary

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