Efficacy and Safety of Dupilumab in Adolescents With Uncontrolled Moderate to Severe Atopic Dermatitis: A Phase 3 Randomized Clinical Trial

Abstract

Importance: Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population.

Objective: To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD.

Design, setting, and participants: A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included.

Interventions: Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85).

Main outcomes and measures: Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator's Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16.

Results: A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%).

Conclusions and relevance: In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults.

Trial registration: ClinicalTrials.gov identifier: NCT03054428.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Simpson reports receiving personal fees from AbbVie, Boehringer-Ingelheim, Dermavant, Dermira, Galderma, GlaxoSmithKline, Incyte, LEO Pharma, Lilly, Menlo Therapeutics, Pfizer Inc, Pierre Fabre Dermo Cosmetique, Regeneron Pharmaceuticals Inc, Sanofi Genzyme, and Valeant Pharmaceutical Co; receiving grants from AbbVie, Celgene, Dermira, Galderma, Leo Pharma, Lilly, Pfizer, Regeneron Pharmaceuticals Inc, Roivant, Sanofi Genzyme; and receiving nonfinancial support from Regeneron Pharmaceuticals Inc and Sanofi Genzyme. Dr Paller reports receiving honoraria as a consultant for AbbVie, Amgen, Asana, Boehringer Ingelheim, Celgene, Dermavant, Dermira Pharmaceutical Co, Forte, Galderma, Incyte, LEO Pharma, Lilly, Matrisys, Menlo Therapeutics, Morphosys/Galapagos, Novan, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Sanofi, and UCB, and receiving grants from AbbVie, Anaptysbio, Galderma, Incyte, LEO Pharma, Janssen, Lilly, Novartis, and Regeneron Pharmaceuticals Inc. Dr Siegfried reports receiving personal fees and honoraria as a consultant and speaker for Regeneron Pharmaceuticals Inc and Sanofi, receiving consulting fees and honoraria as a consultant, speaker, teacher, and advisory board member for Verrica, receiving consulting fees as an advisory board member from Leo Pharma, Novan, Pierre Fabre, and UCB, receiving consulting fees from Pfizer as a speaker, and receiving grants as a principal investigator for clinical trials paid to her institution from Janssen, Lilly, and Regeneron Pharmaceuticals Inc. Dr Boguniewicz reports receiving grants from Regeneron Pharmaceuticals Inc and personal fees as a consultant and speaker for Regeneron Pharmaceuticals Inc and Sanofi Genzyme. Dr Sher reports receiving study grants from Regeneron Pharmaceuticals Inc and Sanofi Genzyme. Dr Gooderham reports being an investigator, speaker, advisor, or consultant for AbbVie, Akros, Amgen, Arcutis, BMS, Boehringer Ingelheim, Celgene, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Merck, Novartis, Pfizer, Roche, Regeneron Pharmaceuticals Inc, Sanofi Genzyme, Sun Pharma, UCB, and Valeant. Dr Beck reports receiving personal fees as a consultant from AbbVie, Allakos, Arena Pharma, Astra-Zeneca, Connect Biopharma, Incyte, LEO Pharma, Lilly, Novan, Novartis, Pfizer, Regeneron., Sanofi, and UCB; receiving compensation as a principal investigator from her institution for trials funded by AbbVie, Leo Pharma, Pfizer, and Regeneron; and holding Pfizer and Medtronics stock. Dr Guttman-Yassky reports receiving personal fees from AbbVie, Allergan, Amgen, Asana Biosciences, Boehringer-Ingelheim, Cara Therapeutics, Celgene, Concert, DBV, Dermavant, Dermira, DS Biopharma, EMD Serono, Escalier, Flx Bio, Galderma, Glenmark, Incyte, Kyowa Kirin, LEO Pharma, Lilly, Mitsubishi Tanabe, Novan, Novartis, Pfizer, Regeneron Pharmaceuticals Inc, Sanofi, Sienna Biopharmaceuticals, and Union Therapeutics, and grants from AbbVie, Anaptysbio, Asana Biosciences, Boehringer-Ingelheim, Celgene, Dermavant, DS Biopharma, Galderma, Glenmark, Innovaderm, Janssen, Kiniska, LEO Pharma, Lilly, Novan, Novartis, Pfizer, Ralexar, Regeneron Pharmaceuticals Inc, UCB, and Union Therapeutics. Dr Pariser reports receiving grants as an investigator for Regeneron Pharmaceutical Inc and Sanofi and receiving honoraria as an advisory board consultant for Regeneron Pharmaceuticals Inc and Sanofi. Dr Blauvelt reports receiving compensation as an investigator and personal fees as a consultant for AbbVie, Dermira, LEO Pharma, Pfizer, Regeneron Pharmaceuticals Inc, and Sanofi. Dr Weisman reports receiving grants from AbbVie, Allergan, Celgene, Dermira, Galderma, Janssen, LEO Pharma, Lilly, Merck, Novartis, Pfizer, and Regeneron Pharmaceuticals Inc, and personal fees from AbbVie, Lilly, Novartis, and Regeneron Pharmaceuticals Inc. Dr Lockshin reports receiving grants as a clinical investigator for AbbVie, Galderma, Incyte, Lilly, Pfizer, Regeneron Pharmaceuticals Inc, and Sanofi Genzyme, and honoraria from AbbVie, Galderma, Incyte, Lilly, Pfizer, Regeneron Pharmaceuticals Inc, and Sanofi Genzyme. Drs Hultsch, Staudinger, Pirozzi, and Eckert report being employees and holding stock and/or stock options in Sanofi. Drs Zhang, Kamal, Davis, Akinlade, Graham, Gadkari, Stahl, Ruddy, and Bansal report being employees and shareholders of Regeneron Pharmaceuticals Inc. Dr Hamilton reports being an employee and shareholder of Regeneron Pharmaceuticals Inc and having patents planned, pending, or issued broadly relevant to the work. Dr Yancopoulos reports being an employee, shareholder, president, and member of board of directors of Regeneron Pharmaceuticals Inc and having patents pending or issued broadly relevant to the work.

Figures

Figure 1.. CONSORT Diagram

OLE indicates open-label extension trial (NCT02612454). aOne patient in the every-4-week dupilumab group who was randomized but did not receive treatment was included in the efficacy, but not the safety, analysis.

Figure 2.. Proportion of Patients Achieving Coprimary End Points Over Time to Week 16

A, Patients achieving 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75). B, Patients achieving Investigator’s Global Assessment (IGA) scores of 0 or 1. aP < .001 vs placebo.

Figure 3.. Least-Squares (LS) Mean Percentage Changes and LS Mean (SE) Changes From Baseline to Week 16

A, LS mean percentage change in Eczema Area and Severity Index score. B, LS mean percentage change in weekly average of daily Peak Pruritus Numerical Rating Scale score. C, LS mean change in Patient-Oriented Eczema Measure score. D, LS mean change in Children’s Dermatology Life Quality Index (CDLQI) score. aP < .001 vs placebo.