Journal of the American Academy of Dermatology
Dupilumab: A review of its use in the treatment of atopic dermatitis
Section snippets
Mechanism of action
Dupilumab, a fully human monoclonal IgG4 antibody, inhibits IL-4 and IL-13 signal transduction through competitively binding to the shared α subunit of the IL-4 receptor.7 Blocking downstream signaling of IL-4 and -13 has been shown to alter the AD transcriptome in a dose-dependent fashion. Differences in gene expression following administration of dupilumab include (1) downregulation of markers of epidermal proliferation, (2) downregulation of inflammatory mediators, (3) upregulation of
Pharmacokinetics
With a bioavailability of 64%, a subcutaneous injection of dupilumab takes 1 week to reach maximum serum concentration following a loading dose of 600 mg.9 Steady-state concentrations were achieved by week 16 in both dosing regimens in the phase III studies.10
Dupilumab decreases to a nondetectable concentration following the last steady-state dose of biweekly and weekly injections in median times of 10 and 13 weeks, respectively.9 The total volume of distribution reflects that of serum and is
Outcome measures
One commonly used outcome measure is the Eczema Area Severity Index (EASI), which was designed to mimic the Psoriasis Area and Severity Index and ranges from 0 to 72. More commonly used in Europe, SCORing Atopic Dermatitis is a composite disease severity score that includes area of involvement, signs and symptoms, and sleep disturbance and ranges from 0 to 103. Patient-reported outcomes include the Dermatology Life Quality Index (DLQI), which assesses the impact of a dermatologic disease on
Safety
In the 3 phase III trials of dupilumab (SOLO1, SOLO2, and CHRONOS), the overall incidence of adverse events was comparable between the dupilumab and placebo groups; however, in the 52-week CHRONOS trial, the proportion of patients with at least 1 adverse event was greater than that in the SOLO trials, which to date, have been reported up to 16 weeks only.10, 15 Similar to in early-phase trials, serious adverse events in the phase III program were more frequently reported in the placebo group
Ongoing studies and future direction
AD has the highest prevalence in the pediatric population and is associated with the atopic march: a progression to other atopic conditions, allergic rhinitis, and asthma.18, 19 A potential benefit from an early targeted therapy for AD may be the prevention of the atopic march.19 Clinical trials are ongoing in this population to evaluate the safety and efficacy of dupilumab in patients from age 6 years to younger than 18 years (NCT0240775620, NCT0261245421) and from age 12 years to younger than
Conclusion
AD is a complex immunologic disorder characterized by the overexpression of Th2 cytokines, including IL-4 and IL-13. Moderate-to-severe AD can be a challenge to treat and current off-label systemic treatment options may suffer from primary or secondary loss of response, off-target side effects, or contraindications. Increased knowledge of AD disease pathogenesis has allowed the development of targeted therapies. Dupilumab is the first such approved monoclonal antibody targeted at the shared
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Publication of this article was supported by Leo Pharma, Bayer, and Sanofi/Regeneron.
Funding sources: Supported by Bayer, LEO Pharma, and Sanofi.
Disclosure: Dr Gooderham has served as an investigator, speaker, consultant and advisory board member for AbbVie, Actelion, Akros, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dermira, Eli Lilly, Galderma, GSK, Incyte, Janssen, Leo Pharma, Medimmune, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, UCB, and Valeant. Dr Hong has served as an investigator, speaker, consultant, and advisory board member for Abbvie, Amgen, Boehringer Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GSK, Incyte, Leo Pharma, Medimmune, Novartis, Pfizer, Roche, Regeneron, Sanofi Genzyme, and Valeant. Dr Papp has served as an investigator, speaker, consultant, and advisory board member for AbbVie, Akros, Allergan, Amgen, Anacor, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers Squibb, CanFile, Celgene, Dermavant, Dermira, Eli Lilly, Forward Pharma, Galderma, Genentech, GSK, Incyte, Janssen, Kyowa Hakko Kirin, LEO Pharma, Medimmune, Meiji Seika Pharma, Merck, Merck Serono, Mitsubishi Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi Genzyme, Takeda, UCB, and Valeant. Ms Eshtiaghi disclosed no conflicts of interest.
Reprints not available from the authors.