Dupilumab: A review of its use in the treatment of atopic dermatitis

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Atopic dermatitis (AD) is a chronic, pruritic immune-mediated inflammatory dermatosis characterized by a T helper 2 (Th2) immune response phenotype and may be associated with systemic inflammation. Dupilumab is an interleukin 4 (IL-4) receptor α-antagonist that inhibits IL-4 and IL-13 signaling through blockade of the shared IL-4α subunit. Blockade of IL-4/13 is effective in reducing Th2 response. Dupilumab has recently been approved in the United States and Europe for the treatment of adult patients with moderate-to-severe AD. Clinical trials have shown that adults with moderate-to-severe AD who receive weekly or biweekly dupilumab injections have significantly improved clinical and patient-reported outcomes, including Eczema Area Severity Index, SCORing Atopic Dermatitis, Dermatology Life Quality Index, and itch Numeric Rating Scale scores. Concomitant use of topical corticosteroids along with dupilumab results in a greater improvement in signs and symptoms of AD than with use of dupilumab alone. Biomarker analyses show that dupilumab modulates the AD molecular signature and other Th2-associated biomarkers. Common adverse events reported in the clinical trials were nasopharyngitis, upper respiratory tract infection, injection site reactions, skin infections, and conjunctivitis. These were mild-to-moderate in nature, and overall rates of adverse events occurred with similar frequency between the treatment and placebo groups. There were no significant serious safety concerns identified in phase III clinical trials. Dupilumab, as monotherapy or with concomitant use of topical corticosteroids, can significantly improve clinical outcomes and quality of life in patients suffering from moderate-to-severe AD. Ongoing studies of dupilumab will help determine the clinical efficacy and safety profile of its long-term use.

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.

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