By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco
Drs. Elliott and Chan report no financial relationships relevant to this field of study.
The FDA has approved the first biologic for the treatment of moderate-to-severe eczema. Dupilumab is a human monoclonal antibody that targets the interleukin-4 receptor alpha subunit (IL-4R alpha), blocking the signaling of the cytokines interleukine-4 and interleukin-13. Dupilumab is marketed as Dupixent.
INDICATIONS
Dupilumab is indicated for the treatment of adults with moderate-to-severe atopic dermatitis (eczema) in whom prescription topical therapies are inadequate or not advisable.1
DOSAGE
The recommended dose is 600 mg (2 x 300 mg) given subcutaneously, in different injection sites, initially followed by 300 mg every other week.1 Dupilumab is available as a 300 mg (2 mL) prefilled syringe.
POTENTIAL ADVANTAGES
The first biologic approved for the treatment of atopic dermatitis, dupilumab also showed benefit when combined with a topical steroid compared to topical steroid alone.
POTENTIAL DISADVANTAGES
The most frequent adverse events were injection site reactions (10% vs. 5-6% for placebo) and conjunctivitis (9-10% vs. 2-5%).1 Long-term safety and effectiveness remains to be established. The drug currently is not approved for use in children.
COMMENTS
Activation of T helper 2 (Th2) and T helper 22 cells play an important role in the pathogenesis of atopic dermatitis.2 Th2 cytokines include interleukin-4 and interleukin-13, which share a common receptor (IL-4R alpha). The safety and efficacy of dupilumab were evaluated in three randomized, placebo-controlled studies in subjects with moderate-to-severe atopic dermatitis. This was defined as an Investigator’s Global Assessment (IGA) score ≥ 3 (scale 0-4), an Eczema Area Severity Index (EASI) score ≥ 16 (scale 0-72), minimum body surface involvement of ≥ 10%, and inadequately controlled on topical steroids (TCS). Two studies were with monotherapy and 16 weeks in duration.1,3 The third study was concomitant therapy with topical corticosteroids for 52 weeks.1
In the two 16-week monotherapy studies, subjects were randomized to dupilumab (224 in study 1 and 233 in study 2) or placebo (224 and 236, respectively). The primary endpoint was change from baseline to week 16 in the proportion of subjects with an IGA score of 0 or 1 and at least a two-point improvement. Other endpoints included the proportion with improvement of at least 75% in EASI score from baseline (EASI-75) and reduction in itch as defined by at least a four-point improvement in peak pruritus. The response rates for dupilumab for the primary endpoint were 38% and 36% for the two studies, compared to 10% and 9% for placebo, respectively. Proportions with EASI-75 were 51% and 44%, compared to 15% and 12%. Forty-one percent and 36% achieved pruritus improvement criteria, compared to 12% and 10%.
In study 3 (n = 106 for dupilumab + TCS vs. n = 315 for TCS), response rate at week 16 was 39% for dupilumab + TCS, compared to 12% for TCS alone. EASI-75 responders were 69% vs. 23%, and pruritus responders were 59% vs. 20%. Eighty-four percent of subjects completed the 52-week study. Twenty-two percent randomized to dupilumab + TCS were responders at weeks 16 and 52, compared to 7% for placebo + TCS. Twenty percent (vs. 7%) were responders at week 16, but not week 52. Thirteen percent (vs. 6%) were non-responders at week 16 and responders at week 52. Forty-four percent (vs. 80%) were non-responders throughout.
CLINICAL IMPLICATIONS
Atopic dermatitis is a chronic, pruritic inflammatory disease affecting adults and children. The prevalence is 20% in children and 10% in adults.5,6 Topical corticosteroids are first line for those who have failed to respond to good skin care and use of emollients alone.7 Topical calcineurins are recommended for steroid-resistant or intolerant cases or for sensitive areas (e.g., face). However, patients with moderate-to-severe disease may require systemic therapy. Current treatment options include cyclosporine, azathioprine, and methotrexate.4,7,8 Dupilumab is the first biologic-targeted therapeutic option for moderate-to-severe disease inadequately controlled with topical therapy in adults. Dupilumab will cost $37,000 per year.
REFERENCES
- Dupixent Prescribing Information. Sanofi-Aventis and Regeneron Pharmaceuticals. March 2017.
- Guttman-Yassky E, Krueger JG, Lebwohl MG. Systemic immune mechanisms in atopic dermatitis and psoriasis with implications for treatment. Exp Dermatol 2017. doi: 10.1111/exd.13336. [Epub ahead of print].
- Simpson EL, Bieber T, Guttman-Yassky E, et al. Two Phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2016;375:2335-2348.
- Gooderham M, Lynde CW, Papp K, et al. Review of systemic treatment options for adult atopic dermatitis. J Cut Med Surg 2017;21:31-39.
- Silverberg JI, Hanifin JM. Adult eczema prevalence and associations with asthma and other health and demographic factors: A US population-based study. J Allergy Clin Immunol 2013;132:1132-1138.
- Flohr C, Mann J. New insights into the epidemiology of childhood atopic dermatitis. Allergy 2014;69:3-16.
- American Academy of Dermatology Association. Atopic dermatitis: Topical corticosteroids recommendations. Available at: http://bit.ly/2pUCOYj. Accessed April 25, 2017.
- Roekevisch E, Spuls PI, Kuester D, et al. Efficacy and safety of systemic treatments for moderate-to-severe atopic dermatitis: A systematic review. J Allergy Clin Immunol 2014;133:429-438.
Dupilumab is indicated for the treatment of adults with moderate-to-severe atopic dermatitis (eczema) in whom prescription topical therapies are inadequate or not advisable.
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