Therapeutic strategies in extrinsic atopic dermatitis: focus on inhibition of IL-4 as a new pharmacological approach.
Di Lernia Vito
Expert opinion on therapeutic targets
INTRODUCTION:Recent data about atopic dermatitis (AD) pathogenesis postulate that T cells and their related cytokines and chemokines are primarily responsible for the inflammatory responses. AREAS COVERED:AD, the primary complex disease associated with filaggrin deficiency, is characterized by cutaneous inflammation driven by type 2 helper T (TH2) cells. TH2-related molecules, such as IL-4, IL-13, dominate the immune infiltrate. Experimental evidences suggest that these cytokines may be considered attractive therapeutic targets in AD, particularly in extrinsic AD with IgE overproduction. Recently, a fully human monoclonal antibody directed against the IL-4 receptor α subunit blocking IL-4 and IL-13 signaling has been evaluated in Phase I and Phase II clinical trials in patients with moderate-to-severe AD with significant improvement in disease severity. Phase III trials are ongoing. EXPERT OPINION:Treatment of AD represents a therapeutic challenge. TH2 cytokine-targeted therapies represent promising treatment options that could improve the therapeutic armamentarium for AD. These therapies are likely to become future therapeutic options in AD, particularly in the extrinsic AD.
Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis.
Simpson Eric L,Bieber Thomas,Guttman-Yassky Emma,Beck Lisa A,Blauvelt Andrew,Cork Michael J,Silverberg Jonathan I,Deleuran Mette,Kataoka Yoko,Lacour Jean-Philippe,Kingo Külli,Worm Margitta,Poulin Yves,Wollenberg Andreas,Soo Yuhwen,Graham Neil M H,Pirozzi Gianluca,Akinlade Bolanle,Staudinger Heribert,Mastey Vera,Eckert Laurent,Gadkari Abhijit,Stahl Neil,Yancopoulos George D,Ardeleanu Marius,
The New England journal of medicine
BACKGROUND:Dupilumab, a human monoclonal antibody against interleukin-4 receptor alpha, inhibits signaling of interleukin-4 and interleukin-13, type 2 cytokines that may be important drivers of atopic or allergic diseases such as atopic dermatitis. METHODS:In two randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1 and SOLO 2), we enrolled adults with moderate-to-severe atopic dermatitis whose disease was inadequately controlled by topical treatment. Patients were randomly assigned in a 1:1:1 ratio to receive, for 16 weeks, subcutaneous dupilumab (300 mg) or placebo weekly or the same dose of dupilumab every other week alternating with placebo. The primary outcome was the proportion of patients who had both a score of 0 or 1 (clear or almost clear) on the Investigator's Global Assessment and a reduction of 2 points or more in that score from baseline at week 16. RESULTS:We enrolled 671 patients in SOLO 1 and 708 in SOLO 2. In SOLO 1, the primary outcome occurred in 85 patients (38%) who received dupilumab every other week and in 83 (37%) who received dupilumab weekly, as compared with 23 (10%) who received placebo (P<0.001 for both comparisons with placebo). The results were similar in SOLO 2, with the primary outcome occurring in 84 patients (36%) who received dupilumab every other week and in 87 (36%) who received dupilumab weekly, as compared with 20 (8%) who received placebo (P<0.001 for both comparisons). In addition, in the two trials, an improvement from baseline to week 16 of at least 75% on the Eczema Area and Severity Index was reported in significantly more patients who received each regimen of dupilumab than in patients who received placebo (P<0.001 for all comparisons). Dupilumab was also associated with improvement in other clinical end points, including reduction in pruritus and symptoms of anxiety or depression and improvement in quality of life. Injection-site reactions and conjunctivitis were more frequent in the dupilumab groups than in the placebo groups. CONCLUSIONS:In two phase 3 trials of identical design involving patients with atopic dermatitis, dupilumab improved the signs and symptoms of atopic dermatitis, including pruritus, symptoms of anxiety and depression, and quality of life, as compared with placebo. Trials of longer duration are needed to assess the long-term effectiveness and safety of dupilumab. (Funded by Sanofi and Regeneron Pharmaceuticals; SOLO 1 ClinicalTrials.gov number, NCT02277743 ; SOLO 2 ClinicalTrials.gov number, NCT02277769 .).