Lack of effect of benralizumab on signs and symptoms of moderate‐to‐severe atopic dermatitis: Results from the phase 2 randomized, double‐blind, placebo‐controlled HILLIER trial

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Dear Editor, Atopic dermatitis (AD) is a common, chronic inflammatory skin disease characterized by itchy skin lesions.1– 4 Some patients with AD present with elevated peripheral eosinophilia. Evidence suggests a role of eosinophils in the pathophysiology of AD; therefore, an eosinophildepleting treatment, such as benralizumab, could prove beneficial, particularly in patients with increased eosinophil counts.5,6 HILLIER (NCT04605094) was a 52week, randomized, doubleblind, placebocontrolled, phase 2 clinical trial in patients with moderatetosevere AD who remained symptomatic despite background topical therapy. Patients were 12 years or older with an investigator global assessment (IGA) ≥3, Eczema Area and Severity Index (EASI) ≥16, ≥10% Body Surface Area of Involvement (BSA), Peak Pruritus Numerical Rating Scale (PPNRS) ≥4, and inadequate response to treatment with topical medications. Patients were randomized 1:1 to benralizumab 30 mg every 4 weeks or placebo groups and stratified by blood eosinophil (bEOS) counts (<300 cells/μL vs. ≥300 cells/μL) and age groups (≥12 to <18 years and ≥18 years). The 16week placebocontrolled period was followed by a 36week openlabel extension. Results are described for the 16week placebocontrolled period. The trial was terminated early due to a lack of efficacy. The primary endpoint was an IGA response defined by the proportion of patients with an IGA 0/1 (clear/almost clear) and a decrease in IGA score of ≥2 points at Week 16 relative to baseline. Secondary endpoints were assessed at Week 16 relative to baseline and included the proportion of patients with skin clearance based on EASI75 and EASI90, and itch response, defined as the proportion of patients with an improvement of ≥4 points in the PPNRS score. Ninetysix patients (including 26 adolescents) and 98 patients (27 adolescents) were randomized into the benralizumab and placebo groups, respectively. Patient demographics and clinical characteristics were comparable between the two groups and consistent with moderatetosevere AD (Table 1). There were no differences between the groups on the primary endpoint, IGA 0/1 response rate absolute difference (benralizumab– placebo rates, −8.62% [95% CI, −17.94 to 0.71]; p = 0.080; Table 2). There were no differences between groups on any secondary endpoints, including EASI75, EASI90 and itch improvement, as well as other endpoints that measured signs, symptoms and healthrelated qualityoflife. Despite the lack of improvement, benralizumab therapy resulted in substantial reductions in mean (SD) bEOS at Week 16, 40.0 (77.19) cells/μL versus baseline, 482.3 (394.63) cells/ μL, which were not observed in the placebo group (Week 16: 354.9 [242.21] cells/μL; baseline: 464.4 [443.74] cells/μL). The benralizumab group also saw greater mean (SD) reductions in serum EDN (12.20 [5.43] mg/L at Week 16 compared to 79.67 [68.37] mg/L at baseline) versus placebo at Week 16, (64.47 [47.38] mg/L vs. baseline, 76.10 [55.01] mg/L). The proportion of patients experiencing any adverse event (AE) was similar between the benralizumab (n = 39 [40.6%]) and placebo (40 [40.8%]) groups. Three benralizumab patients (3.1%) experienced serious AEs, none of which were considered by the investigator to be related to the study drug. No serious AEs occurred in the placebo group and no deaths in any group. The most common AEs were COVID19 (9.4%) and upper respiratory tract infections (5.2%) in the benralizumab group and headaches (5.1%), lymphadenopathy (4.1%), conjunctivitis (4.1%) and COVID19 (4.1%) in the placebo group. Safety and tolerability findings were consistent with the known profile of benralizumab.7– 10