Laboratory safety of dupilumab in moderate-to-severe atopic dermatitis: results from three phase III trials (LIBERTY AD SOLO 1, LIBERTY AD SOLO 2, LIBERTY AD CHRONOS)

Abstract

Background: Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for patients aged ≥ 12 years with inadequately controlled, moderate-to-severe atopic dermatitis (AD). Dupilumab trials of up to 52 weeks demonstrated efficacy and a favourable safety profile in patients with moderate-to-severe AD inadequately controlled with topical medications.

Objectives: To further characterize the safety of dupilumab by evaluating clinical laboratory findings from three randomized, double-blinded, placebo-controlled phase III trials (LIBERTY AD SOLO 1 & 2 and LIBERTY AD CHRONOS).

Methods: Patients were randomized 1 : 1 : 1 (SOLO 1 & 2) or 3 : 1 : 3 (CHRONOS) for 16 and 52 weeks, respectively, to dupilumab weekly, every 2 weeks or placebo. CHRONOS patients received a standardized concomitant topical corticosteroid regimen. Laboratory outcomes were summarized descriptively in 1376 patients from SOLO 1 & 2 and 740 from CHRONOS.

Results: Treatment groups had similar results in baseline laboratory parameters. Platelets and neutrophils showed mild decreases from baseline in dupilumab vs. placebo groups. Some dupilumab-treated patients had small transient increases in eosinophils. Grade 3 eosinophilia was reported in < 1% of dupilumab-treated and placebo-treated patients; no adverse events were associated with eosinophilia. Lactate dehydrogenase levels decreased from baseline during dupilumab treatment in all trials. No clinically meaningful changes were observed between treatment groups in other haematology, chemistry or urinalysis parameters.

Conclusions: There were no clinically important changes in routine laboratory parameters that could be attributed to dupilumab. This study supports the use of dupilumab as a systemic treatment for moderate-to-severe AD that does not require laboratory monitoring. What's already known about this topic? Long-term treatment of atopic dermatitis (AD) with conventional immunosuppressive agents is limited by the risk of significant side-effects and a need for repeated tests to monitor haematological and/or organ (e.g. liver, kidney) toxicities. Dupilumab [a monoclonal antibody blocking the shared receptor subunit for interleukin (IL)-4 and IL-13] is approved for the treatment of patients with inadequately controlled, moderate-to-severe AD. In 16-week and 52-week studies, dupilumab demonstrated a positive risk/benefit profile in moderate-to-severe AD. What does this study add? This study is the first comprehensive analysis of dupilumab laboratory safety data of the 16-week SOLO 1 & 2 (pooled N = 1376) and 52-week CHRONOS (N = 740) trials, demonstrating an absence of clinically important changes in haematology, serum chemistry and urinalysis parameters in patients with moderate-to-severe AD treated with dupilumab. Our data support the use of dupilumab as a systemic treatment for the long-term management of moderate-to-severe AD without routine laboratory monitoring in clinical practice.

Trial registration: ClinicalTrials.gov NCT02277743 NCT02277769 NCT02260986.

© 2019 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.

Figures

Figure 1

(a) Mean change in platelet count from baseline to week 16 (SOLO 1 & 2) and week 52 (CHRONOS). (b) Absolute platelet count. A close‐up view of the box‐and‐whisker plots is depicted below. White horizontal lines indicate medians. X depicts mean values. Top and bottom of each box represent Q3 and Q2, respectively. Upper and lower vertical bars represent Q4 and Q1, respectively; horizontal segments on each end of the vertical bars represent minimum and maximum values. (c) Proportion of patients with thrombocytopenia grades 1–3; patient numbers are provided in Table 1. Thrombocytopenia grade scale follows the guidance provided by the U.S. Food and Drug Administration.37 BL, baseline; Q, quartile; qw, once weekly; q2w, every 2 weeks; TCS, topical corticosteroids; Wk, week.

Figure 2

(a) Absolute mean platelet counts from baseline in the subset of patients with thrombocytopenia grades 2 and 3 through week 16 (SOLO 1 & 2) and week 52 (CHRONOS). (b) Absolute mean neutrophil counts from baseline in the subset of patients with neutropenia grades 2 and 3 through week 16 (SOLO 1 & 2) and week 52 (CHRONOS). (c) Absolute mean eosinophil counts from baseline in the subset of patients with eosinophilia grades 2 and 3 through week 16 (SOLO 1 & 2) and week 52 (CHRONOS). Toxicity grade scales follow the guidance provided by the U.S. Food and Drug Administration.37 qw, once weekly; q2w, every 2 weeks; TCS, topical corticosteroids.

Figure 3

(a) Mean change in neutrophil count from baseline to week 16 (SOLO 1 & 2) and week 52 (CHRONOS). (b) Absolute neutrophil count. A close‐up view of the box‐and‐whisker plots is depicted below. White horizontal lines indicate medians. X depicts mean values. Top and bottom of each box represent Q3 and Q2, respectively. Upper and lower vertical bars represent Q4 and Q1, respectively; horizontal segments on each end of the vertical bars represent minimum and maximum values. (c) Proportion of patients with neutropenia grades 1–3; patient numbers are provided in Table 2. The neutropenia grade scale follows the guidance provided by the U.S. Food and Drug Administration.37 BL, baseline; Q, quartile; qw, once weekly; q2w, every 2 weeks; TCS, topical corticosteroids; Wk, week.

Figure 4

(a) Mean change in eosinophil count from baseline to week 16 (SOLO 1 & 2) and week 52 (CHRONOS). (b) Absolute eosinophil count. A close‐up view of the box‐and‐whisker plots is depicted below. White horizontal lines indicate medians. X depicts mean values. Top and bottom of each box represent Q3 and Q2, respectively. Upper and lower vertical bars represent Q4 and Q1, respectively; horizontal segments on each end of the vertical bars represent minimum and maximum values. Outliers for eosinophil counts 1·501–5·0 × 109 L−1 and > 5·0 × 109 L−1 are presented as light red and dark red dots, respectively. (c) Proportion of patients with eosinophilia grades 1–3; patient numbers are provided in Table 3. Eosinophilia grade scale follows the guidance provided by the U.S. Food and Drug Administration.37 BL, baseline; Q, quartile; qw, once weekly; q2w, every 2 weeks; TCS, topical corticosteroids; Wk, week.

Figure 5

(a) Mean change in LDH from baseline to week 16 (SOLO 1 & 2) and week 52 (CHRONOS). (b) Absolute LDH levels. White horizontal lines indicate medians. X depicts mean values. Top and bottom of each box represent Q3 and Q2, respectively. Upper and lower vertical bars represent Q4 and Q1, respectively; horizontal segments on each end of the vertical bars represent minimum and maximum values. (c) Proportion of patients with shifts from high to normal values from baseline to week 16 (SOLO 1 & 2) and week 52 (CHRONOS). Normal range: 135–330 IU L−1 (female) and 135–281 IU L−1 (male) in SOLO 1 & 2, respectively, and 53–234 IU L−1 in CHRONOS. BL, baseline; LDH, lactate dehydrogenase; n, number of patients; N1, total number of patients with at least one value at visit; Q, quartile; qw, once weekly; q2w, every 2 weeks; TCS, topical corticosteroids; Wk, week.