Digital Features for this article can be found at https://doi.org/10.6084/m9.figshare.21684995.

FormalPara Key Points

This analysis of laboratory outcomes among children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis treated with dupilumab did not reveal any laboratory outcomes that were of clinical concern and none that indicated a need for routine laboratory monitoring.

Laboratory abnormalities reported as treatment-emergent adverse events were uncommon, were not associated with clinical symptoms, and did not lead to treatment discontinuation or study withdrawal for any patient.

These findings suggest that dupilumab can be used for the continuous treatment of moderate-to-severe atopic dermatitis in children aged 6 months to < 6 years without the need for routine laboratory monitoring.

1 Introduction

Atopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease, with some AD treatments requiring regular monitoring for untoward changes in laboratory parameters [1,2,3,4]. Routine laboratory monitoring can be burdensome for patients and can reduce treatment compliance. Thus, medications that do not require monitoring would reduce the overall burden of laboratory tests on patients, especially among infants and children.

Dupilumab is a fully human VelocImmune®-derived [5, 6] monoclonal antibody that blocks the shared receptor subunit for interleukin (IL)-4 and IL-13, key and central drivers of type 2 inflammation in multiple diseases [7]. In phase III clinical trials in adults, adolescents, and children with moderate-to-severe AD, dupilumab with or without topical corticosteroids (TCS) versus placebo showed significant improvements in AD signs, symptoms, and quality of life with an acceptable safety profile [8,9,10,11,12,13,14,15,16]. In adults, dupilumab has shown sustained efficacy and an acceptable long-term safety profile for up to 4 years [17, 18]. To further characterize the safety profile of dupilumab, we report laboratory findings from a randomized, double-blind, placebo-controlled phase III trial in children aged 6 months to < 6 years with moderate-to-severe AD.

2 Methods

2.1 Study Design, Patients, and Treatment

LIBERTY AD PRESCHOOL (NCT03346434, part B) was a randomized, placebo-controlled, double-blind, parallel-group, phase III trial [19]. Patients were enrolled from 31 hospitals, clinics, and academic institutions in Europe and North America. Full details of the study design, patient population, and efficacy and safety outcomes have been previously reported [19]. In brief, patients aged 6 months to < 6 years with moderate-to-severe AD whose disease was inadequately controlled with topical treatment or for whom topical treatment was inadvisable were randomized 1:1 to receive subcutaneous placebo or dupilumab (5 kg to < 15 kg: 200 mg; 15 kg to < 30 kg: 300 mg) plus low-potency TCS (hydrocortisone acetate 1% cream) every 4 weeks (q4w) for 16 weeks. Specific exclusion criteria related to laboratory abnormalities included platelets ≤ 100 × 109/L, neutrophils ≤ 1.0 × 109/L for patients aged < 1 year, neutrophils ≤ 1.5 × 109/μL for patients aged 1 year to < 6 years, eosinophils > 5000/μL, creatine phosphokinase > 2.5 × upper limit of normal (ULN), serum creatinine > 1.5 × ULN, or evidence of liver disease indicated by persistent (confirmed by repeated tests ≥ 2 weeks apart) elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3 × ULN during the screening period.

2.2 Ethics

The study was conducted following the ethical principles derived from the Declaration of Helsinki, the International Council for Harmonisation guidelines, Good Clinical Practice, and local applicable regulatory requirements. Written informed consent was obtained from the patients’ parents/guardians prior to the start of any study treatment.

2.3 Laboratory Measurements

Blood samples were collected at a pretreatment screening visit (hereafter referred to as “baseline”) and at weeks 4 and 16. Hematology assessments, including red blood cell, white blood cell, and platelet parameters and serum chemistry assessments, including renal function, liver function, electrolytes, metabolic function, and lipids were analyzed by a central laboratory (PPD Global Central Labs LLC, Highland Heights, KY, USA). Investigators were instructed to report laboratory abnormalities as adverse events if one or more of the following occurred: the test result was associated with accompanying symptoms, the test result required additional diagnostic testing or medical/surgical intervention, the test result prompted dose adjustment outside of that stipulated by the protocol and/or discontinuation from the study, or management of the event required significant additional concomitant drug treatment or other therapy. The study drug was to be permanently discontinued in the case of severe laboratory abnormalities, including neutrophils ≤ 0.5 × 109/L, platelets ≤ 50 × 109/L, ALT and/or AST > 3 × ULN with total bilirubin > 2 × ULN (unless the elevated bilirubin levels were related to confirmed Gilbert syndrome), or confirmed AST and/or ALT > 5 × ULN persisting > 2 weeks. If the laboratory abnormality was not suspected to be related to the study drug, treatment was resumed when the abnormality normalized. If the laboratory abnormality was deemed related to the study drug, the drug was to be permanently discontinued.

2.4 Statistical Analysis

This analysis was conducted using the safety analysis set (all randomized patients who received at least one dose of study drug). All statistics are descriptive, using an all-observed-values method without any imputation for missing values; statistics were computed based on the number of available samples at each time point. Analyses included values at baseline and change from baseline by visit as means with standard deviation. The number and percent of patients with one or more treatment-emergent adverse event (TEAE) reported due to laboratory abnormalities during the 16-week treatment period were also assessed.

3 Results

3.1 Patients

A total of 162 patients were randomized and 161 were included in the laboratory safety analysis (one patient in the placebo plus TCS treatment group was randomized in error, did not receive study treatment, and was therefore excluded from the safety analysis set). Baseline demographics and clinical characteristics are presented in Table 1. Baseline laboratory parameters were balanced across treatment groups (Table 2).

Table 1 Baseline demographics and clinical characteristics [19]
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Table 2 Hematology and chemistry at baseline and week 16
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3.2 Clinical Laboratory Parameters Reported During the Treatment Period

3.2.1 Hematology

Eosinophil counts were at the ULN (normal reference range: 0–1.10 × 109/L) and similar across treatment groups at baseline, with mean (standard deviation) and median (first quartile [Q1], third quartile [Q3]) values of 1.09 (0.73) × 109/L and 0.95 (0.52, 1.42) × 109/L for the dupilumab plus TCS group, and 1.10 (0.74) × 109/L and 0.92 (0.51, 1.55) × 109/L for the placebo plus TCS group (Table 2). Absolute eosinophil counts at baseline ranged from 0.10 to 3.34 × 109/L for the dupilumab plus TCS group, and from 0.02 to 3.22 × 109/L for the placebo plus TCS group. At weeks 4 and 16, eosinophil counts were elevated relative to both baseline and the normal reference range among patients receiving dupilumab plus TCS (Table 2), with mean (standard deviation) changes of 0.31 (1.37) × 109/L and −0.18 (0.75) × 109/L from baseline to week 16 for the dupilumab plus TCS and placebo plus TCS groups, respectively (Figs. 1A, 2). The median (Q1, Q3) change in eosinophils from baseline to week 16 was −0.08 (−0.37, 0.41) for the dupilumab plus TCS group, and −0.10 (−0.58, 0.11) for the placebo plus TCS group. The range of absolute eosinophil values at week 16 was 0.02–8.55 × 109/L for the dupilumab plus TCS group, and 0.02–4.52 × 109/L for the placebo plus TCS group. Elevated eosinophil counts were not associated with clinical symptoms. Two patients in the dupilumab plus TCS group had eosinophilia reported as a TEAE, by the investigator. In both cases, study treatment was not discontinued and the investigator deemed the TEAE to be “resolved” or “resolving” by the end of the treatment period (Table 3). Absolute eosinophil values at baseline, week 4, and week 16 were 2.73 × 109/L, 6.00 × 109/L, and 7.02 × 109/L in the first case, and 2.66 × 109/L, 9.17 × 109/L, and 5.83 × 109/L in the second case, respectively. No other events were associated with eosinophilia.

Fig. 1
figure 1

A Mean change in eosinophil count from baseline to week 16. B Mean change in platelet count from baseline to week 16. C Mean change in leukocyte count from baseline to week 16. D Mean change in neutrophil count from baseline to week 16. E Mean change in hemoglobin from baseline to week 16. F Mean change in alkaline phosphatase (ALP) from baseline to week 16. G Mean change in alanine aminotransferase (ALT) from baseline to week 16. H Mean change in lactate dehydrogenase from baseline to week 16. LDH lactate dehydrogenase, q4w every 4 weeks, SD standard deviation, TCS topical corticosteroids

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Fig. 2
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Eosinophil counts at baseline, week 4, and week 16. q4w every 4 weeks, TCS topical corticosteroids

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Table 3 Safety overview and laboratory abnormalities reported as TEAEs
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Platelet counts were elevated above the ULN reference range in all treatment groups at baseline and at weeks 4 and 16 (Table 2). A small decrease in platelet counts was observed in the dupilumab plus TCS group at weeks 4 and 16 relative to baseline, with mean changes of −0.16 × 109/L and 17 × 109/L from baseline to week 16 for the dupilumab plus TCS and placebo plus TCS groups, respectively (Table 2, Fig. 1B); mean values are reported in Table 2. No clinically meaningful differences or changes in mean leukocyte counts, neutrophil counts, or hemoglobin were observed from baseline to week 16 (Table 2, Fig. 1C–E). One case each of increased white blood cell counts and neutropenia were reported as TEAEs in the dupilumab plus TCS group; neither case was serious, led to treatment discontinuation, or was associated with clinical symptoms (Table 3). The case of increased white blood cell counts was considered by the investigator to be “resolved” by the end of the treatment period, while the case of neutropenia was not deemed “resolved” by the end of the treatment period. In the patient with neutropenia, absolute neutrophil counts were 1.7, 1.2, and 1.3 × 109/L at baseline, week 4, and week 16, respectively.

3.2.2 Serum Chemistry

Elevations in alkaline phosphatase (ALP) levels were observed throughout the treatment period in the dupilumab plus TCS group, while levels remained closer to baseline in the placebo plus TCS group (Fig. 1F). All values remained within the range of normal. No corresponding changes in other liver function tests were observed. Levels of ALT and lactate dehydrogenase (LDH) decreased slightly from baseline to week 16 in both groups, with more pronounced decreases observed in the dupilumab plus TCS group (Fig. 1G, H).

3.2.3 Other Laboratory Parameters

There were no clinically meaningful differences or trends in mean change from baseline in any treatment group for metabolic function parameters, electrolyte parameters, renal function parameters, liver function parameters, or lipid parameters.

4 Discussion

This analysis of laboratory outcomes among children aged 6 months to < 6 years treated with dupilumab did not reveal any laboratory outcomes that were of clinical concern and none that indicated a need for routine laboratory monitoring. Laboratory abnormalities reported as TEAEs were uncommon, were not associated with clinical symptoms, and did not lead to treatment discontinuation or study withdrawal for any patient. In general, the laboratory outcomes observed in this patient population were similar to those observed in adults, adolescents, and children aged 6 to < 12 years [13,14,15]. Details and discussion of the full safety outcomes of this study have been previously reported [19].

At baseline and week 16, platelet counts were elevated above the ULN reference range in all treatment groups, and there was a trend toward decreasing platelet counts over the 16-week treatment duration among patients receiving dupilumab plus TCS, similar to that previously observed in adults, adolescents, and children [13,14,15]. This trend may reflect a reduction in systemic inflammation and AD severity, as previous studies suggest that platelets are nonspecific acute-phase reactants that are elevated in many inflammatory states [20, 21].

Elevated mean eosinophil counts were observed at week 4 and remained elevated at week 16 in the dupilumab plus TCS group. Mean baseline eosinophil counts and mean increase in eosinophil counts at week 4 were both higher in this age group compared with those seen previously in other age groups; however, these elevations were not associated with clinical symptoms, just as clinical symptoms were not associated in previous reports [13,14,15]. Moreover, mean eosinophil counts were trending toward baseline at week 16. Further evaluation of this trend will be possible in an ongoing open-label extension study of this population. Of note, median eosinophil values were closer together than the means, which suggests that outliers may have skewed the mean values and disproportionately impacted the trend toward baseline at week 16.

Two patients in the dupilumab plus TCS group experienced eosinophilia reported as a TEAE and had absolute eosinophil counts above the 1.50 × 109/L cut-off typically used to define hypereosinophilia. The cases were deemed by the investigator to be “resolved” or “resolving” by the end of the treatment period. Investigators were not required to provide a rationale for why they reported eosinophilia as a TEAE. Eosinophilia is characteristic of AD and other atopic diseases and correlates with disease activity [22, 23]. In mouse models of asthma, dupilumab blockade of IL-4 and IL-13 signaling prevents eosinophils from entering tissues, resulting in accumulation of eosinophils in the bloodstream [24,25,26]. Thus, the increase in blood eosinophil counts observed here is consistent with the hypothesis that dupilumab blocks IL-4 and IL-13 function in promoting eosinophil recruitment from the blood into tissue, resulting in a slight increase in mean values of circulating blood eosinophils. Interestingly, in other age groups (children aged 6 to < 12 years, adolescents, and adults), dupilumab treatment was associated with transient elevations in eosinophil counts that resolved with continued treatment, rather than sustained elevations as seen here [13,14,15]. Transient elevations in eosinophil counts have also been observed in dupilumab-treated patients with asthma and chronic rhinosinusitis with nasal polyps, but not eosinophilic esophagitis [27,28,29,30]. Such transient increases with dupilumab treatment did not impact efficacy and rarely had clinical consequences.

In previous studies of dupilumab-treated patients, clinical symptoms associated with eosinophilia included fever, myalgia, arthralgia, pneumonia, lymphadenitis, myositis, radiculopathy, eosinophilic granulomatosis with polyangiitis, asthma exacerbation, and insomnia [27, 29, 30]. Hypereosinophilic syndrome is an uncommon heterogenous group of disorders characterized by persistent hypereosinophilia in the absence of a secondary cause associated with end-organ damage [31]. Hypereosinophilic syndrome can have features that mimic AD, such as eczematous skin lesions [32]; however, hypereosinophilic syndrome has not been reported and is not expected to occur in patients treated with dupilumab.

In both the dupilumab plus TCS and placebo plus TCS groups, LDH levels decreased slightly from baseline to week 16. Lactate dehydrogenase is considered a marker of tissue damage and is strongly correlated with disease severity in AD [33,34,35,36]. Thus, decreases in LDH may reflect its normalization in both patient groups. In the dupilumab plus TCS group, ALT levels also decreased slightly over time, while they remained closer to baseline values in the placebo plus TCS group. In contrast, ALP levels increased in the dupilumab plus TCS group and remained closer to baseline in the placebo plus TCS group. This increase in ALP with dupilumab treatment (but not placebo) was also observed in children aged 6 to < 12 years and adolescents, but not in adults [13,14,15]. No other corresponding changes were observed in other liver parameters (ALT, AST, or bilirubin), suggesting that the increase in ALP is not due to liver damage. This finding is of uncertain clinical significance; however, given that ALP is a marker of growth/bone turnover in children and adolescents, it may be related to increased bone formation in patients treated with dupilumab [37, 38]. Analyses examining bone-specific biomarkers may be warranted.

Limitations of this study include short study duration and, unlike other studies of laboratory safety of dupilumab, no assessments at week 8 to minimize blood draws from young children. Furthermore, the study excluded patients with abnormalities in laboratory test results at screening; therefore, the findings of this study were observed in children with no laboratory abnormalities at baseline. A further limitation is the small number of patients in the 6 months to < 2 years age group.

5 Conclusions

In this analysis of children aged 6 months to < 6 years with moderate-to-severe AD, 16 weeks of dupilumab treatment revealed no clinically relevant laboratory abnormalities, consistent with previous studies of adults, adolescents, and children aged 6 to < 12 years. While slight changes were observed in selected laboratory parameters, including increased eosinophil counts, gradual sustained decreases in platelets, ALT, and LDH (suggesting lowered acute phase reactivity), and gradual sustained increases in ALP, these changes were not associated with clinical symptoms. Taken together, these findings suggest that dupilumab can be used for the continuous treatment of moderate-to-severe AD without the need for routine laboratory monitoring.