Digital Features for this article can be found at https://doi.org/10.6084/m9.figshare.25476070

FormalPara Key Points

For young children aged ≥ 6 months with atopic dermatitis (AD) inadequately controlled with topical therapies, 16 weeks of treatment with dupilumab has proven efficacious, with an acceptable safety profile. Many of these children experience persistent disease into adolescence and adulthood; therefore, long-term safety and efficacy data are important to inform continuous disease management.

This was an analysis of data from a long-term open-label extension study in children aged 6 months to 5 years with uncontrolled AD. Data presented here demonstrate that dupilumab treatment every 4 weeks, for up to 52 weeks, had an acceptable safety profile.

Dupilumab provided sustained clinical benefits in reducing AD clinical signs and symptoms, as well as improvements in the health-related quality of life of patients.

1 Introduction

Atopic dermatitis (AD) is the most common inflammatory skin disease in childhood [1], with reported prevalence around the world ranging from 3% to 40% in children aged < 6 years [2,3,4]. Approximately 50% of patients with AD develop symptoms within their first year of life, with onset below 5 years of age in up to 95% of cases [5]. AD has a chronic relapsing course [5] and commonly precedes development of other atopic conditions such as food allergy, allergic rhinitis, and asthma [6, 7].

Moderate-to-severe AD is characterized clinically by flares featuring eczematous skin changes and intense itch and increased susceptibility to recurrent skin infections. The pathophysiology of the condition is related to the presence of a defective skin barrier, as well as both local and systemic type 2 immune skewing [8]. The main symptom of AD is pruritus [9], which often results in significant sleep disruption, irritability, and stress for the patient’s family members [10]. AD has been associated with a markedly impaired patient and family quality of life, similar to or greater than that seen in other chronic skin and extracutaneous diseases, including diabetes, asthma, and sickle cell disease [11, 12]. More than half of children with severe AD have moderate-to-high impairments in their quality of life [13]. Parents of children with AD experience sleep loss, and may experience depression, anxiety, and helplessness due to the stress caused by their child’s disease [14].

Children with moderate-to-severe AD often have a family history of atopy, an increased risk of developing other atopic conditions, and a higher risk of persistent skin disease into adolescence and adulthood [15, 16].

Data from the real-world PEDISTAD registry of children with AD inadequately controlled by topical therapies revealed that only 22.3% of children aged 2 to < 6 years and 11.7% of children aged 0 to < 2 years were receiving systemic medications for AD [17], despite a significant disease burden among the patients and their families. These findings reveal an unmet need for effective and well-tolerated therapeutic options for long-term disease control in children aged younger than 6 years with moderate-to-severe AD [17].

Although treatment with systemic glucocorticoids is not recommended by published guidelines for children with AD, until recently this class of medication was the only US Food and Drug Administration (FDA)-approved systemic option for children aged younger than 6 years [18]. Dupilumab is a fully human VelocImmune®-derived [19, 20] monoclonal antibody that blocks the shared receptor component for interleukin (IL)-4 and IL-13, inhibiting signaling of both IL-4 and IL-13 [21, 22], which are key drivers of type 2-mediated inflammation in multiple diseases [21, 23, 24]. Dupilumab has been approved by the US FDA and the European Medicines Agency (EMA) for patients with type 2 inflammatory diseases, including (since 2017) for adults with moderate-to-severe AD and (since 2022) for children aged 6 years and older with moderate-to severe AD [25, 26]. Results from the 16-week randomized placebo-controlled phase 3 LIBERTY AD PRESCHOOL R668-AD-1539 trial (NCT03346434 part B) [27] supported the approval of dupilumab as the first systemic treatment (and only biologic agent available) for children as young as 6 months with moderate-to-severe AD [25, 28].

The objective of this analysis was to evaluate long-term safety and efficacy data for dupilumab in children aged 6 months to 5 years with moderate-to-severe AD who had previously participated in PRESCHOOL part B and who were subsequently enrolled in the open-label LIBERTY AD PED-OLE trial (NCT02612454).

2 Methods

2.1 Study Design

PED-OLE is an ongoing phase 3 open-label extension (OLE) study in patients aged ≥ 6 months to < 18 years with moderate-to-severe AD who had previously participated in a dupilumab AD parent study. This analysis includes patients aged 6 months to 5 years who previously participated in the PRESCHOOL part B study, referred to here as the parent study [27]. The study design and safety and efficacy results of the parent study have been previously reported [27]. Briefly, in PRESCHOOL part B, patients were randomized 1:1 to subcutaneous placebo or a weight-tiered regimen of dupilumab plus low-potency topical corticosteroids (TCS; hydrocortisone acetate 1% cream) for 16 weeks.

PED-OLE had a screening period (day −28 to day −1) from the time patients exited the parent study until they entered the PED-OLE. This was followed by a treatment period that lasted until regulatory approval of the product for the age group of the patient in their geographic region (or 5 years in patients aged 6 months to 11 years, according to Protocol Amendment 4, which was adopted in March 2020) and a 12-week follow-up period. This analysis presents results through week 52 of the PED-OLE, with a data cutoff date of 10 March 2022 for patients who had previously participated in PRESCHOOL part B and were aged 6 months to 5 years with moderate-to-severe AD at randomization in PRESCHOOL.

2.2 Main Inclusion and Exclusion Criteria

Patients included in this analysis were aged 6 months to 5 years at the time of screening, had previously participated in the PRESCHOOL part B [with moderate-to-severe AD at parent study baseline (PSBL)], and had completed ≥ 50% of visits and assessments as defined in the parent study protocol. The full inclusion and exclusion criteria for PRESCHOOL have been previously reported [27]. Patients were excluded from PED-OLE if they experienced a serious adverse event (SAE) during their participation in the parent study that was deemed related to the study drug, or an adverse event (AE) related to the study drug that led to discontinuation from the parent study. Full inclusion and exclusion criteria for PED-OLE can be found in Appendix S1 in the electronic supplementary material (ESM).

2.3 Treatment

Patients included in this analysis had received either dupilumab or placebo in the parent study and were started on a weight-tiered regimen of subcutaneous dupilumab upon entering the PED-OLE: patients with body weight ≥ 5 to < 15 kg received 200 mg every 4 weeks (q4w); and those with body weight ≥ 15 kg to < 30 kg received 300 mg q4w.

Basic skin care (including bleach baths), antihistamines, concomitant TCS, and topical calcineurin inhibitors were permitted without restriction, and use of topical crisaborole was permitted if approved locally for treatment of AD. Patients were not permitted to use systemic medications for AD (including corticosteroids and non-steroidal immunosuppressants), except as rescue treatment. Concomitant use of TCS or other AD therapies was not standardized.

Patients who had an Investigator’s Global Assessment (IGA) score of 0/1 maintained continuously for a 12-week period beginning at week 40 or later were discontinued from dupilumab (i.e., patients who had an IGA score of 0 or 1 through week 40 to week 52, inclusive, were discontinued from dupilumab at week 52). Disease activity was closely monitored in these patients during the remaining study visits, and treatment with dupilumab was reinitiated in patients who experienced a relapse of disease (IGA score ≥ 2). In these cases, investigators were encouraged to first consider treatment with topical therapy (i.e., medium-potency TCS) and to reinitiate dupilumab only for patients who did not adequately respond after at least 7 days of topical treatment. Such patients were reinitiated directly on their previous dupilumab dose (without a loading dose). These data will be presented in a subsequent manuscript.

2.4 Outcomes

The primary outcomes of PED-OLE were incidence and rate [patients per 100 patient-years (100PY) and/or events per 100PY] of treatment-emergent adverse events (TEAEs) through the last study visit.

Key secondary outcomes were incidence and rate (patients and/or events per 100PY) of treatment-emergent SAEs and incidence and rate (patients and/or events per 100PY) of TEAEs of special interest, [i.e., anaphylactic reactions, conjunctivitis, injection-site reactions, skin infections (excluding herpes viral infections), herpes viral infections, and helminthic infections].

Other secondary outcomes included: proportion of patients with an IGA score of 0/1 (clear/almost clear skin) by visit through week 52; proportion of patients with ≥ 75% reduction in Eczema Area and Severity Index from baseline of parent study (EASI-75) by visit through week 52; change and percentage change from PSBL in EASI by visit through week 52; change from baseline of parent study in body surface area (BSA) affected by AD by visit through week 52; percentage change from baseline of parent study in SCORing Atopic Dermatitis (SCORAD) by visit through week 52; change from baseline of parent study in Children’s Dermatology Life Quality Index (CDLQI) by visit through week 52, for patients ≥ 4 years of age; and change from baseline of parent study in Infant’s Dermatitis Quality of Life Index (IDQoL) by visit through week 52, for patients < 4 years of age. This analysis also included the additional outcomes of proportion of patients achieving EASI-50/-90 (≥ 50/90% reduction, respectively, in EASI) from baseline of parent study by visit through week 52. Since evaluation of itch requires daily assessment, itch was not included as an outcome to minimize patient burden and ensure the highest possible patient retention in this long-term study.

2.5 Analyses

For this study, no formal sample size was estimated, and no power calculations were performed. All clinical safety and efficacy variables were evaluated in the safety analysis set, which consisted of all patients who received one or more doses of dupilumab. All safety data were included from the baseline of the PED-OLE to the database lock. For the evaluation of conjunctivitis, grouped Medical Dictionary for Regulatory Activities (MedDRA) Preferred Terms (PTs) consistent with conjunctivitis and selected eye disorder terms were selected for further analysis. A compiled term was used, including all PTs containing the word “conjunctivitis” (conjunctivitis, conjunctivitis allergic, conjunctivitis bacterial, conjunctivitis viral, and atopic keratoconjunctivitis).

All efficacy analyses were descriptive; no formal statistical hypothesis was tested. All observed values, regardless of whether rescue treatment was used or data were collected after withdrawal from study treatment, were used for analysis. No missing values were imputed.

For continuous variables, descriptive statistics included the following: the number of patients reflected in the calculation (n), mean, median, Q1 (25th percentile), Q3 (75th percentile), standard deviation (SD), minimum, and maximum. For categorical or ordinal data, frequencies and percentages are displayed for each category.

2.6 Compliance with Ethical Standards

PED-OLE and the parent study, PRESCHOOL part B [27], were conducted in accordance with the ethical principles outlined in the Declaration of Helsinki and with the International Council for Harmonisation guidelines for good clinical practice and applicable regulatory requirements. Patients (as appropriate, based on the age of the child and country-specific requirements) provided assent, and at least one parent or guardian for each child provided written informed consent. At each study site, the protocol, informed-consent form (ICF), and patient information were approved by an institutional review board and independent ethics committee.

3 Results

Of the 142 patients screened, all patients met the inclusion criteria (Fig. 1). At the time of the database lock (10 March 2022), 142 patients from the PRESCHOOL part B trial had been enrolled in PED-OLE and were included in the safety analysis set (39 patients received 200 mg q4w; 103 received 300 mg q4w). Of the 142 patients, at the time of the database lock, 10 patients had withdrawn from the study prematurely, 60 (42.3%) patients had completed the week 52 visit, 132 (93.0%) were ongoing (< 52 weeks), and none had completed the study (planned for at least 5 years). The reasons for premature study discontinuation were withdrawal by the patient (n = 6), patient lost to follow-up (n = 2), adverse events (n = 1), and lack of efficacy (n = 1) (Fig. 1).

Fig. 1
figure 1

Patient disposition for patients in PED-OLE who enrolled from PRESCHOOL part Ba. aOnly patients from PRESCHOOL part B were screened in this analysis

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3.1 Patient Baseline Demographics and Clinical Characteristics

Mean age of the patients was 4.1 years [SD, 1.13; range, 1.0–5.9 years], and the majority were white (65.5%) and male (62.7%) (Table 1; Table S1 in the ESM). Mean weight and body mass index was 17.5 kg and 16.3 kg/m2, respectively, and 37 (26.1%) patients were overweight (body mass index > 85th percentile for age and sex). Mean duration of AD was 3.7 years, suggesting that most patients had been diagnosed with AD at an early age. A majority of patients had moderate-to-severe disease at PED-OLE baseline, with 42.3% having IGA 3 and 21.1% having IGA 4 (Table 1). Likely reasons for the severity at baseline are the treatment interruption (28-day screening period) between the parent study and the PED-OLE study and the inclusion of patients from the placebo arm of the parent study. All patients had one or more comorbid allergic conditions at baseline, reflecting the high type 2 inflammatory profile in this young patient population. Approximately one-third (35.9%) of patients had received one or more prior systemic immunosuppressive medications for AD besides dupilumab, suggestive of patients with severe disease.

Table 1 Patient demographics and clinical characteristics at baseline of PED-OLE
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3.2 Safety Assessment

Safety data for the 142 patients are presented from the baseline of the PED-OLE study up to the database lock. A majority of patients [111 patients (78.2%); 204.9 patients per 100PY] reported ≥ 1 TEAE, most of which were mild or moderate in intensity (Table 2) and transient in nature. A total of 18 patients (12.7%; 14.7 patients per 100PY) reported TEAEs that were judged by the investigator as being related to treatment, 6 patients (4.2%; 4.6 patients per 100PY) reported severe TEAEs, and 8 (5.6%; 6.2 patients per 100PY) reported a total of 9 serious TEAEs (6.8 events per 100PY) (Table 2). The nine serious events (listed here as MedDRA PTs) consisted of one event each of enterobiasis, dermatitis atopic, adenoidal hypertrophy, tonsillar hypertrophy, gastroenteritis viral, periorbital cellulitis, otitis media, otitis media acute, and diabetic ketoacidosis (Table S2; see the ESM). Of the serious TEAEs, all had resolved (one event of diabetic ketoacidosis had resolved with sequelae) by the time of the database lock (Table S2; see the ESM). Only one TEAE [severe urticaria (MedDRA PT)] led to permanent treatment discontinuation; however, the event resolved after 1 day (Table S3; see the ESM).

Table 2 Safety assessment in the PED-OLE
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Five TEAEs of special interest [3.8 events per 100PY; 4 patients (2.8%); 129.6 patients per 100PY] were reported: two events of anaphylactic reaction (both were assessed by the investigator to be related to food allergy, and both were not related to treatment) and one event each of enterobiasis (related to treatment), blepharitis (related to treatment), and keratitis (assessed by the investigator as not related to treatment). All of these events were resolved at the time of the database lock (Table S4; see the ESM).

The most frequently reported TEAEs were: nasopharyngitis (19.7%; 23.9 patients per 100PY); cough (15.5%; 18.3 patients per 100PY); and pyrexia (14.1%; 16.4 patients per 100PY) (Table 2). Injection-site reactions (MedDRA high-level term, HLT) were reported in three patients (2.1%; 2.3 patients per 100PY); none of these events were serious, all were mild or moderate in severity, and none led to treatment discontinuation (Table 2).

Treatment-emergent conjunctivitis was reported in 18 patients (12.7%; 14.6 patients per 100PY), including conjunctivitis allergic (8 patients; 5.6%; 6.3 patients per 100PY), conjunctivitis (5 patients; 3.5%; 3.9 patients per 100PY), bacterial conjunctivitis (5 patients; 3.5%; 3.8 patients per 100PY), and viral conjunctivitis (1 patient; 0.7%; 0.8 patients per 100PY). All conjunctivitis events were mild or moderate, and the majority had resolved by the time of the database lock and did not recur with continued treatment (Table 2 and Table S5; see the ESM). Of these 18 patients, 15 (83.3%) had reported conjunctivitis TEAEs in the parent study, and 5 (27.8%) had reported history of conjunctivitis prior to the parent study (Table S5; see the ESM). Skin infections (excluding herpes viral infections) were reported in 24 patients (16.9%; 20.2 patients per 100PY) (Table 2). Herpes viral infections (MedDRA HLT) were reported in 14 patients (9.9%; 11.0 patients per 100PY), among which herpes simplex, oral herpes, and varicella infections were the most common, each being reported in 4 patients (2.8%; 3.1 patients per 100PY) (Table 2 and Table S6; see the ESM). Other skin structures and soft tissue infections (MedDRA HLT) were reported in ten patients (7.0%; 7.9 patients per 100PY), among which impetigo was the most common, being reported in five patients (3.5%; 3.9 patients per 100PY) (Table S6; see the ESM). Further details of conjunctivitis and skin infections are presented in Tables S5 and S6, respectively; see the ESM.

In patients younger than 2 years, the trends in safety data were similar to those observed in the overall population (Table S7; see the ESM); one patient in this age group experienced conjunctivitis and one experienced a non-herpes virus-related skin infection [impetigo (MedDRA PT)] (Table S7; see the ESM). However, it should be noted that this group consisted of only seven patients.

3.3 Efficacy Outcomes

Efficacy data for the 142 patients included in the analysis are presented from the baseline of the parent study up to week 52 of treatment in the OLE (Fig. 2, Fig. S1; see the ESM). Clinical signs showed substantial and incremental improvements over time. The proportions of patients with an IGA score of 0/1 (Fig. 2a) or EASI-75 (Fig. 2b) increased from PSBL through week 52 of the PED-OLE. By week 52, 36.2% of patients (21/58) had an IGA score of 0/1, and 96.6%, 79.3%, and 58.6% of patients had EASI-50, EASI-75, and EASI-90, respectively (Table 3). Additionally, 91.4% of patients had mild disease or better (IGA ≤ 2) at week 52 of the PED-OLE (Fig. S2a; see the ESM).

Fig. 2
figure 2

Efficacy outcomes from parent study baseline through week 52 of the PED-OLE. BL baseline of OLE, BSA body surface area, CDLQI Children’s Dermatology Life Quality Index, EASI Eczema Area and Severity Index, EASI-75 patients achieving a 75% reduction in EASI compared with PSBL, IDQOL Infants’ Dermatitis Quality of Life Index, IGA Investigator’s Global Assessment, OLE open-label extension, PSBL parent study baseline, SCORAD SCORing Atopic Dermatitis, SD standard deviation. aAmong patients with CDLQI ≥ 6 at PSBL. bAmong patients with IDQOL ≥ 6 at PSBL. Note: The safety analysis set included 60 patients; however, one patient did not perform the week 52 assessment due to varicella zoster infection and another due to COVID-19 infection.

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Table 3 Efficacy assessment at weeks 4, 16, and 52 in the PED-OLE
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Similar incremental improvements through week 52 were seen for achievement of IGA 0/1 or EASI-75 in patients with body weight < 15 kg or ≥ 15 to < 30 kg (Fig. S1a and S1b in the ESM).

Mean percent changes from PSBL in EASI (Fig. 2c) and SCORAD (Fig. 2d) showed substantial improvement through week 52, with mean percent (SD) change of −86.6 (16.3) in EASI and −70.2 (21.3) in SCORAD at week 52. At week 52, mean (±SE) EASI was 4.2 (0.7), with mean (±SD) change in EASI from PSBL of −26.9 (12.6) (Fig. S2b and S2c; see the ESM). Again, a similar incremental improvement in EASI was seen through week 52 (Fig. S2c; see the ESM). The proportion of BSA affected by AD decreased from PSBL through week 52 (Fig. 2e), with a mean (SD) percent change in BSA affected by AD of −45.6 (22.5) at week 52 (Table 3).

Patients also showed improvement in health-related quality of life, with 90.0% (27/30) of patients aged ≥ 4 years having a ≥ 6-point improvement in CDLQI by week 52; many experienced this improvement as early as week 4 (Fig. 2f). Mean (SD) change in CDLQI from PSBL was −13.7 (6.4) at week 52 (Table 3). Similarly, among patients aged < 4 years, 100.0% (10/10) had ≥ 6-point improvement in IDQoL by week 52; many of these younger patients also experienced this improvement by week 4 (Table 3 and Fig. 2g). Mean (SD) change from PSBL in IDQoL was −15.0 (4.4) at week 52 (Table 3).

A similar trend in efficacy data was observed in patients younger than 2 years as was observed in the overall population (Table S8; see the ESM).

4 Discussion

Dupilumab is the first systemic treatment other than oral steroids, and the first biologic agent, approved by the US FDA for the treatment of children as young as 6 months with moderate-to-severe AD [25, 26]. In PED-OLE, dupilumab treatment for up to 52 weeks was well tolerated and provided sustained and substantial clinical benefit in AD signs, symptoms, and quality of life in children aged 6 months to 5 years with inadequately controlled moderate-to-severe AD.

The overall safety profile in children aged 6 months to 5 years was consistent with the results previously obtained in OLE trials in adults [29], adolescents [30], and children aged 6–11 years with AD [31]. Results presented here were also consistent with the safety profile seen in the 16-week phase 3 trial of dupilumab in this age group of patients with AD (PRESCHOOL part B) [27]. The number of events leading to permanent study drug discontinuation was low (nE per 100PY: 0.8) in this study: only one TEAE (severe urticaria) led to permanent study drug discontinuation; this event lasted for 1 day. This event was deemed related to the study drug by the investigator; however, it resolved rapidly and was not serious. There were nine serious TEAEs, of which one was considered related to dupilumab (enterobiasis); all resolved over time. The event of enterobiasis related to dupilumab was moderate in severity and the dupilumab dose was not changed due to this serious TEAE.

A total of 18 (12.7%) patients experienced conjunctivitis; all events were mild or moderate in severity, most (12/18) resolved by the time of database lock (remaining events were ongoing), and none led to discontinuation of treatment. In the PED-OLE, there was a low incidence of injection-site reactions (three patients; 2.1%); all were mild or moderate in severity, none were serious, and none led to treatment discontinuation. No reports of systemic hypersensitivity, including anaphylactic reactions, were considered to be related to dupilumab.

Overall, infections and infestations were reported in 35 (24.6%) patients. A total of 24 (16.9%) patients experienced a TEAE of skin infection (MedDRA System Organ Class, excluding herpes viral infections); none of these infections were severe or serious, and none led to treatment discontinuation. Furthermore, no opportunistic infections were reported in this patient subgroup with a developing immune system. In the 16-week phase 3 trial, dupilumab treatment resulted in lower rates of skin infections compared with placebo [27]. Similarly, in previous controlled studies in adults, adolescents, and older children, incidence of skin infection TEAEs was lower in the dupilumab arm compared with the placebo arm [32,33,34,35,36]. The profile of skin infections was consistent with what is typically seen in patients with AD in this age group [37, 38]. Since the patients enrolled in this study had a high level of disease severity at baseline, occurrence of these skin infections was not unexpected.

Although data in this subpopulation are limited and the dataset was small, the safety profile in patients aged < 2 years was consistent with that seen in the overall population. Dupilumab was consistently well tolerated across subgroups, including in patients aged < 2 years.

Clinical efficacy of dupilumab that was demonstrated in children aged 6 months to 5 years in PRESCHOOL part B was sustained in children with moderate-to-severe AD treated with dupilumab in PED-OLE for up to 1 year. Efficacy data for all patients enrolled in the PED-OLE (N = 142) demonstrated a substantial and progressively incremental clinical benefit of dupilumab with longer-term treatment. Improvements were observed across efficacy endpoints. Notably, 90% of children ≥ 4 years and 100% of children < 4 years experienced a clinically meaningful change in health-related quality of life as measured by CDLQI and IDQoL, respectively. Similar trends for substantial and sustained clinical benefit were seen in patients aged < 2 years. Improvements in efficacy endpoints were also independent of patient weight. The significant clinical benefit experienced with dupilumab treatment, coupled with the acceptable safety profile, are aligned with the high retention rate in the study.

A key strength of this analysis is that this is the first long-term study (through 1 year) of dupilumab safety and efficacy, or any biologic agent, in infants and young children aged 6 months to 5 years. This ongoing study will provide additional information about the safety and efficacy of this treatment in pediatric patients over several years. Limitations of this analysis include the open-label, non-randomized nature of the study, the fact that concomitant use of TCS and other AD therapies was not standardized, the small sample size of patients aged < 2 years, and that efficacy data are reported as observed and do not account for potential confounding factors resulting from additional AD therapies. Notably, there was no imputation for patients who withdrew from the study (n = 10) and not all patients had completed the week 52 visit. Another limitation was the small number of patients for whom data were available after discontinuation of dupilumab post-remission. These data continue to be accumulated, as the study is ongoing, and will be presented in a subsequent manuscript. Finally, additional important questions remain for further investigation, including immunization safety and efficacy (manuscript in development), pharmacokinetic analysis (manuscript in development), rate of relapse off-treatment, durability of response after restarting, and whether early intervention in this age group can modify the course of the disease.

5 Conclusions

Dupilumab treatment demonstrated an acceptable long-term safety profile and sustained efficacy in children aged 6 months to 5 years with inadequately controlled moderate-to-severe AD. These results support long-term continuous use of dupilumab in this patient population. The dupilumab long-term safety profile was comparable with that previously observed in AD. Further studies in children aged 6 months to 5 years treated with dupilumab are ongoing to evaluate longer-term safety and efficacy in this age group.