Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial

Meltzer, Steven; Wang, Zhixiao; Mannent, Leda; Amin, Nikhil; Sun, Yiping; Laws, Elizabeth; Akinlade, Bolanle; Dillon, Myles; Kosloski, Matthew P.; Kamal, Mohamed; Dubost-Brama, Ariane; Patel, Naimish; Weinreich, David M.; Yancopouloš, George D.; O’Malley, John T.; Bansal, Ashish; Pepper, Amber N.; Paller, Amy S.; Lockshin, Benjamin; Cohen, David J.; Pariser, David M.; Siegfried, Elaine C.; Simpson, Eric L.; Leflein, Jeffrey; Weinberg, Jeffrey M; Browning, John; Teng, Joyce; Lee, Lara Wine; Sher, Lawrence; Diaz, Lucia Z.; Schneider, Lynda C.; González, Mercedes E.; Rupp, Ned T.; Ong, Peck Y.; Cartwright, Robert; Sidbury, Robert; Soong, Weily; Pinter, Andreas; Wollenberg, Andreas; Schnopp, Christina; Cork, Michael J.; Arkwright, Peter D.; Korkosz, Anna; Bystrzanowska, Dorota; Sygula, Ewa; Zdybski, Jacek; Padlewska, Kamila

doi:10.1016/s0140-6736(22)01539-2

Cited by 148 publications

(154 citation statements)

References 33 publications

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“…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].…”

Section: Discussionsupporting

confidence: 76%

“…All values remained within the range of normal. No corresponding Table 1 Baseline demographics and clinical characteristics [19] Data are n (%), median (interquartile range; range), or mean (standard deviation). Higher score indicates worse disease/larger impact AD atopic dermatitis, BMI body mass index, BSA body surface area, EASI Eczema Area and Severity Index, IGA Investigator's Global Assessment, NRS numerical rating scale, TCS topical corticosteroids, q4w every 4 weeks a One patient was randomized in error and did not receive study treatment and was therefore not included in the safety analysis b Mean duration of AD for patients aged 6 months to younger than 2 years (n = 11) was 0.8 (standard deviation 0. changes in other liver function tests were observed.…”

Section: Serum Chemistrymentioning

confidence: 99%

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Laboratory Safety from a Randomized 16-Week Phase III Study of Dupilumab in Children Aged 6 Months to 5 Years with Moderate-to-Severe Atopic Dermatitis

et al. 2022

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Background and Objective Previous studies of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents, and severe atopic dermatitis in children aged 6 to < 12 years demonstrate no clinically important changes in laboratory parameters. The objective of this study was to assess laboratory outcomes in children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis treated with dupilumab. Methods In this randomized, placebo-controlled, phase III trial of dupilumab, 161 children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis were enrolled from 31 sites in Europe and North America and randomized 1:1 to receive subcutaneous placebo or dupilumab (5 kg to < 15 kg: 200 mg; 15 kg to < 30 kg: 300 mg) every 4 weeks plus topical corticosteroids for 16 weeks. Hematology, serum chemistry, and urinalysis assessments were analyzed on blood and urine samples collected at screening and weeks 4 and 16; descriptive statistics are provided. ResultsNo clinically meaningful changes in laboratory parameters were observed. While two cases of eosinophilia and one case each of neutropenia and leukocytosis were reported as treatment-emergent adverse events in the dupilumab plus topical corticosteroids group, these events were not associated with clinical symptoms and did not lead to treatment discontinuation or study withdrawal. Conclusions These results suggest that routine laboratory monitoring of children aged 6 months to < 6 years treated with dupilumab plus topical corticosteroids is not required. Limitations of this study include short study duration, and exclusion of patients with abnormalities in laboratory test results at screening.

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Section: Discussionsupporting

confidence: 76%

Section: Serum Chemistrymentioning

confidence: 99%

Laboratory Safety from a Randomized 16-Week Phase III Study of Dupilumab in Children Aged 6 Months to 5 Years with Moderate-to-Severe Atopic Dermatitis

et al. 2022

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“…In regarding to the drug safety, only two patients in this study have reported mild ocular symptoms, which similar to that in treatment of atopic dermatitis, in the entire 20-week treatment period. It goes without saying that dupilumab has accumulated a lot of experience and safety profiles in pediatric population, especially it has recently been approved for children up to 6 months of age ( 21 ). Contrarily, IL-17A biologicals Secukinumab and Ixekizumab have not approved for children under 6 years and the safety data for children and infants are scarce.…”

Section: Discussionmentioning

confidence: 99%

Dupilumab improves clinical symptoms in children with Netherton syndrome by suppressing Th2-mediated inflammation

Shi

Jiang

et al. 2022

Front. Immunol.

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BackgroundNetherton syndrome is a rare, life-threatening autosomal recessive genetic disorder with no effective treatment yet. Skin barrier dysfunction caused by SPINK5 gene mutations is a hallmark of the disease. Antigen penetration through the defective skin and nonspecific inflammation provide a pro-T helper 2 (Th2) immune microenvironment in the disease. Therefore, Th2 cytokines are considered to be candidate therapeutic targets.ObjectiveTo evaluate the clinical responses of patients with Netherton syndrome to dupilumab, an IL-4Rα antagonist, and identify changes in the Th1/2/17 pathway activity, skin barrier defect protein LEKTI expression after treatment.MethodsFour children with severe Netherton syndrome (aged 2 y to 4 y and 6 m) who were treated with dupilumab from January to June 2022 were evaluated at baseline, and at 4, 8, 12, 16, and 20 weeks after the start of dupilumab administration. Treatment response was assessed using the Eczema Area and Severity Index (EASI), the Numerical Rating Scale (NRS), the Dermatology Life Quality Index (CDLQI), and the Dermatitis Family Impact-questionnaire (DFI). Blood eosinophil counts, serum IgE levels and inflammatory cytokines were measured. The immunotyping of Th1/2/17 cells was performed by flow cytometry and cytokine expressions in T cell subsets were analyzed by single-cell RNA sequencing. In addition, expression of the LEKTI in skin lesions was evaluated by immunohistochemical analysis.ResultsAll four patients experienced clinical improvement, with significantly reduced EASI scores (by 75.0–83.9%) and NRS (by 87.5–90.0%) from baseline to 20 weeks of treatment. Improved quality of life scores were also seen for all patients, as measured by CDLQI and DFI. Serum IgE levels also fell by 75.6–86.9%. The serum Th2 cytokines IL-4, IL-5 and IL-13 were found at low level, with no significant changes during the treatment. However, Th2 cytokines expressed by T cells, especially IL-4, decreased at single-cell level after treatment (P = 0.029). The baseline percentage of Th2 cells (among total CD3+CD4+ T cells) was significantly higher in patients than that in healthy controls (HC) (P < 0.0001); this percentage fell from 8.25% ± 0.75% to 4.02% ± 0.62% after 20 weeks dupilumab treatment. There was no noticeable change in LEKTI protein expression in skin lesions pre- and post-treatment. Two patients reported mild ocular adverse effects, but there were no severe adverse events.ConclusionDupilumab may be an effective and safe treatment option in a subset of pediatric patients with Netherton syndrome, especially in improving itch and the quality of life. These effects were achieved in part by suppression of the Th2-mediated inflammation.

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“…TCS found significantly more patients achieved IGA0/1 (28% versus 4%) and EASI75 (53% versus 11%) with DUPI versus placebo [48,49]. A significant improvement in itch was also noted with DUPI [47]. This trial led to expanded FDA approval for children C 6 months to 5 years in June 2022 [48].…”

Section: Biologics Dupilumabmentioning

confidence: 99%

Modern Interventions for Pediatric Atopic Dermatitis: An Updated Pharmacologic Approach

Kondratuk

Netravali

Castelo‐Soccio

2022

Dermatol Ther (Heidelb)

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Pediatric atopic dermatitis (AD) has historically challenged dermatologists given the variable response of patients to treatment and limited available therapeutic options, often with significant potential side effects. Over the last decade, targeted treatments including dupilumab and Janus kinase (JAK) inhibitors have emerged as significant treatment advances. An updated therapeutic approach for incorporating these new practice-changing medications can help clinicians manage these challenging patients. In this review, we discuss emerging topical and systemic (oral and injectable) treatments in pediatric AD, including topical PDE4 inhibitors and tapinarof, oral JAK inhibitors, and injected biologics including IL-4Ra inhibitor dupilumab, IL-13 inhibitor tralokinumab, IL-13Ra inhibitor lebrikizumab, IL-31Ra inhibitor nemolizumab, and IL-5Ra inhibitor benralizumab. We also review experimental agents in early clinical trials, such as targeted microbiome transplant lotions/antimicrobials, which may gain relevance in AD treatment. Finally, we propose a therapeutic approach for pediatric AD that incorporates newer therapies including dupilumab and JAK inhibitors, recognizing that these agents may not be universally available or approved. Further trials that include pediatric patients, especially head-to-head studies among therapeutic classes, are needed to clarify the role of emerging treatments.

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Dupilumab in children aged 6 months to younger than 6 years with uncontrolled atopic dermatitis: a randomised, double-blind, placebo-controlled, phase 3 trial

Cited by 148 publications

References 33 publications

Laboratory Safety from a Randomized 16-Week Phase III Study of Dupilumab in Children Aged 6 Months to 5 Years with Moderate-to-Severe Atopic Dermatitis

Laboratory Safety from a Randomized 16-Week Phase III Study of Dupilumab in Children Aged 6 Months to 5 Years with Moderate-to-Severe Atopic Dermatitis

Dupilumab improves clinical symptoms in children with Netherton syndrome by suppressing Th2-mediated inflammation

Modern Interventions for Pediatric Atopic Dermatitis: An Updated Pharmacologic Approach

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