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Delgocitinib ointment in pediatric patients with atopic dermatitis: A phase 3, randomized, double-blind, vehicle-controlled study and a subsequent open-label, long-term study

Open AccessPublished:June 09, 2021DOI:https://doi.org/10.1016/j.jaad.2021.06.014

      Background

      Delgocitinib 0.5% ointment, a topical Janus kinase inhibitor, has been approved in Japan for adult patients with atopic dermatitis (AD).

      Objective

      To evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD.

      Methods

      Part 1 of this study was a 4-week double-blind period in which Japanese patients aged 2 through 15 years were randomized in a 1:1 ratio to delgocitinib 0.25% ointment or vehicle ointment. Part 2 was a 52-week extension period. Eligible patients entered part 2 to receive 0.25% or 0.5% delgocitinib ointment.

      Results

      At the initiation of the study, approximately half of the patients had moderate AD. At the end of treatment in part 1, the least-squares mean percent change from baseline in modified Eczema Area and Severity Index score, the primary efficacy endpoint, was significantly greater for delgocitinib ointment than for vehicle (−39.3% vs +10.9%, P < .001). In part 2, improvements in AD were also seen through week 56. Most adverse events were mild and unrelated to delgocitinib across the study periods.

      Limitations

      Only Japanese patients were included. In part 2, no control group was included and rescue therapy was allowed.

      Conclusion

      Delgocitinib ointment was effective and well tolerated when applied to Japanese pediatric patients with AD for up to 56 weeks.

      Key words

      Abbreviations used:

      AD (atopic dermatitis), AE (adverse event), EASI (eczema area and severity index), EOT (end of treatment), IGA (investigator's global assessment), JAK (Janus kinase), mEASI (modified eczema area and severity index)
      • Delgocitinib ointment, a topical Janus kinase inhibitor, was effective and well tolerated when applied for up to 56 weeks to Japanese pediatric patients with atopic dermatitis.
      • Delgocitinib ointment is a promising therapeutic option for atopic dermatitis in children as well as in adults.

      Introduction

      Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by eczematous lesions and intense pruritus,
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      The epithelial immune microenvironment (EIME) in atopic dermatitis and psoriasis.
      with a higher prevalence in children (up to 25%) than in adults (7% to 10%).
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      Atopic dermatitis.
      AD in childhood tends to resolve with age, although some patients continue to have symptoms of AD in adulthood.
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      Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march.
      Topical therapies form the mainstay of treatment of AD in both adults and children. Currently, topical corticosteroids and topical calcineurin inhibitors are widely used to reduce skin inflammation. Although generally safe for most patients, these drugs can cause local adverse reactions, such as skin atrophy and telangiectasia for topical corticosteroids and symptoms of skin irritation for topical calcineurin inhibitors.
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      Clinical practice guidelines for the management of atopic dermatitis 2018.
      ,
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      Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies.
      Although novel drugs for AD are currently under clinical development, few of them target AD in children.
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      JAK/STAT inhibitors for the treatment of atopic dermatitis.
      ,
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      Therapeutic pipeline for atopic dermatitis: end of the drought?.
      Additionally, given its chronic and relapsing course, long-term treatment of AD is generally required. Therefore, novel topical treatment options without long-term safety concerns are still needed for AD in children.
      Janus kinase (JAK) inhibitors represent a new drug class for the treatment of AD.
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      JAK/STAT inhibitors for the treatment of atopic dermatitis.
      • Paller A.S.
      • Kabashima K.
      • Bieber T.
      Therapeutic pipeline for atopic dermatitis: end of the drought?.
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      • Eichenfield L.
      Emerging therapies for atopic dermatitis: JAK inhibitors.
      The JAK-signal transducer and activator of transcription pathway plays an important role in exerting the biologic effects of many inflammatory cytokines, including interleukin 4, interleukin 13, and interleukin 31,
      • O'Shea J.J.
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      JAK and STAT signaling molecules in immunoregulation and immune-mediated disease.
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      JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.
      • Bao L.
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      The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis.
      which are closely associated with the pathophysiology of AD.
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      • Howell M.D.
      • Nomura I.
      • Hamid Q.A.
      New insights into atopic dermatitis.
      • Nomura T.
      • Honda T.
      • Kabashima K.
      Multipolarity of cytokine axes in the pathogenesis of atopic dermatitis in terms of age, race, species, disease stage and biomarkers.
      • Howell M.D.
      • Kim B.E.
      • Gao P.
      • et al.
      Cytokine modulation of atopic dermatitis filaggrin skin expression.
      • Neis M.M.
      • Peters B.
      • Dreuw A.
      • et al.
      Enhanced expression levels of IL-31 correlate with IL-4 and IL-13 in atopic and allergic contact dermatitis.
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      • et al.
      IL-31: a new link between T cells and pruritus in atopic skin inflammation.
      Delgocitinib is a novel JAK inhibitor that has inhibitory effects on all types in the JAK family (JAK1, JAK2, JAK3, and tyrosine kinase 2).
      • Tanimoto A.
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      • et al.
      Pharmacological properties of JTE-052: a novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo.
      It has been developed for AD in Japan by Japan Tobacco and Torii Pharmaceutical and is in development in a cream formulation for dermatologic conditions worldwide, excluding Japan by LEO Pharma. Delgocitinib 0.5% ointment was found to be clinically effective in adult patients with AD
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      • Nemoto O.
      • Igarashi A.
      • Saeki H.
      • Kaino H.
      • Nagata T.
      Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study.
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • et al.
      Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • Nagata T.
      Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study.
      and has been approved in Japan.
      • Dhillon S.
      Delgocitinib: first approval.
      A 4-week phase 2 study in pediatric patients with AD demonstrated the potential effectiveness of 0.25% and 0.5% delgocitinib ointment in that patient population.
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • et al.
      Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis.
      In the present phase 3 study, the efficacy and safety of delgocitinib ointment in Japanese pediatric patients with AD was evaluated over a 4-week double-blind period (part 1) and a 52-week extension period (part 2).

      Methods

       Study design

      This study was conducted at 23 medical institutions in Japan in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The protocol was approved by the institutional review boards. The study information is registered with the Japan Pharmaceutical Information Center Clinical Trials Information (identifier JapicCTI-184064).
      Part 1 was a 4-week, randomized, double-blind, vehicle-controlled study in which Japanese patients aged 2-15 years with AD were randomized 1:1 to delgocitinib 0.25% ointment or vehicle ointment (Supplemental Fig 1; available via Mendeley at https://doi.org/10.17632/6yrdmwydzj.1). Randomization was stratified by age (2-6, 7-11, and 12-15 years) and investigator's global assessment (IGA) score. After completing part 1, patients could enter part 2, which was a 52-week, open-label extension study. Patients who did not complete part 1 because of worsening of AD were withdrawn from the study or entered part 2 early, at the investigator's discretion. In part 2, all patients received 0.25% or 0.5% delgocitinib ointment.

       Patients

      Written informed consent was obtained from the parents or guardians of the patients. Assent was obtained from patients, if possible. At initiation of part 1, patients were required to have an AD diagnosis according to the Japanese Dermatological Association criteria
      • Katoh N.
      • Ohya Y.
      • Ikeda M.
      • et al.
      Clinical practice guidelines for the management of atopic dermatitis 2018.
      ; a modified eczema area and severity index (mEASI) score of ≥ 5, which was calculated by excluding the head/neck region score from the EASI
      • Hanifin J.M.
      • Thurston M.
      • Omoto M.
      • et al.
      The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group.
      total score; an IGA score of 2 (mild), 3 (moderate), or 4 (severe); and inflammatory eczema affecting 5% to 30% of the body surface area. Exclusion criteria are summarized in the Supplemental Table I and Supplemental Fig 1.

       Study treatment

      In part 1, a concentration of 0.25% was selected for delgocitinib ointment. In part 2, delgocitinib ointment at a concentration of 0.5% could be used according to the patient's disease condition (eg, mEASI score ≥ 10 at initiation of part 2 or inadequate response to the 0.25% ointment) and at the investigator's discretion. Patients were instructed to apply the study drug twice daily (maximum dose per application, 5 g) to the areas affected by inflammatory eczema, excluding dry skin areas and the scalp. Concomitant use of any therapy to the application areas was prohibited.
      In part 2, topical corticosteroids and tacrolimus ointment could be used as rescue therapy, at the investigator's discretion; however, concurrent use of rescue therapy and delgocitinib ointment to the same area was prohibited. Other prohibited and permitted concomitant therapies are summarized in the Supplemental Table I and Supplemental Fig 1.

       Efficacy and safety evaluations

      Efficacy was evaluated based on the following parameters: mEASI, EASI, IGA, face/neck IGA, pruritus score, and percent of body surface area affected by AD. These parameters are detailed in the Supplemental Table I and Supplemental Fig 1. In part 1, the primary efficacy endpoint was the percent change from baseline in mEASI score at the end of treatment (EOT). Secondary efficacy endpoints included the proportions of patients achieving at least 50% or 75% improvement from baseline in mEASI score (mEASI-50, mEASI-75) at EOT, the proportions of patients achieving an IGA or face/neck IGA score of 0 (clear) or 1 (almost clear) with at least a 2-point improvement from baseline (IGA success, face/neck IGA success) at EOT, and the changes or percent changes from baseline in the efficacy parameters at each study visit across parts 1 and 2. Safety evaluations included the incidence and severity of adverse events (AEs), vital signs, and clinical laboratory tests. Plasma concentrations of delgocitinib were measured at selected visits.

       Statistical analyses

      Sample-size calculation was based on the results of a phase 2 study of delgocitinib ointment in pediatric patients with AD.
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • et al.
      Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis.
      A sample size of 60 patients per group would yield at least 90% power to detect a significant difference between delgocitinib and vehicle groups in the primary efficacy endpoint, with a 1-sided test at the 2.5% significance level. This assumes that the mean (±standard deviation) percent change from baseline in the mEASI score would be −50% (±60%) for delgocitinib and −5% (±60%) for vehicle.
      The population of patients who underwent the study-specified evaluation at least once after the start of study treatment was used in the primary analyses of efficacy, safety, and pharmacokinetics. The EOT value for efficacy evaluations was defined as the value at week 4, study discontinuation, or immediately before part 2. For long-term efficacy evaluations across parts 1 and 2, baseline (week 0) was defined as the first day of delgocitinib treatment.
      Between-group differences in the least-squares percent change or change at EOT from baseline in mEASI, EASI, and pruritus scores were tested by analysis of covariance at a 1-sided significance level of 2.5%, with the baseline value as the covariate. These endpoints at other study visits were evaluated descriptively. For responder analyses of mEASI and IGA scores, Fisher's exact tests were performed at a 2-sided significance level of 5%. No formal multiple comparison adjustment was made.

      Results

       Patients

      A total of 137 patients were randomized in part 1 (Supplemental Fig 2). Of 69 patients in the delgocitinib group, 62 (89.9%) completed part 1, and 7 (10.1%) entered part 2 early. Of 68 patients in the vehicle group, 48 (70.6%) completed part 1 and 19 (27.9%) entered part 2 early, although 1 (1.5%) was withdrawn from the study. A total of 135 patients entered part 2 and 118 (87.4%) patients completed it.
      No major differences between treatment groups in part 1 were found in the demographic and baseline characteristics (Table I). At initiation of part 1, approximately half of the patients had moderate AD (IGA score of 3). In part 2, approximately 80% of the patients received the 0.5% concentration of delgocitinib ointment at least once and approximately half of the patients received rescue therapy (Supplemental Table I).
      Table IPatient demographics and baseline characteristics
      CharacteristicsVehicle ointment (n = 68)Delgocitinib 0.25% ointment (n = 69)Total (n = 137)
      Age (years)8.3 (3.7)8.2 (3.9)8.3 (3.8)
      Age category (n [%])
       2-6 years27 (39.7)26 (37.7)53 (38.7)
       7-11 years25 (36.8)28 (40.6)53 (38.7)
       12-15 years16 (23.5)15 (21.7)31 (22.6)
      Sex (n [%])
       Men31 (45.6)39 (56.5)70 (51.1)
       Women37 (54.4)30 (43.5)67 (48.9)
      Duration of AD (years)6.2 (3.7)5.8 (3.8)6.0 (3.7)
      mEASI score10.6 (4.2)10.7 (4.3)10.6 (4.2)
      IGA score (n [%])
       2 (mild)16 (23.5)16 (23.2)32 (23.4)
       3 (moderate)38 (55.9)37 (53.6)75 (54.7)
       4 (severe)14 (20.6)16 (23.2)30 (21.9)
      Face/neck IGA score (n [%])
       0 (clear)8 (11.8)7 (10.1)15 (10.9)
       1 (almost clear)2 (2.9)11 (15.9)13 (9.5)
       2 (mild)27 (39.7)21 (30.4)48 (35.0)
       3 (moderate)29 (42.6)23 (33.3)52 (38.0)
       4 (severe)2 (2.9)7 (10.1)9 (6.6)
      Pruritus score
       Daytime score2.3 (0.7)2.3 (0.7)2.3 (0.7)
       Nighttime score1.8 (0.7)1.8 (0.7)1.8 (0.7)
      Percentage of BSA affected by AD21.4 (6.3)21.0 (6.6)21.2 (6.4)
      Data are displayed as mean (standard deviation) unless otherwise indicated.
      AD, Atopic dermatitis; BSA, body surface area; IGA, Investigator's Global Assessment; mEASI, modified Eczema Area and Severity Index.

       Efficacy

      In part 1, the least-squares mean percent changes from baseline in the mEASI score were −39.3% in the delgocitinib group and +10.9% in the vehicle group at EOT. The reduction in mEASI score was significantly greater in the delgocitinib group (P < .001, Fig 1). Treatment difference from this result was similar to that from the post-hoc analysis at week 4 (Supplemental Table II). The mEASI score in the delgocitinib group was numerically reduced over time from week 1 through week 4. Representative clinical photographs show improvements at week 4 compared with baseline (Supplemental Fig 3). The delgocitinib group showed greater improvements in the other efficacy parameters at EOT, such as IGA and pruritus scores, than the vehicle group (Supplemental Tables III and IV). A numerical reduction in pruritus score was noted immediately after the start of study treatment in the delgocitinib group, which was maintained through week 4 (Fig 2).
      Figure thumbnail gr1
      Fig 1Percent change (mean – SD) from baseline in the mEASI score over time. Values obtained after use of prohibited therapies or outside the analysis visit window were excluded from analyses of weekly percent change. EOT, End of treatment; LS, least-squares; mEASI, modified Eczema Area and Severity Index; SD, standard deviation.
      Figure thumbnail gr2
      Fig 2Daily change (mean – SD) from baseline in pruritus score over time. Pruritus score was a 5-point scale ranging from 0 to 4, with higher scores indicating more severe pruritus. Values obtained after use of prohibited therapies were excluded from analyses of daily change. EOT, End of treatment; LS, least-squares; SD, standard deviation.
      In part 1, significantly greater proportions of patients achieved mEASI-50 and mEASI-75 at EOT in the delgocitinib group than in the vehicle group (P < .001 for both, Fig 3). An mEASI-50 was achieved by 50.7% (35 of 69) of patients in the delgocitinib group compared with 17.6% (12 of 68) of patients in the vehicle group. An mEASI-75 was achieved by 37.7% (26 of 69) of patients in the delgocitinib group compared with 4.4% (3 of 68) of patients in the vehicle group. Similarly, numerically greater proportions of patients achieved IGA success (not significant) and face/neck IGA success at EOT in the delgocitinib group than in the vehicle group (P = .24 for IGA success, P = .003 for face/neck IGA success) (Supplemental Table IV). In the delgocitinib group, the proportion of patients with an IGA score of 3 or 4 was reduced over time and that of patients with an IGA score of 0 or 1 was increased (Supplemental Fig 4).
      Figure thumbnail gr3
      Fig 3Proportion of patients achieving at least 50% or at least 75% improvement in mEASI score at the end of treatment. The error bars represent 95% confidence intervals. mEASI, Modified Eczema Area and Severity Index; mEASI-50, at least 50% improvement from baseline in mEASI score; mEASI-75, at least 75% improvement from baseline in mEASI score.
      In part 2, the improvements in mEASI, IGA, and pruritus scores were also seen through week 56 (Supplemental Fig 4 and Supplemental Table V). In patients who received delgocitinib ointment in part 1, the proportions of patients achieving mEASI-50 and mEASI-75 at week 56 were 73.6% (39 of 53) and 52.8% (28 of 53), respectively (Supplemental Fig 5). In patients who received vehicle ointment in part 1, the proportions of patients achieving mEASI-50 and mEASI-75 at week 52 were 70.5% (43 of 61) and 52.5% (32 of 61), respectively.

       Safety and tolerability

      In part 1, AEs were reported in 30 of 69 (43.5%) patients in the delgocitinib group and in 21 of 68 (30.9%) patients in the vehicle group (Table II). Treatment-related AEs were reported in 4 (5.8%) patients in the delgocitinib group and 1 (1.5%) patient in the vehicle group. The most common treatment-related AE in either of the treatment groups was application site folliculitis (n = 3 [4.3%]) in the delgocitinib group.
      Table IISummary of adverse events
      Adverse eventsVehicle-controlled period (4 weeks)Long-term treatment period (up to 56 weeks)
      Patients with AEs on delgocitinib treatment across the study periods are counted; thus, data from the delgocitinib group in the vehicle-controlled period are included.
      Vehicle ointment (n = 68)Delgocitinib 0.25% ointment (n = 69)Delgocitinib ointment 0.25% or 0.5%
      Patients with AEs on delgocitinib treatment across the study periods are counted; thus, data from the delgocitinib group in the vehicle-controlled period are included.
      (n = 134)
      AEs21 (30.9)30 (43.5)115 (85.8)
      Maximum severity
       Mild20 (29.4)28 (40.6)92 (68.7)
       Moderate1 (1.5)2 (2.9)23 (17.2)
       Severe000
      Treatment-related AEs1 (1.5)4 (5.8)13 (9.7)
      Maximum severity
       Mild04 (5.8)13 (9.7)
       Moderate1 (1.5)00
       Severe000
      Serious AEs006 (4.5)
      Serious treatment-related AEs000
      AEs leading to discontinuation001 (0.7)
      AEs occurring in ≥2 patients in either of the treatment groups (vehicle-controlled period) or ≥ 5% of patients (long-term treatment period)
       Nasopharyngitis7 (10.3)11 (15.9)55 (41.0)
       Influenza1 (1.5)3 (4.3)36 (26.9)
       Impetigo1 (1.5)018 (13.4)
       Gastroenteritis1 (1.5)1 (1.4)12 (9.0)
       Conjunctivitis allergic0011 (8.2)
       Upper respiratory tract infection2 (2.9)1 (1.4)11 (8.2)
       Fungal skin infection0010 (7.5)
       Skin papilloma01 (1.4)9 (6.7)
       Molluscum contagiosum008 (6.0)
       Pharyngitis1 (1.5)1 (1.4)8 (6.0)
       Arthropod sting1 (1.5)2 (2.9)8 (6.0)
       Application site folliculitis03 (4.3)7 (5.2)
       Wound01 (1.4)7 (5.2)
       Rhinitis allergic007 (5.2)
       Miliaria007 (5.2)
       Pyrexia2 (2.9)1 (1.4)4 (3.0)
       Conjunctivitis2 (2.9)03 (2.2)
       Injury2 (2.9)02 (1.5)
      Treatment-related AEs occurring in ≥1 patient in either of the treatment groups (vehicle-controlled period) or ≥ 1% of patients (long-term treatment period)
       Application site folliculitis03 (4.3)4 (3.0)
       Application site acne01 (1.4)2 (1.5)
       Molluscum contagiosum002 (1.5)
       Skin papilloma01 (1.4)1 (0.7)
       Impetigo1 (1.5)01 (0.7)
      Data are displayed as number of patients (%).
      AEs, Adverse events.
      Patients with AEs on delgocitinib treatment across the study periods are counted; thus, data from the delgocitinib group in the vehicle-controlled period are included.
      Across parts 1 and 2, AEs were reported in 115 of 134 (85.8%) patients after the start of treatment with delgocitinib ointment (Table II). Serious AEs, including 1 Kaposi's varicelliform eruption not at the application site, were reported in 6 (4.5%) patients, none of which were considered by the investigators to be related to delgocitinib ointment. No severe AEs were reported. The majority of AEs were considered mild. The only 1 AE leading to study discontinuation was application site acne. The most common AE was nasopharyngitis (n = 55 [41.0%]), followed by influenza (n = 36 [26.9%]) and impetigo (n = 18 [13.4%]). The majority of AEs were considered unrelated to delgocitinib ointment, and treatment-related AEs were reported in 13 (9.7%) patients, all of which were mild.
      The most common treatment-related AE was application site folliculitis (n = 4 [3.0%]). Mild application site irritation was reported in only 1 patient and no other application site symptoms, such as burning or stinging, were found. The incidence of AEs did not increase over time, except for influenza, a seasonal disease (Supplemental Table VI). The incidence of AEs under treatment with the 0.5% ointment was similar to that under treatment with the 0.25% ointment (Supplemental Table VII). No major differences in the incidence of AEs were noted between the age groups (Supplemental Table VIII).

       Pharmacokinetics

      No plasma concentrations of delgocitinib were detected in most patients (83.6% to 95.1%) during the study (the lower limit of quantification, 1.00 ng/mL). No major differences between study visits or between the age groups were found in the proportion of patients with detectable plasma concentrations of delgocitinib. The maximum plasma concentration of delgocitinib at each study visit ranged from 1.55 to 11.8 ng/mL (Supplemental Table IX).

      Discussion

      In the present phase 3 study, the 4-week treatment (part 1) with delgocitinib 0.25% ointment provided clinically meaningful improvements in signs and symptoms in Japanese pediatric patients with AD. Long-term treatment for up to 56 weeks with 0.25% or 0.5% delgocitinib ointment also showed the improvement effect on AD and was well tolerated.
      Delgocitinib, a pan-JAK inhibitor, broadly inhibits signaling of inflammatory cytokines involved in the pathophysiology of AD. Additionally, delgocitinib can improve skin barrier function by promoting the production of terminal differentiation proteins, such as filaggrin.
      • Amano W.
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      The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling.
      This effect of delgocitinib ointment on skin barrier function may have contributed to the positive efficacy results in the present study.
      Pruritus is a distressing symptom of AD in children, leading to impairment of quality of life, such as sleep disturbance.
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      In the present study, treatment with delgocitinib ointment led to a rapid reduction in pruritus score, which was consistent with previous clinical studies with delgocitinib ointment
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      and a recent report suggesting that JAK inhibitors potentially have a direct antipruritic effect.
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      • et al.
      Janus kinase inhibitor delgocitinib suppresses pruritus and nerve elongation in an atopic dermatitis murine model.
      The antipruritic effect of delgocitinib ointment can help reduce distress in pediatric patients with AD.
      In part 2, the 0.5% ointment could be used according to the patient's disease condition (eg, mEASI score ≥ 10 or inadequate response to the 0.25% ointment). Consequently, approximately 80% of the patients received the 0.5% ointment at least once. The 0.5% ointment, which is the same strength for AD in adults, is expected to be used for AD in children in clinical practice, if deemed necessary.
      Overall, delgocitinib ointment was well tolerated in pediatric patients with AD over the treatment period. Safety results in the present study were similar to those in the long-term study in adult patients with AD.
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • Saeki H.
      • Kaino H.
      • Nagata T.
      Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study.
      ,
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • et al.
      Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.
      No new safety concerns with delgocitinib ointment emerged in pediatric patients with AD.
      Treatment-related skin infections, including application site folliculitis and molluscum contagiosum, were all mild and the incidences were low. Systemic exposure to delgocitinib was low in all the age groups of the present study, which was consistent with previous studies in adults,
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • Saeki H.
      • Kaino H.
      • Nagata T.
      Delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with moderate to severe atopic dermatitis: a phase 3, randomized, double-blind, vehicle-controlled study and an open-label, long-term extension study.
      ,
      • Nakagawa H.
      • Nemoto O.
      • Igarashi A.
      • et al.
      Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.
      indicating that delgocitinib ointment is unlikely to pose an increased risk of systemic infections irrespective of age. Additionally, long-term treatment with delgocitinib ointment did not cause skin atrophy or telangiectasia, as reported with topical corticosteroids.
      • Katoh N.
      • Ohya Y.
      • Ikeda M.
      • et al.
      Clinical practice guidelines for the management of atopic dermatitis 2018.
      No strong irritation (eg, burning or stinging sensations), as reported with tacrolimus ointment,
      • Katoh N.
      • Ohya Y.
      • Ikeda M.
      • et al.
      Clinical practice guidelines for the management of atopic dermatitis 2018.
      was found at the application sites. Collectively, delgocitinib ointment was shown to have a favorable safety profile as a topical drug for pediatric patients with AD.
      The present study has limitations. Because only Japanese patients were included, it is unclear whether the study results are applicable to non-Japanese patients who have different clinical phenotypes of AD.
      • Nomura T.
      • Honda T.
      • Kabashima K.
      Multipolarity of cytokine axes in the pathogenesis of atopic dermatitis in terms of age, race, species, disease stage and biomarkers.
      ,
      • Czarnowicki T.
      • He H.
      • Krueger J.G.
      • Guttman-Yassky E.
      Atopic dermatitis endotypes and implications for targeted therapeutics.
      Delgocitinib ointment, which targets multiple cytokine axes, is potentially effective in those populations. Additionally, in part 2, no control group was included and rescue therapy was allowed, both of which limit discussions on the long-term efficacy of delgocitinib ointment.

      Conclusion

      Delgocitinib ointment was effective and well tolerated when applied for up to 56 weeks to Japanese pediatric patients with AD. The study results indicate that delgocitinib ointment is a promising therapeutic option for AD in children as well as in adults.

      Conflicts of interest

      Dr Nakagawa received consulting fees and/or speaker honoraria from Eli Lilly Japan, Japan Tobacco Inc, Kyowa Kirin, LEO Pharma, Maruho, Novartis, Torii Pharmaceutical, and UCB Japan. Dr Nemoto received advisory board honoraria and/or speaker honoraria from Japan Tobacco Inc, Kyowa Kirin, LEO Pharma, and Maruho. Dr Igarashi received advisory board honoraria, consulting fees or speaker honoraria from AbbVie, Eli Lilly Japan, Japan Tobacco Inc, Maruho, Novartis, Sanofi, LEO pharma, and Torii Pharmaceutical, and received research grants from AbbVie, Eli Lilly Japan, Pfizer, Novartis, Otsuka Pharmaceutical, Amgen Inc, and Sanofi. Dr Saeki received advisory board honoraria and/or speaker honoraria from Japan Tobacco Inc, Maruho, Taiho Pharma, Tanabe Mitsubishi, AbbVie, Sanofi and Torii Pharmaceutical, and received research grants from Maruho, Taiho Pharma, and Eisai. Dr Kabashima received consulting fees or advisory board honoraria from Chugai Pharmaceutical, Japan Tobacco Inc, Maruho, and Pola Pharma, and received research grants from AbbVie, Eli Lilly Japan, Japan Tobacco Inc, Kyorin Pharmaceutical, Kyowa Kirin, LEO Pharma, Ono Pharmaceutical, P&G Japan, Pola Pharma, Sanofi, and Tanabe Mitsubishi. Mr Oda and Mr Nagata are employees of Japan Tobacco Inc.
      The authors thank the patients who participated in the study as well as the investigators and staff at the study sites (Supplemental Table X). We also thank the delgocitinib project team members at Japan Tobacco Inc, especially Shuichi Fukasawa for medical writing and editorial assistance, Toshiaki Kobayashi and Kenjiro Murakami for statistical assistance, and Ryusei Murata for critical review of the manuscript.

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