BJD British Journal of Dermatology. Summary. What s already known about this topic? What does this study add? CLINICAL TRIAL

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1 CLINICAL TRIAL BJD British Journal of Dermatology Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-tosevere atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study* H. Nakagawa, 1 O. Nemoto, 2 A. Igarashi 3 and T. Nagata 4 1 Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan 2 Kojinkai Sapporo Skin Clinic, Hokkaido, Japan 3 Division of Dermatology, NTT Medical Center Tokyo, Tokyo, Japan 4 Pharmaceutical Division, Japan Tobacco Inc., 4-1, Nihonbashi-Honcho 3-chome, Chuo-ku, Tokyo, Japan Linked Comment: Bissonnette. Br J Dermatol 2018; 178:321. Summary Correspondence Takeshi Nagata. takeshi.nagata@jt.com Accepted for publication 24 September 2017 Funding sources This study was funded by Japan Tobacco Inc. Conflicts of interest H.N. is a consultant for and/or has received research grants and/or honoraria from Japan Tobacco Inc., LEO Pharma and Maruho Co. Ltd. O.N. has received honoraria from Japan Tobacco Inc. A.I. has received honoraria from Japan Tobacco Inc., Maruho Co. Ltd, Novartis Pharma K.K. and Torii Pharmaceutical Co. Ltd. T.N. is an employee of Japan Tobacco Inc. *Plain language summary available online DOI /bjd Background JTE-052 is a novel Janus kinase inhibitor presently under clinical development for the topical treatment of atopic dermatitis (AD). Objectives To evaluate the efficacy and safety of JTE-052 ointment in Japanese adult patients with AD. Methods Patients with moderate-to-severe AD were randomized (2: 2: 2: 2: 1: 1) to receive JTE-052 ointment at 025%, 05%, 1% or 3%, the vehicle ointment or tacrolimus 01% ointment (reference) twice daily for 4 weeks. The primary efficacy end point was the percentage change in modified Eczema Area Severity Index (measi) score from baseline at the end of treatment (EOT). Secondary efficacy end points included change from baseline in the pruritus numerical rating scale (NRS) score. Results In total, 327 patients were enrolled. At EOT, the least-squares mean percentage changes from baseline in measi score for JTE-052 at 025%, 05%, 1% and 3% and the vehicle ointment were 417%, 571%, 549%, 729% and 122%, respectively. All JTE-052 groups showed significant reductions of measi score vs. the vehicle group (P < 0001 for all). In the tacrolimus group, the mean percentage change in measi score was 620%. The JTE-052 groups also showed significant improvement in other parameters; notably, the pruritus NRS score was reduced as early as day 1 night-time. JTE-052 ointment at doses up to 3% was safe and well tolerated. Conclusions Topical JTE-052 markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate-to-severe AD, with a favourable safety profile. The study results indicate that topical JTE-052 is a promising therapeutic option for AD. The trial registration number is JapicCTI What s already known about this topic? Atopic dermatitis (AD) is a chronic inflammatory skin disease with impaired skin barrier function and pruritus. The results of some clinical and experimental studies support the concept that inhibition of cytokine signalling via Janus kinase (JAK) may contribute to the improvement of AD. What does this study add? Topical JTE-052, a novel JAK inhibitor, markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate-to-severe AD and showed a favourable safety profile. 424 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

2 Topical JTE-052 for atopic dermatitis, H. Nakagawa et al. 425 The study results indicate that topical JTE-052 is a promising therapeutic option for AD. Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease characterized by pruritus and inflammation accompanied by cutaneous dysfunction such as dry and barrier-disrupted skin. 1 The worldwide prevalence of AD is estimated to be 15 30% in children and 2 10% in adults. 2 The principal goal of treatment of AD is to reach and maintain a state of absent or minor clinical symptoms that do not disrupt the patient s daily activities, requiring as little pharmacotherapy as possible. 1 Topical corticosteroids and tacrolimus ointment (the only topical calcineurin inhibitor available in Japan) form the mainstay of controlling skin inflammation in AD. However, these drugs have some limitations. Long-term use of topical corticosteroids is known to be associated with cutaneous adverse reactions such as atrophy and teleangiectasia. 1 Concerning treatment with tacrolimus ointment, irritation symptoms at the application site, such as a burning sensation and hot flushes, often appear, especially during the early phase of treatment, and a possible increased risk of local skin infections should be considered. 3 The anti-inflammatory effect of these drugs is well known, whereas sufficient evidence of improvement of the disrupted skin barrier function and pruritus has not been established. Although the pathogenesis of AD is multifactorial, immunological abnormalities, skin barrier dysfunction and pruritus are well known to be major factors involved in the pathogenesis and progression. 4 Immunological abnormalities include the abnormal production of cytokines such as interleukin (IL)-4, IL-5, IL-12, IL-13, interferon-c, thymic stromal lymphopoietin (TSLP) and granulocyte macrophage colony-stimulating factor. 5 7 Skin barrier dysfunction is believed to be due mainly to filaggrin gene mutations, 8,9 and the overexpression of IL-4 and IL-13 is associated with a reduction in filaggrin production. 10 Pruritus has been shown to be induced by IL ,12 Various cytokines exert their biological effects via the Janus kinase (JAK) signal transducer and activator of transcription (STAT) pathway, and several JAK inhibitors are approved or under development for the treatment of cytokine-mediated diseases. 13 JTE-052 is a novel JAK inhibitor developed by Japan Tobacco Inc. (also in development for dermatological conditions by LEO Pharma, code LEO124249). JTE-052 has been shown to inhibit the JAK1, JAK2, JAK3 and tyrosine kinase 2 enzymes in enzymatic assays. 14 JTE-052 has also been shown to inhibit the activation of inflammatory cells such as T cells, B cells, monocytes and mast cells in vitro, 14 and to suppress skin inflammation in animal dermatitis models. 15 Additionally, JTE-052 improves the skin barrier dysfunction by promoting the production of keratinocyte proteins including filaggrin, 16 and suppresses pruritus induced by IL Consequently, topical JTE-052 is expected to be a novel drug for the treatment of AD, suppressing inflammation and pruritus, as well as restoring skin barrier function. Indeed, tofacitinib ointment, another JAK inhibitor, has demonstrated favourable efficacy in a phase IIa study of patients with AD. 18 In a phase I clinical study, JTE-052 ointment was found to be efficacious and safe in patients with AD when administered at doses up to 3% for 1 week (unpublished data). In the present phase II study, we evaluated the efficacy and safety of JTE-052 ointment in Japanese adult patients with moderateto-severe AD over a 4-week period. Patients and methods Study design This study was conducted at 38 medical institutions in Japan. The study information is registered with JAPIC Clinical Trials Information ( number JapicCTI This was a phase II, randomized, vehicle-controlled, intergroup comparison study, comprising six treatment groups: four JTE-052 groups, one vehicle group and one tacrolimus group. This study was not under double-blind conditions in the JTE-052 and vehicle groups because the appearance of each strength of the JTE-052 ointments and vehicle ointment was different. However, to keep the investigators and patients blinded concerning the study treatment, the following methods were performed: the designated site personnel other than the investigators dispensed the study drugs and collected them from patients, and neither investigators nor patients were informed about the appearance of the ointments. The tacrolimus group was under open-label conditions; neither investigators nor patients were blinded concerning the study treatment, as this group was included in the study as a reference group for exploratory comparison with the JTE-052 groups. After a screening period of approximately 4 weeks, patients were randomized (2: 2: 2: 2: 1: 1) to receive JTE-052 ointment at 025%, 05%, 1% or 3%, the vehicle ointment or tacrolimus 01% ointment for 4 weeks (Fig. S1; see Supporting Information). A computer-generated randomization scheme was performed based on a permuted block method. An appropriate amount of each ointment was applied twice daily to the areas affected by eczema with inflammation, depending on the size of the affected area; however, the scalp, palms and soles, as well as dry skin areas, were excluded. The maximum dose per application was limited to 5 g. Rescue medication could be used for the treatment of worsening of AD according to the investigator s judgement and was limited to prednisolone valerate acetate 03%. The patients who used the rescue medication could continue the study; however, concomitant application of the study treatment and rescue medication to the same area was prohibited.

3 426 Topical JTE-052 for atopic dermatitis, H. Nakagawa et al. This study was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. Studyrelated documents were approved by the institutional review boards, and all patients provided written informed consent before study initiation. Study population We enrolled Japanese patients aged years with moderate-to-severe AD. The diagnosis of AD was made according to the criteria of the Japanese Dermatological Association, 1 and the severity classification was based on the measures of severity by the research group granted by the Ministry of Health, Labour and Welfare. 19 At screening and baseline, eligible patients had to have a modified Eczema Area Severity Index (measi) score 10 (the measi score was calculated by excluding the head/neck region score from the EASI 20 total score); an Investigator s Global Assessment (IGA) score of 3 (moderate) or higher; and eczema with inflammation, affecting 10 30% of the body surface area (BSA). A summary of the exclusion criteria is provided in File S1 (see Supporting Information). Assessments The primary efficacy end point was the percentage change in measi score from baseline at the end of treatment (EOT). For the measi score, the percentage change at each time point and the proportions of patients achieving 50%, 75% or 90% improvement from baseline (measi-50, 75, 90 response rates) were also assessed as secondary efficacy end points. Other secondary efficacy end points included changes or percentage changes from baseline at EOT and each time point in the EASI score, IGA score, face/neck IGA score, pruritus NRS score (including daily changes) and percentage BSA affected by AD. In addition, the proportion of patients with an IGA score of 0 or 1, and achieving 2-point improvement from baseline at EOT was assessed. A detailed description of the parameters is provided in File S1 and Table S1 (see Supporting Information). Safety parameters included symptoms, objective findings, vital signs and laboratory tests. Verbatim terms of adverse events (AEs) reported by the investigators were coded using the Medical Dictionary for Regulatory Activities version 180. Blood samples were collected at week 2 and week 4 to measure plasma concentrations of JTE-052. The lower limit of quantification was 100 ng ml 1. Sample size The sample-size calculation was based on the results of a phase I study of JTE-052 ointment in patients with AD (JapicCTI , unpublished data). The sample size was estimated to be 60 for each JTE-052 group and 30 for the vehicle group, under the conditions of an assignment ratio of 2 : 1, to detect a significant difference between the groups in the percentage change from baseline in the EASI score with the t-test (5% significance level, 90% power). For the tacrolimus group, the target sample size was 30, given the nature of the group for exploratory comparisons. Statistical evaluation Primary analyses of efficacy, safety and pharmacokinetics were performed on the population that comprised patients who had undergone the respective study-specified assessments at least once after the start of study treatment. The baseline value for efficacy parameters was defined as the measured value on the day of the start of study treatment (day 1), except for the pruritus NRS score, the baseline value of which was the mean value of the past week before the start of study treatment. The EOT value for efficacy parameters was defined as the value at week 4 or study discontinuation. For patients receiving rescue medication, the values obtained after the use of rescue medication were excluded from all of the efficacy analyses, and the EOT value was defined as the last value immediately before the use of rescue medication. For patient demographics and baseline values of efficacy assessments, imbalances between treatment groups were assessed at a two-sided significance level of roughly 15%. Efficacy parameters were analysed using ANCOVA with the relevant baseline value as the covariate. The least-squares mean change or percentage change from baseline was calculated. The difference between each JTE-052 group and the vehicle group was assessed at EOT and each time point. Odds ratios were calculated for responder analyses of measi and IGA scores. The statistical tests of efficacy assessments were two sided at the 5% significance level. No statistical comparisons of the JTE-052 groups with the tacrolimus group were performed. Results Patients Of the 366 patients providing written informed consent, 327 received study treatment (Fig. 1). Overall, 309 patients completed the study and 18 patients discontinued prematurely. The vehicle group showed the highest rate of use of rescue medication among the treatment groups (13 patients, 41%); the use rate of rescue medication in the JTE-052 groups appeared to decrease dose dependently, with 10% (n = 7) for JTE-052 at 025%, 6% (n = 4) for JTE-052 at 05%, 2% (n = 1) for JTE-052 at 1%, and 3% (n = 2) for JTE-052 at 3%. The rate in the tacrolimus group was 7% (n = 2). Concerning patient demographics, a difference between treatment groups was noted in the mean duration of AD; however, the difference was not considered to be relevant in the study assessments (Table 1). There were no statistically differences in the other baseline patient demographics for efficacy assessments among the treatment groups (Table S2; see Supporting Information). Of note, one patient in the vehicle

4 Topical JTE-052 for atopic dermatitis, H. Nakagawa et al. 427 Fig 1. Patient disposition. A patient who completed the study was considered a completer even if they had used rescue medication. group was excluded from efficacy analyses because the patient never had efficacy data after the start of study treatment. The mean age was 308 years, more than half of the patients were male (644%), and most patients had moderate AD (877%). Efficacy At EOT, all JTE-052 groups showed significant reductions of measi score from baseline vs. the vehicle group (P < 0001 for JTE-052 at all concentrations; Table S2; see Supporting Information). The least-squares mean percentage changes from baseline in measi score were 122% for vehicle, 417% for JTE-052 at 025%, 571% for JTE-052 at 05%, 549% for JTE-052 at 1% and 729% for JTE-052 at 3%. The reductions in measi score appeared to be dose dependent in the JTE-052 groups. In the tacrolimus group, the mean percentage change in measi score at EOT was 620%. In addition, all JTE-052 groups showed significantly greater reductions in measi score than the vehicle group from week 1 through week 4, except for JTE-052 at 025% at week 3 (Fig. 2; Table S3; see Supporting Information) and higher response rates (measi-50, 75 and 90) than the vehicle group at EOT (Table S4; see Supporting Information). At EOT, the JTE-052 groups at 05%, 1% and 3% showed significant improvement from baseline vs. the vehicle group in the other parameters including the EASI score, IGA score, face/neck IGA score, pruritus NRS score and percentage BSA affected by AD. The JTE-052, 025% group showed significant improvement in these efficacy parameters except for the IGA score and the face/neck IGA score. The tacrolimus group also showed a tendency of improvement in these efficacy parameters (Table S2; see Supporting Information). For the pruritus NRS score as assessed twice daily by the patients, all JTE-052 groups and the tacrolimus group showed a tendency for decrease in the weekly mean score over the treatment period (Fig. 3a, b). Significant reductions from baseline in both daytime and night-time NRS scores were noted at week 1 in the JTE-052 groups at 05%, 1% and 3% (P < 0001 for each vs. vehicle). Analysis of the pruritus NRS scores over the first week of study treatment revealed the rapid improvement of pruritus from day 1 night-time in the JTE %, 1% and 3% groups (P < 0001 for each vs. vehicle, Fig. 3c). Similarly, there was a tendency of improvement in the other efficacy parameters in all JTE-052 groups over time (data not shown). The proportion of patients with an IGA score of 0 (clear) or 1 (almost clear) and achieving 2-point improvement from baseline at EOT was significantly higher (P = 0039) in the JTE-052, 3% group (23%) than in the vehicle group (3%) (Table S5; see Supporting Information). A representative photograph of a patient treated with JTE-052 at 3% shows symptomatic improvement (Fig. S2; see Supporting Information).

5 428 Topical JTE-052 for atopic dermatitis, H. Nakagawa et al. Table 1 Patient demographics and baseline characteristics JTE-052 Tacrolimus (n = 30) P-value Total (n = 326) 025% (n = 69) 05% (n = 65) 1% (n = 66) 3% (n = 65) Vehicle (n = 31) Age (years) a Sex Male 19 (61) 48 (70) 39 (60) 48 (73) 42 (65) 14 (47) 019 b 210 (644) Female 12 (39) 21 (30) 26 (40) 18 (27) 23 (35) 16 (53) 116 (356) Body mass index (kg m 2 ) a Duration of atopic dermatitis (years) a Severity of atopic dermatitis Moderate 26 (84) 61 (88) 61 (94) 56 (85) 56 (86) 26 (87) 057 b 286 (877) Severe 5 (16) 8 (12) 4 (6) 10 (15) 9 (14) 4 (13) 40 (123) Data are displayed as the mean SD or n (%). a Analysis of variance; b Fisher s exact test. Safety and tolerability Overall, AEs were reported in five of 32 (16%) patients in the vehicle group, 51 of 265 (192%) in all JTE-052 groups, and 13 of 30 (43%) in the tacrolimus group (Table 2). Among the 265 patients treated with JTE-052, the most common AE was nasopharyngitis (n = 9, 34%), and no other AEs occurring in 2% of patients in the JTE-052 groups were noted (Table S6; see Supporting Information). Skin infections at the application site of study treatment occurred at a low frequency: furuncle (n = 3, 11%), application-site acne (n = 3, 11%), Kaposi varicelliform eruption (KVE) (n = 3, 11%), acne (n = 1, 04%), application-site folliculitis (n = 1, 04%), erysipelas (n = 1, 04%) and herpes simplex (n = 1, 04%). In the tacrolimus group, AEs that occurred in at least two patients were application-site pain (n = 3, 10%) and application-site irritation (n = 2, 7%). All AEs were considered mild or moderate in severity, and the majority were mild. Neither severe AEs nor serious AEs including death were reported during the study. AEs leading to study discontinuation were reported in four patients: contact dermatitis (JTE-052 at 025%, n = 1), application-site irritation (JTE-052 at 05%, n = 1 and tacrolimus, n = 1) and KVE (JTE-052 at 1%, n = 1). All of these events occurred at the application site of study treatment and resolved after study discontinuation. Except for KVE, all events were considered to be related to the study treatment by the investigators. The onset of KVE was found not at an application site of study treatment and thereafter the eruption spread to the application site because of increased susceptibility to infection in AD. Therefore, the event was considered to be unrelated to study treatment by the investigator. No clinically significant changes in laboratory parameters or vital signs over time were noted in any of the treatment groups. Pharmacokinetics At week 2, the plasma concentrations of JTE-052 were low across the JTE-052 groups based on the median concentrations. The proportion of patients with detectable JTE-052 plasma concentrations appeared to be higher in the groups with JTE-052 at 1% (23%, n = 15) and 3% (52%, n = 33) than in the groups of JTE-052 at 025% (10%, n = 7) and 05% (6%, n = 4). A similar trend was noted at week 4 (Table S7; see Supporting Information). Discussion In this study, we demonstrated that topical JTE-052, a JAK inhibitor, markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate-to-severe AD. All doses of JTE-052 ointment, ranging from 025% to 3%, had greater efficacy than vehicle in all efficacy parameters, including the measi, EASI, IGA and pruritus NRS

6 Topical JTE-052 for atopic dermatitis, H. Nakagawa et al. 429 Fig 2. Percentage change from baseline in modified Eczema Area Severity Index (measi) score over time (mean SD). The values obtained after the use of rescue medication were excluded from the analyses of weekly percentage change. EOT, end of treatment. scores, and percentage BSA affected by AD. Tofacitinib ointment, another JAK inhibitor, also showed favourable efficacy in patients with mild-to-moderate AD. 18 Therefore, our findings support the concept that inhibition of the JAK STAT pathway is a potential therapeutic option for AD. JTE-052 has been shown to inhibit all the types of JAK enzymes (JAK1, JAK2, JAK3 and tyrosine kinase 2). 14 In AD, JAK1, JAK2 and JAK3 are overexpressed, and various JAK-related cytokines such as IL-4, IL-5, IL-13, IL-31 and TSLP play important roles in the pathophysiology of AD. 13,21,22 Additionally, the efficacy of JAK inhibitors seen in patients with AD may be attributed to the improving effect on skin barrier dysfunction, as well as the anti-inflammatory effect, given the involvement of IL-4 and IL-13 in keratinocyte differentiation, 10 and the promoting effect of JTE-052 on the production of keratinocyte proteins such as filaggrin. 16 One of the notable efficacy results in this study was the rapid antipruritic effect of JTE-052, with significant reductions in the pruritus NRS score noted from the night of study treatment initiation with JTE-052 at 05% and higher doses. Pruritus can be induced by upregulation of IL-31, 11,12 whose signalling is suppressed by inhibition of the JAK STAT pathway. Therefore, the rapid antipruritic effect could be explained by the mechanism of action of JTE Oral and topical tofacitinib has also shown the benefit of JAK inhibitors on pruritus in both patients with AD and patients with psoriasis. 18,22 25 Pruritus is a distressing symptom in patients with AD and can lead to impairment of quality of life through sleep disturbance, as well as an increased risk of secondary infection and further exacerbation of AD due to scratching. 26 Therefore, the antipruritic effect of JAK inhibitors is considered a favourable factor in a new treatment for AD. Topical treatment with JTE-052 at doses up to 3% for 4 weeks was safe and well tolerated in patients with AD. The majority of AEs reported in the JTE-052 groups were mild in severity. No apparent differences between the JTE-052 and vehicle groups were noted in the incidence of AEs. No apparent dose-related AEs were noted either. Existing topical corticosteroids or tacrolimus can occasionally cause local skin infections. 1,3 AEs associated with skin infections at the application site of JTE-052 included furuncles, acne and KVE, the incidences of which were very low in this study. Nonetheless, as JTE-052 has immunosuppressive activity, appropriate monitoring of local skin infections is necessary in future clinical studies of JTE-052. Tacrolimus ointment is associated with a high incidence of application-site reactions such as a burning sensation and application-site warmth, irritation and pain, especially in the early phase of treatment. 3 Fewer such symptoms were seen in the JTE-052 groups in this study. It is of note that the tacrolimus group in this study did not show a high incidence of these events, which may be due to the small sample size of the group or to the fact that many of the enrolled patients had been notified of application-site reactions by the investigators. In a phase I clinical study of an oral formulation of JTE- 052, multiple administration of JTE-052 for 14 days was safe and tolerable at doses up to 50 mg per day. The mean maximum concentration was 436 ng ml 1 and the mean area under the concentration time curve during the dosing interval was 1756 ng h ml 1 at the dose of 50 mg once daily (unpublished data). Compared with the exposure to JTE-052 by oral administration, that in the dermal application in the present study was found to be obviously low, although the proportions of patients with detectable JTE-052 plasma concentrations were greater for the 1% and 3% doses than for the lower doses. The distribution of patients by JTE-052 plasma concentration indicates that systemic exposure to JTE- 052 was comparable between week 2 and week 4 during the 4-week treatment. The low systemic exposure may contribute

7 430 Topical JTE-052 for atopic dermatitis, H. Nakagawa et al. (a) (b) (c) Fig 3. Weekly change (mean SD) from baseline in pruritus numerical rating scale (NRS) score over time. (a) Daytime NRS, (b) night-time NRS, (c) daily change (mean) from baseline in pruritus NRS score over the first week of treatment. The values obtained after the use of rescue medication were excluded from the analyses of weekly and daily changes. N, night-time; D, daytime; EOT, end of treatment. to the lack of serious systemic infection such as opportunistic infections due to excessive immunosuppression in this study. Our study included an active comparator, tacrolimus 01% ointment, to investigate the clinical effectiveness of JTE-052 ointment. Neither investigators nor patients were blinded concerning the study treatment in the tacrolimus group because this group was included as a reference group for explorative purposes and no statistical comparisons between tacrolimus and JTE-052 were performed. Therefore, the discussion on the differences between JTE-052 and tacrolimus is limited. Another study limitation is that the use of rescue medication was allowed for the treatment of worsening of AD, and the values obtained after the use of rescue medication were excluded from all of the efficacy analyses. The results of this study should not be directly compared with those of other existing drugs for the treatment of AD because of the short study period and small sample size. We need to conduct further clinical studies of JTE-052 ointment to confirm the results of this study and to investigate the long-term safety in patients with AD. Clinical evaluation in paediatric patients should also be considered given the higher prevalence of AD in this population.

8 Topical JTE-052 for atopic dermatitis, H. Nakagawa et al. 431 Table 2 Summary of adverse events Vehicle (n = 32) JTE % (n = 69) 05% (n = 65) 1% (n = 66) 3% (n = 65) Total (n = 265) Adverse events 5 (16) 13 (19) 12 (18) 14 (21) 12 (18) 51 (192) 13 (43) Severe adverse events Adverse drug reactions 0 3 (4) 4 (6) 6 (9) 3 (5) 16 (60) 5 (17) Deaths Serious adverse events Serious adverse drug reactions Discontinued due to adverse events 0 1 (1) 1 (2) 1 (2) 0 3 (11) 1 (3) Data are displayed as the number of patients (%). Tacrolimus (n = 30) In conclusion, our study demonstrates that topical JTE-052 has marked efficacy with rapid onset in the treatment of moderate-to-severe AD, as well as a favourable safety profile. The study results also support inhibition of the JAK STAT pathway as a promising therapeutic option in patients with AD. Future studies of topical JTE-052 will make our findings in this study more robust. Acknowledgments The authors would like to thank all of investigators, staff and participating patients of this study. The principal investigators are listed in File S1 (see Supporting Information). The authors also thank the JTE-052 project team members at Japan Tobacco Inc., especially Shuichi Fukasawa for medical writing assistance, Manabu Oda for support with the publication process, Kana Yamada for statistical assistance, and Hiroyuki Yamada, Hironobu Kaino and Ryusei Murata for critical review of the manuscript. References 1 Saeki H, Nakahara T, Tanaka A et al. Clinical practice guidelines for the management of atopic dermatitis J Dermatol 2016; 43: Bieber T. Atopic dermatitis. N Engl J Med 2008; 358: Japanese FK. 506 Ointment Study Group. [Clinical guidance for treatment of patients with atopic dermatitis by tacrolimus ointment 0.1% and 0.03%]. Jpn J Clin Dermatol 2003; 57: (in Japanese). 4 Kabashima K. New concept of the pathogenesis of atopic dermatitis: Interplay among the barrier, allergy, and pruritus as a trinity. J Dermatol Sci 2013; 70: Leung DY, Boguniewicz M, Howell MD et al. New insights into atopic dermatitis. J Clin Invest 2004; 113: Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in chronic inflammatory skin disease atopic dermatitis. JAKSTAT 2013; 2:e Zhang Y, Zhou B. Functions of thymic stromal lymphopoietin in immunity and disease. Immunol Res 2012; 52: Kubo A, Nagao K, Amagai M. Epidermal barrier dysfunction and cutaneous sensitization in atopic diseases. J Clin Invest 2012; 122: Irvine AD, McLean WH, Leung DY. Filaggrin mutations associated with skin and allergic diseases. N Engl J Med 2011; 365: Howell MD, Kim BE, Gao P et al. Cytokine modulation of atopic dermatitis filaggrin skin expression. J Allergy Clin Immunol 2009; 124:R Neis MM, 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. J Allergy Clin Immunol 2006; 118: Sonkoly E, Muller A, Lauerma AI et al. IL-31: A new link between T cells and pruritus in atopic skin inflammation. J Allergy Clin Immunol 2006; 117: O Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 2012; 36: Tanimoto A, Ogawa Y, Oki C et al. Pharmacological properties of JTE-052: A novel potent JAK inhibitor that suppresses various inflammatory responses in vitro and in vivo. Inflamm Res 2015; 64: Tanimoto A, Shinozaki Y, Yamamoto Y et al. A novel JAK inhibitor JTE-052 reduces skin inflammation and ameliorates chronic dermatitis in rodent models: Comparison with conventional therapeutic agents. Exp Dermatol 2018; 27: Amano W, Nakajima S, Kunugi H et al. The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling. J Allergy Clin Immunol 2015; 136: Yamamoto Y, Otsuka A, Nakashima C et al. The effect of janus kinase inhibitor on pruritus in an atopic dermatitis murine model. J Invest Dermatol 2016; 136:S Bissonnette R, Papp KA, Poulin Y et al. Topical tofacitinib for atopic dermatitis: A phase IIa randomized trial. Br J Dermatol 2016; 175: Kohno Y, Yamamoto S. Guidelines for the Treatment of Atopic Dermatitis Tokyo: Ministry of Health, Labour and Welfare of Japan, 2008 (in Japanese). 20 Hanifin JM, Thurston M, Omoto M et al. The eczema area and severity index (EASI): Assessment of reliability in atopic dermatitis. EASI Evaluator Group. Exp Dermatol 2001; 10: Damsky W, King BA. JAK inhibitors in dermatology: The promise of a new drug class. J Am Acad Dermatol 2017; 76: Alves de Medeiros AK, Speeckaert R, Desmet E et al. JAK3 as an emerging target for topical treatment of inflammatory skin diseases. PLoS ONE 2016; 11:e Levy LL, Urban J, King BA. Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate. JAm Acad Dermatol 2015; 73:395 9.

9 432 Topical JTE-052 for atopic dermatitis, H. Nakagawa et al. 24 Feldman SR, Thacßi D, Gooderham M et al. Tofacitinib improves pruritus and health-related quality of life up to 52 weeks: Results from 2 randomized phase III trials in patients with moderate to severe plaque psoriasis. J Am Acad Dermatol 2016; 75: Papp KA, Bissonnette R, Gooderham M et al. Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: A phase 2b randomized clinical trial. BMC Dermatol 2016; 16: Hong J, Buddenkotte J, Berger TG, Steinhoff M. Management of itch in atopic dermatitis. Semin Cutan Med Surg 2011; 30: Supporting Information Additional Supporting Information may be found in the online version of this article at the publisher s website: File S1 Summary of the exclusion criteria, parameters for efficacy assessments and principal investigators. Fig S1. Study design. Fig S2. Representative photograph of a patient with atopic dermatitis (shoulder) treated with JTE-052, 3%. Table S1 Investigator s Global Assessment score. Table S2 Summary of efficacy parameters at baseline and the end of treatment. Table S3 Percentage change from baseline in modified Eczema Area Severity Index score over time (ANCOVA model). Table S4 Proportion of patients achieving 50%, 75% or 90% improvement in modified Eczema Area Severity Index score at the end of treatment. Table S5 Proportion of patients with an Investigator s Global Assessment score of 0 or 1, and achieving 2-point improvement from baseline at the end of treatment. Table S6 Adverse events occurring in at least two patients in any of the treatment groups by preferred term. Table S7 Summary of JTE-052 plasma concentrations and proportion of patients with detectable JTE-052 plasma concentrations.