delgocitinib and Dermatitis--Atopic

Delgocitinib ointment is a newly approved topical medication for the treatment of atopic dermatitis (AD). AD usually has onset in early childhood and is a common, often chronic relapsing inflammatory skin condition that affects all age groups. AD has a large impact on patients' quality of life including physical health and emotional impacts. Conventional management of AD consists of phototherapy and treatments that comprise corticosteroids (both topically and systemically), topical calcineurin inhibitors (tacrolimus and pimecrolimus) or systemic immunosuppressants like ciclosporin. New targeted therapies for AD, including interleukin (IL)-4/13 inhibitors, Janus kinase (JAK) inhibitors and IL-13 inhibitors have been introduced for both topical and systemic use. In this review, we give an overview of the use of delgocitinib, the first topical JAK inhibitor to be approved for AD, including its preclinical pharmacology, pharmacokinetics and metabolism, safety, existing clinical trials and future directions.

Topics: Child, Preschool; Dermatitis, Atopic; Humans; Janus Kinase Inhibitors; Pyrroles; Quality of Life

Atopic dermatitis (AD) is a widely acquired, relapsing inflammatory skin disease. Biologics are now widely used in patients with moderate-to-severe AD.. This work aims to summarize both label and off-label biologics on AD treatment in phase II and phase III stages, and compile evidence on the efficacy of the most-studied biologics.. We conducted a comprehensive literature search through PubMed, EMBASE, and ClinicalTrials.gov to identify all documented biological therapies for AD. The criteria were further refined to focus on those treatments with the highest evidence level for AD with at least one randomized clinical trial supporting their use. Only studies or articles published in English were enrolled in this study.. Primary searches identified 525 relevant articles and 27 trials. Duplicated articles and papers without a full text were excluded. Only completed trials were enrolled. We included 28 randomized controlled trials, 4 unpublished trials, 2 observational studies, and 1 meta-analysis. Eight kinds of biologics, including IL-4/IL-13 inhibitors, JAK inhibitors, anti-IL-13 antibodies, anti-IL-22 antibodies, anti-IL-33 antibodies, thymic stromal lymphopoietin inhibitor (TSLP), OX40 antibodies, and H4R-antagonists were included in this work. Dupliumab, as the most widely used and investigated biologic, was reported in 1 meta-analysis and 4 trials exploring its long-term use and application in both adults and pediatric patients. Besides dupilumab, four other IL-4/IL-13 inhibitors recruited were all randomized, clinical trials at phase 2-3 stage. Six different kinds of JAK inhibitors were summarized with strong evidence revealing their significant therapeutic effects on AD. There were 3 trials for nemolizumab, an anti-IL-13 antibody, all of which were in the phase 2 clinical trial stage. Results showed nemolizumab could be another alternative therapy for moderate-to-severe AD with long-term efficiency and safety.. The biological therapies with the most robust evidence on efficacy and long-term safety for AD treatment include dupilumab, barcitinib, abrocitinib, and delgocitinib. Most of the biologics mentioned in this review were still at the exploratory stage. This review will help practitioners advise patients seeking suitable biological therapies and offer experimental study directions for treatment.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azetidines; Biological Products; Carbamates; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Heterocyclic Compounds, 3-Ring; Humans; Nitriles; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Sulfonamides

Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD.

Topics: Acrylamides; Administration, Topical; Antibodies, Monoclonal, Humanized; Biological Products; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Humans; Immunotherapy; Interleukin-13; Janus Kinase Inhibitors; Molecular Targeted Therapy; Phosphodiesterase 4 Inhibitors; Piperidines; Pyridines; Pyrimidines; Pyrroles; Resorcinols; Stilbenes; TRPV Cation Channels

Chronic hand eczema (CHE) is a burdensome disease, and new well-documented, safe and efficacious treatments are warranted. In a recent CHE phase IIa trial, the pan-Janus kinase (JAK) inhibitor delgocitinib in an ointment formulation was found to be efficacious and well tolerated.. This trial assessed the dose response, efficacy and safety of delgocitinib cream in CHE.. In this double-blind, phase IIb dose-ranging trial, adults with CHE and a recent history of inadequate response or contraindication to topical corticosteroids were randomized to delgocitinib cream 1, 3, 8, 20 mg g. Patients (n = 258) were randomized 1 : 1 : 1 : 1 : 1 to delgocitinib cream 1, 3, 8, 20 mg g. In this trial, delgocitinib cream showed a dose-response relationship in terms of efficacy and was well tolerated.

Topics: Adult; Dermatitis, Atopic; Double-Blind Method; Eczema; Emollients; Humans; Immunoglobulin A; Janus Kinase Inhibitors; Pain; Pruritus; Pyrroles; Severity of Illness Index; Treatment Outcome

Delgocitinib 0.5% ointment, a topical Janus kinase inhibitor, has been approved in Japan for adult patients with atopic dermatitis (AD).. To evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD.. 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.. 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.. Only Japanese patients were included. In part 2, no control group was included and rescue therapy was allowed.. Delgocitinib ointment was effective and well tolerated when applied to Japanese pediatric patients with AD for up to 56 weeks.

Topics: Adult; Child; Dermatitis, Atopic; Double-Blind Method; Eczema; Emollients; Humans; Ointments; Pyrroles; Treatment Outcome

Previous studies demonstrated that delgocitinib ointment, a novel topical Janus kinase inhibitor, rapidly improved clinical signs and symptoms of atopic dermatitis (AD) in Japanese adult patients. We sought to evaluate the long-term safety and efficacy of delgocitinib 0.5% ointment in a 52-week study (QBA4-2). Japanese patients aged 16 years or older with AD received delgocitinib 0.5% ointment b.i.d. for up to 52 weeks. Topical corticosteroids for the treatment of worsening of AD could be used at the investigators' discretion during the treatment period. Safety end-points included the incidence and severity of adverse events (AEs). Pooled safety analyses included the data from the other long-term study (QBA4-1). Efficacy end-points included the percentage change from baseline in the modified Eczema Area and Severity Index (mEASI). A total of 506 patients were included in the pooled safety population. Overall, AEs were reported in 69.0% of patients; most AEs were mild and unrelated to delgocitinib ointment. The most common AE was nasopharyngitis, followed by contact dermatitis, acne, and application site folliculitis. No skin atrophy or telangiectasia was found at the application sites of delgocitinib ointment. Application site irritation symptoms were infrequent (<2%) and mild. The incidence of AEs did not increase over time, except for seasonal diseases. The improvement effects on AD as assessed by mEASI were maintained throughout the treatment period. Delgocitinib 0.5% ointment was well tolerated and effective when administrated to Japanese adult patients with AD for up to 52 weeks.

Topics: Acne Vulgaris; Adolescent; Adult; Dermatitis, Atopic; Dermatitis, Contact; Drug Administration Schedule; Female; Folliculitis; Humans; Incidence; Janus Kinase Inhibitors; Japan; Male; Nasopharyngitis; Ointments; Pyrroles; Severity of Illness Index; Time Factors; Treatment Outcome; Young Adult

Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD).. This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment.. In part 1, a 4-week double-blind period, Japanese patients aged 16 years or older with moderate or severe AD were randomly assigned in a 2:1 ratio to delgocitinib 0.5% ointment or vehicle ointment. Eligible patients entered part 2, a 24-week extension period, to receive delgocitinib 0.5% ointment.. At the end of treatment in part 1, the least-squares mean percent changes from baseline in the modified Eczema Area and Severity Index score, the primary efficacy endpoint, were significantly greater in the delgocitinib group than in the vehicle group (-44.3% vs 1.7%, P < .001). The improvement in modified Eczema Area and Severity Index score was maintained in part 2. Most adverse events were mild and unrelated to delgocitinib across the study periods.. Only Japanese patients were included. The vehicle-controlled period lasted only 4 weeks. In part 2, topical corticosteroids were allowed for the treatment of worsening of AD.. Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.

Topics: Adult; Dermatitis, Atopic; Dermatologic Agents; Double-Blind Method; Female; Humans; Janus Kinase Inhibitors; Male; Ointments; Pyrroles; Treatment Outcome; Young Adult

Topical delgocitinib (JTE-052), a novel Janus kinase inhibitor, had been shown to be clinically effective in adults with atopic dermatitis (AD). However, the efficacy of topical delgocitinib in pediatric patients with AD remained unclear.. We sought to evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD.. In this phase 2 clinical study (JapicCTI-173553) Japanese patients aged 2 through 15 years with AD were randomized in a 1:1:1 ratio to receive 0.25% or 0.5% delgocitinib ointment or vehicle ointment twice daily for 4 weeks. The primary efficacy end point was the percentage change from baseline in the modified Eczema Area and Severity Index score at the end of treatment (EOT).. At EOT, modified Eczema Area and Severity Index scores in both delgocitinib groups were significantly reduced compared with that in the vehicle group. The least-squares mean percentage change from baseline was -54.2% in the 0.25% group and -61.8% in the 0.5% group versus -4.8% in the vehicle group (P < .001 for both comparisons). Similarly, all other efficacy parameters, including Investigator's Global Assessment and pruritus scores, in both delgocitinib groups were significantly improved compared with those in the vehicle group at EOT. Adverse events in both delgocitinib groups were mild in severity, and no serious adverse events were reported.. Delgocitinib ointment improved clinical signs and symptoms in pediatric patients with AD and was well tolerated. These study results indicate that delgocitinib ointment can be a promising therapeutic option for pediatric patients with AD.

Topics: Adolescent; Child; Child, Preschool; Dermatitis, Atopic; Double-Blind Method; Female; Humans; Male; Ointments; Pyrroles

JTE-052 is a novel Janus kinase inhibitor presently under clinical development for the topical treatment of atopic dermatitis (AD).. To evaluate the efficacy and safety of JTE-052 ointment in Japanese adult patients with AD.. Patients with moderate-to-severe AD were randomized (2: 2: 2: 2: 1: 1) to receive JTE-052 ointment at 0·25%, 0·5%, 1% or 3%, the vehicle ointment or tacrolimus 0·1% 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.. In total, 327 patients were enrolled. At EOT, the least-squares mean percentage changes from baseline in mEASI score for JTE-052 at 0·25%, 0·5%, 1% and 3% and the vehicle ointment were -41·7%, -57·1%, -54·9%, -72·9% and -12·2%, respectively. All JTE-052 groups showed significant reductions of mEASI score vs. the vehicle group (P < 0·001 for all). In the tacrolimus group, the mean percentage change in mEASI score was -62·0%. 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.. 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-152887.

Topics: Administration, Cutaneous; Adolescent; Adult; Aged; Anti-Inflammatory Agents; Dermatitis, Atopic; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Ointments; Pruritus; Pyrroles; Treatment Outcome; Young Adult

The purpose of the present two phase 1 studies was to assess the safety, tolerability and pharmacokinetics for topical application of a novel Janus kinase (JAK) inhibitor, JTE-052, in Japanese healthy adult male volunteers and Japanese adult patients with atopic dermatitis (AD). Additionally, exploratory investigation was performed on the efficacy for disease severity and pruritus score in AD patients. In the QBX1-1 study, the cutaneous safety of JTE-052 ointment by a patch test and a photo patch test was assessed in an intra-individual comparative study using placebo ointment, white petrolatum and non-application as comparators. The study demonstrated that JTE-052 ointment would be associated with a low potential for phototoxicity but had no potential for skin irritation or photoallergy. In the QBX1-2 study, it was revealed that the systemic exposure to JTE-052 in both healthy volunteers with normal skin and AD patients with inflamed skin was low in application of not only 1% but also 3% JTE-052 ointment. JTE-052 ointments of 1% and 3% were generally safe and well tolerated in both populations. In a repeated twice-daily application for 7 days, the efficacy of JTE-052 ointment to AD patients was observed with both 1% and 3% ointments in the exploratory investigations evaluated by Eczema Area and Severity Index, Investigator's Global Assessment and Numeric Rating Scale assessments. The mean scores for each assessment declined from the baseline throughout the study. These results suggest that the treatment of JTE-052 ointment is generally safe and effective in AD patients, although further large confirmatory studies are needed.

Topics: Administration, Cutaneous; Adult; Dermatitis, Atopic; Dermatitis, Phototoxic; Female; Healthy Volunteers; Humans; Janus Kinase Inhibitors; Japan; Male; Middle Aged; Ointments; Patch Tests; Placebos; Pruritus; Pyrroles; Severity of Illness Index; Skin; Treatment Outcome; Young Adult

Previous studies have shown the efficacy of delgocitinib (DEL) ointment, a topical Janus kinase inhibitor, against atopic dermatitis (AD). However, there is no available information regarding the efficacy of DEL ointment in maintaining remission. Data of patients with AD who received remission maintenance therapy twice weekly with DEL or topical corticosteroid (TCS) on the affected skin of each upper limb were extracted from the medical records. Efficacy was assessed based on changes in pruritus numerical rating scale (NRS) score, stratum corneum hydration (SCH), erythema index (EI). Of 25 patients, four patients (16%) had eczema flare-ups on the TCS side and eight patients (32%) on the DEL side. The extent of change in each parameter between TCS- and DEL-treated areas of the skin did not differ significantly. The mean changes in the NRS and EI showed a slight improvement on the side treated with TCS and were slightly worse on the side treated with DEL. However, the SCH of the DEL group was maintained, while that of the TCS group worsened. TCS is more likely to be effective than DEL in terms of remission maintenance therapy. However, topical DEL is as effective as topical steroid in the maintenance therapy of AD in dry skin patients.

Topics: Adult; Dermatitis, Atopic; Dermatologic Agents; Emollients; Glucocorticoids; Humans; Ointments; Pyrroles; Treatment Outcome

Topics: Administration, Topical; Adult; Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Dermatologic Agents; Drug Eruptions; Humans; Interleukin-4 Receptor alpha Subunit; Male; Ointments; Pyrroles; Treatment Outcome; Young Adult

Topics: Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Humans; Ointments; Pyrroles; Treatment Outcome

Topics: Administration, Topical; Blepharitis; Dermatitis, Atopic; Dermatologic Agents; Humans; Janus Kinase 1; Male; Pyrroles; Treatment Outcome; Young Adult

Dermatologic disorders such as atopic dermatitis arise from genetic and environmental causes and are complex and multifactorial in nature. Among possible risk factors, aberrant immunological reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clinical settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochemical properties and antidermatitis efficacy in the animal models. One of these compounds, JTE-052 (

Topics: Dermatitis, Atopic; Dermatologic Agents; Drug Design; Humans; Inhibitory Concentration 50; Janus Kinase Inhibitors; Janus Kinases; Models, Molecular; Protein Conformation; Pyrroles

Topics: Administration, Cutaneous; Animals; Antipruritics; Dermatitis, Atopic; Disease Models, Animal; Female; Humans; Janus Kinase Inhibitors; Male; Mice; Pruritus; Pyrroles; Skin

Janus kinases (JAKs) are required for several inflammatory cytokine signalling pathways and are implicated in the pathogenesis of chronic dermatitis, including atopic dermatitis and psoriasis. JAK inhibitors are therefore promising therapeutic candidates for chronic dermatitis. In this study, we evaluated the effects of the novel JAK inhibitor JTE-052 on inflammatory responses associated with chronic dermatitis, and compared its profile with those of conventional therapeutic agents in rodent models of chronic dermatitis. JTE-052 inhibited the Th1-, Th2- and Th17-type inflammatory responses of human T cells and mast cells in vitro. Oral administration of JTE-052 inhibited skin inflammation in hapten-induced chronic dermatitis in mice, associated with reduced levels of inflammatory cytokines in the skin and immunoglobulin (Ig) E in serum. In contrast, although ciclosporin partly inhibited skin inflammation, it did not reduce interleukin (IL)-4 production in skin, and enhanced IgE production in serum. Oral administration of JTE-052 also inhibited skin inflammation in mouse models of atopic dermatitis and psoriasis induced by a mite extract, thymic stromal lymphopoietin or IL-23. The maximal efficacy of JTE-052 in these dermatitis models was superior to the conventional therapeutic agents, ciclosporin and methotrexate. Topical application of JTE-052 ointment ameliorated hapten-induced chronic dermatitis in rats more effectively than tacrolimus ointment. Furthermore, JTE-052 ointment did not cause the thinning of normal skin associated with topical corticosteroids. These results indicate that JTE-052 is a promising candidate as an anti-inflammatory drug for various types of chronic dermatitis, with a distinctly different profile from conventional therapy following either oral or topical application.

Topics: Animals; Cyclosporine; Cytokines; Dermatitis, Atopic; Female; Haptens; Humans; Immunoglobulin E; Inflammation; Interleukin-23; Interleukin-23 Subunit p19; Janus Kinase Inhibitors; Male; Methotrexate; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Pyrroles; Rats; Rats, Inbred BN; Skin; Thymic Stromal Lymphopoietin

Topics: Adult; Dermatitis, Atopic; Eczema; Humans; Janus Kinase Inhibitors; Pyrroles