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Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.

ABSTRACT: 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.

SUBMITTER: Nakagawa H

PROVIDER: S-EPMC7028108 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.

Nakagawa Hidemi H Nemoto Osamu O Igarashi Atsuyuki A Saeki Hidehisa H Murata Ryusei R Kaino Hironobu H Nagata Takeshi T

The Journal of dermatology 20191209 2

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 a ...[more]

PMID: 31820485

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Project description:ImportanceAtopic dermatitis is associated with substantial patient and caregiver burden. Currently available treatments for atopic dermatitis are inadequate or contraindicated for some patients. Abrocitinib (PF-04965842) is an oral Janus kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis.ObjectiveTo investigate the efficacy and safety of abrocitinib for patients with moderate to severe atopic dermatitis.Design, setting, and participantsA phase 2b, randomized, double-blinded, placebo-controlled, parallel-group trial was conducted from April 15, 2016, to April 4, 2017, at 58 centers in Australia, Canada, Germany, Hungary, and the United States among 267 patients 18 to 75 years of age with a clinical diagnosis of moderate to severe atopic dermatitis for 1 year or more and inadequate response or contraindication to topical medications for 4 weeks or more within 12 months. Efficacy was assessed in the full analysis set, which was a modified intention-to-treat population that included all patients who received 1 dose or more of the study drug except for 4 patients from 1 site.InterventionsParticipants were randomly assigned 1:1:1:1:1 to receive abrocitinib (200 mg, 100 mg, 30 mg, or 10 mg) or placebo once daily for 12 weeks.Main outcomes and measuresThe primary outcome was the proportion of patients achieving an Investigator's Global Assessment of clear (0) or almost clear (1) with an improvement from baseline of 2 grades or more at week 12. The secondary outcome was the percentage change from baseline in the Eczema Area and Severity Index at week 12.ResultsOf the 267 participants, 144 were women (mean [SD] age, 40.8 [16.1] years). At week 12, 21 of 48 patients receiving 200 mg of abrocitinib (43.8%; P < .001, 2-sided), 16 of 54 patients receiving 100 mg of abrocitinib (29.6%; P < .001), and 3 of 52 patients receiving placebo (5.8%) achieved grades of clear or almost clear on the Investigator's Global Assessment scale with improvement of 2 grades or more; these rates correspond to maximum effect model-based estimates of 44.5% (95% CI, 26.7%-62.3%) for those receiving 200 mg of abrocitinib, 27.8% (95% CI, 14.8%-40.9%) for those receiving 100 mg of abrocitinib, and 6.3% (95% CI, -0.2% to 12.9%) for those receiving placebo. Reductions in the Eczema Area and Severity Index were 82.6% (90% CI, 72.4%-92.8%; P < .001) for those receiving 200 mg of abrocitinib, 59.0% (90% CI, 48.8%-69.3%; P = .009) for those receiving 100 mg of abrocitinib, and 35.2% (90% CI, 24.4%-46.1%) for those receiving placebo. Adverse events were observed in 184 of 267 patients (68.9%); the most frequently reported adverse events (in ≥3 patients in any group) were dermatitis atopic, upper respiratory tract infection, headache, nausea, and diarrhea. Dose-dependent decreases in platelet count were observed but trended upward toward baseline levels after week 4.Conclusions and relevanceOnce-daily oral abrocitinib was effective and well tolerated for short-term use in adults with moderate to severe atopic dermatitis. Additional trials are necessary to evaluate long-term efficacy and safety.Trial registrationClinicalTrials.gov identifier: NCT02780167.

Project description:IntroductionPhosphodiesterase 4 (PDE4), which regulates inflammatory cytokine production leading to atopic dermatitis (AD), is selectively inhibited by difamilast. The objective of this phase III, long-term, open-label study was to evaluate the safety and efficacy of topical difamilast in Japanese adult and pediatric patients with AD.MethodsAdult patients (n = 166) began treatment with difamilast 1% ointment, and pediatric patients began treatment with difamilast 0.3% ointment (n = 144) or difamilast 1% ointment (n = 56). Treatment was continued twice daily for 52 weeks. All patients had an Investigator's Global Assessment (IGA) score of 2 (mild), 3 (moderate), or 4 (severe/very severe), and an AD-affected body surface area (BSA) of ≥ 5% before treatment, with no restriction on the upper limit for the AD-affected BSA.ResultsDuring therapy, 120 adult patients (72.3%) and 178 pediatric patients (89.0%) experienced treatment-emergent adverse events (TEAEs), most of which were mild or moderate in severity. Discontinuation due to TEAEs was reported in 13 adult patients (7.8%) and in 7 pediatric patients (3.5%). Treatment-related adverse events were reported in 14 adult patients (8.4%) and 16 pediatric patients (8.0%), most frequently dermatitis atopic (1.8%) and acne (1.2%) in adult patients and dermatitis atopic and pigmentation disorder (each 2.0%) in pediatric patients. The cumulative success rates in Eczema Area and Severity Index (EASI)-75 in adult and pediatric patients were 55.4% and 73.5%, respectively, at week 52, and the cumulative success rates increased from week 4 to week 52. The cumulative success rates in IGA score showed the same trend as those in EASI -75.ConclusionsThis study demonstrates that difamilast ointments are well tolerated and effective in Japanese adult and pediatric patients with AD when applied twice daily for 52 weeks, and are expected to be used for a long-term treatment for AD.Clinical trial registrationClinical Trials.gov identifier: NCT03961529.

Project description:BackgroundCurrent therapeutic options for atopic dermatitis (AD) are limited. Janus kinase (JAK) inhibitors may be viable alternatives.ObjectivesTo assess the efficacy and safety of JAK inhibitors for AD treatment.MethodsWe searched PubMed, Embase, the Cochrane Controlled Register of Trials, Web of Science, Global Resource of Eczema Trials database, and ClinicalTrials.gov from inception to September 1, 2020. Randomized clinical trials (RCTs) comparing JAK inhibitors with placebo/vehicle treatment for AD patients were included. The primary study outcomes included (1) the change (%) from the Eczema Area and Severity Index (EASI) baseline expressed as weighted mean difference (WMD) and 95% confidence interval (95% CI), and (2) the Investigator's Global Assessment (IGA) response and safety outcomes expressed as relative risk (RR) and 95% CI.ResultsWe included 14 RCTs published in 13 studies (3,822 patients). Treatment with JAK inhibitors significantly improved IGA response (RR 2.83, 95% CI 2.25-3.56, p < 0.001) and EASI score (WMD -28.82, 95% CI -34.48 to -23.16, p < 0.001). JAK inhibitor treatment achieved the largest improvement in both IGA response (RR 3.59, 95% CI 2.66-4.84, p < 0.001) and EASI score (WMD -42.00, 95% CI -48.64 to -35.36, p < 0.001) by week 4 of treatment. Topical JAK inhibitors were significantly more efficacious than oral inhibitors. Upadacitinib treatment for 4 weeks was most effective in reducing EASI score (WMD -53.92, 95% CI -69.26 to -38.58, p < 0.001), while abrocitinib for 4 weeks led to the most effective IGA response (RR 5.47, 95% CI 2.74-10.93, p < 0.001). There was no difference in the frequency of adverse events (AEs) leading to discontinuation; however, JAK inhibitors use, especially abrocitinib, led to a higher incidence of treatment-emergent AEs (RR 1.25, 95% CI 1.10-1.42, p = 0.001).ConclusionOur results imply that JAK inhibitors are an effective and safe AD treatment. Nevertheless, further trials with longer duration and head-to-head comparisons of different JAK inhibitors are needed.

Project description:BackgroundAtopic dermatitis is a chronic, inflammatory condition causing a substantial burden to patients and caregivers. SHR0302 is an oral, highly selective, Janus kinase 1 inhibitor under investigation for inflammatory skin diseases.ObjectiveThe aim of this study was to investigate the efficacy and safety of SHR0302 in Chinese patients with moderate to severe atopic dermatitis.Design and settingA randomized, double-blind, placebo-controlled, multicenter, phase II trial was conducted in China between October 2019 and August 2020.ParticipantsPatients (n = 105) aged 18-75 years with moderate to severe dermatitis and nonresponsive or intolerant to topical or conventional systemic treatments were included.InterventionsPatients were randomly assigned in a ratio of 1:1:1 to receive SHR0302 4 mg once daily, SHR0302 8 mg once daily, or placebo for 12 weeks.Main outcome measuresThe primary efficacy endpoint was the proportion of patients achieving Investigator's Global Assessment (IGA) response (IGA of 0 [clear] or 1 [almost clear] with improvement of ≥2 grades) at week 12. Secondary efficacy assessments included Eczema Area and Severity Index (EASI) and pruritus Numerical Rating Scale (NRS) scores.ResultsAt week 12, IGA response was achieved in nine patients (25.7%; 90% confidence interval [CI] 13.6-37.9%; p = 0.022) in the SHR0302 4 mg group, 19 patients (54.3%; 90% CI 40.4-68.1%; p < 0.001) in the SHR0302 8 mg group, and two patients (5.7%; 90% CI 0.0-12.2%) in the placebo group. EASI75 was achieved in 51.4% (p = 0.013), 74.3% (p < 0.001), and 22.9% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively, while an NRS ≥3-point improvement occurred in 65.7% (p < 0.001), 74.3% (p < 0.001), and 22.9% of patients, respectively. Treatment-emergent adverse events were reported in 60.0%, 68.6%, and 51.4% of patients in the SHR0302 4 mg, SHR0302 8 mg, and placebo groups, respectively. The adverse events were mild in most cases. Three serious adverse events were reported, all being worsening of atopic dermatitis. No serious infection was reported.Conclusions and relevanceOral SHR0302 was effective and well tolerated in Chinese adult patients with moderate to severe atopic dermatitis.Trial registrationClinicalTrials.gov identifier: NCT04162899; URL: https://clinicaltrials.gov/ . Date first registered: 14 November 2019.

Project description:ImportanceTopical calcineurin inhibitors (TCIs), primarily used to treat atopic dermatitis (AD), carry a black box label warning users about the potential for increased skin cancer risk. The risk associated with keratinocyte carcinoma (KC), the most common cancer, defined as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), remains poorly defined because findings from large-scale postmarketing surveillance studies have not been reported.ObjectivesTo examine KC risk overall and by subtype (BCC and SCC) among adults with AD exposed to TCIs compared with those exposed to topical corticosteroids (primary comparator group) and those unexposed to TCIs or topical corticosteroids (alternative comparator group) as well as alterations in risk with TCI dose, frequency, and duration of exposure.Design, setting, and participantsA retrospective cohort study was conducted at Kaiser Permanente Northern California, a large, integrated health care delivery system, of adults 40 years or older (n = 93 746) with a physician-rendered diagnosis of AD or dermatitis. Patients who were diagnosed from January 1, 2002, to December 31, 2013, were included, with follow-up through December 31, 2017. Data analysis was conducted from June 1, 2016, to October 1, 2018.ExposuresTime-varying pharmacy-dispensed TCI exposure (n = 7033) over the study period was compared with topical corticosteroids (n = 73 674) and no TCI or topical corticosteroid exposure (n = 46 141).Main outcomes and measuresElectronic pathologic testing-validated incident KCs (n = 7744).ResultsAmong a cohort of 93 746 members, the mean (SD) age was 58.5 (12.7) years, and 55 023 patients (58.7%) were women. Multivariable Cox proportional hazards regression revealed no association between TCI exposure and KC risk (adjusted hazard ratio [aHR], 1.02; 95% CI, 0.93-1.13) compared with topical corticosteroid exposure. Similarly, there were no significant differences in BCC risk (aHR, 1.01; 95% CI, 0.90-1.14, TCI vs topical corticosteroids) or SCC risk (aHR, 0.94; 95% CI, 0.82-1.08, TCI vs topical corticosteroids). Changing the comparator group to unexposed individuals yielded similar findings (aHR, 1.04; 95% CI, 0.91-1.19, TCI vs unexposed for basal cell carcinoma). There were no associations between TCI dose, frequency, and duration of use and BCC, SCC, or overall KC risk.Conclusions and relevanceThe results of this postmarketing surveillance study of adult health plan members with AD revealed no apparent association between TCI exposure and overall KC, BCC, or SCC risk. Secondary analyses examining dose, frequency, and duration of TCI exposure revealed no associations. These findings suggest that use of TCIs may be safe with respect to KC risk among adults with AD.

Dataset Information

Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.

Publications

Long-term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis.

Similar Datasets

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