Safety, efficacy, and pharmacokinetics of delgocitinib ointment in infants with atopic dermatitis: A phase 3, open-label, and long-term study.

BACKGROUND: Delgocitinib ointment, a topical Janus kinase inhibitor, is used as treatment of patients with atopic dermatitis (AD) aged ≥2 years in Japan. Although initiating appropriate and early treatment upon the onset of AD in childhood is important, the safety and efficacy of delgocitinib ointment in infants with AD have not been established. METHODS: This phase 3 study was conducted from October 2020 to June 2022 (number JapicCTI-205412). Eligible Japanese infants with AD aged 6 to <24 months received 0.25% or 0.5% of delgocitinib ointment twice daily for 52 weeks in an open-label uncontrolled manner. Topical corticosteroids were allowed to apply for worsening AD during the treatment period at the investigators' discretion. RESULTS: A total of 22 infants were enrolled. Adverse events (AEs) were reported in 21 (95.5%) infants and were mostly mild. No treatment-related AEs were reported. The Modified Eczema Area and Severity Index (mEASI) score continuously decreased until week 4, and the score reduction was maintained until week 52. The mean percent changes in the mEASI score from baseline were -73.5% at week 4, -81.7% at week 28, and -81.9% at week 52. Delgocitinib was not detected in the plasma of most infants (68.2%-95.2%). CONCLUSIONS: Delgocitinib ointment is well tolerated and effective for up to 52 weeks when applied to Japanese infants with AD.

Generation of induced pluripotent stem cell (iPSC) from NY-ESO-I-specific cytotoxic T cells isolated from the melanoma patient with minor HLAs: The practical pilot study for the adoptive immunotherapy for melanoma using iPSC technology.

Melanoma is one of the most severe skin cancers, derived from melanocytes. Among various therapies for melanoma, adoptive immunotherapy using tumor-infiltrating lymphocytes/chimeric antigen receptor-T cells (TCs) is advanced in recent years; however, the efficacy is still limited, and major challenges remain in terms of safety and cell supply. To solve the issues of adoptive immunotherapy, we utilized induced pluripotent stem cells (iPSCs), which have an unlimited proliferative ability and various differentiation capability. First, we monoclonally isolated CD8+ TCs specifically reactive with NY-ESO-1, one of tumor antigens, from the melanoma patient's monocytes after stimulated with NY-ESO-1 peptide by manual procedure, and cultured NY-ESO-1-specific TCs until proliferated and formed colonies. iPSCs were consequently generated from colony-forming TCs by exogenous expression of reprogramming factors using Sendai virus vector. After the RAG2 gene in TC-derived iPSCs (T-iPSCs) was knocked out for preventing T-cell receptor (TCR) rearrangement, T-iPSCs were re-differentiated into rejuvenated cytotoxic TCs. We confirmed that TCR of T-iPSC-derived TC was maintained as the same of original TCs. In conclusion, T-iPSCs have a potential to be an unlimited cell source for providing cytotoxic TCs. Our study could be a "touchstone" to develop iPSC-based adoptive immunotherapy for the treatment of melanoma for the future clinical use.

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.

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.

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.

BACKGROUND: Previous studies showed the potential effectiveness of delgocitinib ointment, a novel topical Janus kinase inhibitor, in atopic dermatitis (AD). OBJECTIVE: This study aimed to evaluate the efficacy and safety of delgocitinib 0.5% ointment. METHODS: 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. RESULTS: 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. LIMITATIONS: 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. CONCLUSION: Delgocitinib ointment was effective and well tolerated in Japanese adult patients with moderate to severe AD for up to 28 weeks.

Phase 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis.

BACKGROUND: 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. OBJECTIVE: We sought to evaluate the efficacy and safety of delgocitinib ointment in pediatric patients with AD. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Role of interleukin-24 in the tumor-suppressive effects of interferon-ß on melanoma.

BACKGROUND: Type 1 interferons (IFNs), including IFN-ß, are widely used in adjuvant therapy for patients who undergo surgery for malignant melanoma to inhibit recurrence and in-transit metastasis. The precise mechanisms underlying the tumor-suppressive effects of IFN-ß on melanoma are not yet completely understood. OBJECTIVE: The purpose was to reveal the mechanisms underlying the tumor-suppressive effects of IFN-ß via interleukin (IL)-24. METHODS: Genome-wide oligonucleotide microarray, quantitative real-time reverse transcription-polymerase chain reaction (PCR), enzyme-linked immunosorbent assay and western blotting assay were performed using four melanoma cell lines (A375, RPMI-7951, SK-MEL-5 and SK-MEL-1) treated with natural-type IFN-ß to assess the expression of IL-24. Proliferation assay was performed using these melanoma cells and IL-24 knock-down melanoma cells. RESULTS: Genome-wide microarray analysis detected candidate genes upregulated in IFN-ß-sensitive cells after treatment with IFN-ß. We focused on IL-24 among the candidate genes encoding secretory proteins. Peak IL-24 mRNA expression completely correlated with the order of sensitivity of melanoma cells to IFN-ß. IFN-ß treatment induced extracellular IL-24 protein in IFN-ß-sensitive cells, but did not induce intracellular IL-24 protein. Knock-down of IL-24 changed melanoma cells into IFN-ß-resistant cells. The expression ratio of IL-22R1, one of the IL-24 receptors, correlated with the order of sensitivity of melanoma cells to IFN-ß. Treatment with recombinant human IL-24 did not have any effects on all the melanoma cell lines. CONCLUSION: Our data suggest that IFN-ß suppresses the proliferation of melanoma cells through extracellular IL-24 protein derived from melanoma cells.

Secukinumab in plaque psoriasis--results of two phase 3 trials.

BACKGROUND: Interleukin-17A is considered to be central to the pathogenesis of psoriasis. We evaluated secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe plaque psoriasis. METHODS: In two phase 3, double-blind, 52-week trials, ERASURE (Efficacy of Response and Safety of Two Fixed Secukinumab Regimens in Psoriasis) and FIXTURE (Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in Psoriasis), we randomly assigned 738 patients (in the ERASURE study) and 1306 patients (in the FIXTURE study) to subcutaneous secukinumab at a dose of 300 mg or 150 mg (administered once weekly for 5 weeks, then every 4 weeks), placebo, or (in the FIXTURE study only) etanercept at a dose of 50 mg (administered twice weekly for 12 weeks, then once weekly). The objective of each study was to show the superiority of secukinumab over placebo at week 12 with respect to the proportion of patients who had a reduction of 75% or more from baseline in the psoriasis area-and-severity index score (PASI 75) and a score of 0 (clear) or 1 (almost clear) on a 5-point modified investigator's global assessment (coprimary end points). RESULTS: The proportion of patients who met the criterion for PASI 75 at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 81.6% with 300 mg of secukinumab, 71.6% with 150 mg of secukinumab, and 4.5% with placebo; in the FIXTURE study, the rates were 77.1% with 300 mg of secukinumab, 67.0% with 150 mg of secukinumab, 44.0% with etanercept, and 4.9% with placebo (P<0.001 for each secukinumab dose vs. comparators). The proportion of patients with a response of 0 or 1 on the modified investigator's global assessment at week 12 was higher with each secukinumab dose than with placebo or etanercept: in the ERASURE study, the rates were 65.3% with 300 mg of secukinumab, 51.2% with 150 mg of secukinumab, and 2.4% with placebo; in the FIXTURE study, the rates were 62.5% with 300 mg of secukinumab, 51.1% with 150 mg of secukinumab, 27.2% with etanercept, and 2.8% with placebo (P<0.001 for each secukinumab dose vs. comparators). The rates of infection were higher with secukinumab than with placebo in both studies and were similar to those with etanercept. CONCLUSIONS: Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target. (Funded by Novartis Pharmaceuticals; ERASURE and FIXTURE ClinicalTrials.gov numbers, NCT01365455 and NCT01358578, respectively.).

Initial Experience of Using Dual-Energy CT with an Iodine Overlay Image for Hand Psoriatic Arthritis: Comparison Study with Contrast-enhanced MR Imaging.

Purpose To determine the feasibility of dual-energy (DE) computed tomography (CT) with an iodine overlay image (IOI) for evaluation of psoriatic arthritis in the hand. Materials and Methods Approval from the institutional ethics committee and written informed consent from all patients were obtained. This prospective study included 16 patients who had psoriasis with finger joint symptoms from January 2015 to January 2016. Contrast material-enhanced (CE) DE CT and 1.5-T CE magnetic resonance (MR) imaging were performed within 1 month of each other. DE CT was performed with a tube voltage of 80 kV and 140 kV with use of a 0.4-mm tin filter. Images acquired with both modalities were evaluated by two radiologists independently by using a semiquantitative scoring system. Interreader agreement was calculated for each modality: Weighted κ values were calculated for synovitis, flexor tenosynovitis, and extensor peritendonitis, and κ values were calculated for periarticular inflammation. With consensus scores and CE MR images as the reference, the sensitivity and specificity of IOI DE CT for inflammatory lesions were calculated. Statistical analysis of discordant readings was performed by using the McNemar test. Results Interreader agreement for inflammatory lesions was excellent or good (weighted κ = 0.83 and κ = 0.75 in IOI DE CT; weighted κ = 0.81 and κ = 0.87 in CE MR imaging). The sensitivity and specificity of IOI DE CT were 0.78 and 0.87, respectively. Total agreement was 86.3%; however, there were significantly more lesions detected with IOI DE CT than with CE MR imaging alone (134 vs 20 lesions in 1120 evaluated items; P < .001). Sixty-nine percent of the abnormalities detected with IOI DE CT alone were located in distal interphalangeal joints. Conclusion IOI DE CT is a new imaging modality that may be useful for evaluating psoriatic arthritis in the hand, particularly in the detection of inflammatory lesions in small joints, and may be more useful than CE MR imaging, within the limitation that there is no histopathologic reference. © RSNA, 2017.

Silencing of homeobox A5 gene in the stratum corneum of psoriasis.

Analysis of psoriatic parakeratotic cells is helpful for understanding the pathogenesis of psoriasis. Methylation analysis can be performed on psoriatic scales, but it is unclear whether genes can be silenced by DNA methylation in psoriatic stratum corneum. The present study was conducted to detect genes silenced in psoriatic stratum corneum. Methylation array analysis with 485 577 probes, quantitative real-time methylation-specific PCR (RT-MSP) and bisulphite sequencing were performed for 30 psoriatic scale samples, 6 fully developed psoriatic skin samples and 12 normal skin samples. Immunohistochemical staining of HOXA5 was performed for 29 psoriatic epidermal samples and 13 normal epidermal samples. The genome-wide methylation array detected two CpG sites within CpG islands (CGIs) located in promoter regions of HOXA5 and LIAS that had methylation levels of >0.6 in at least one of the three psoriatic scale samples and of <0.2 in all three normal skin tissue samples (methylation rate range, 0.0-1.0). RT-MSP for HOXA5CGI, in which the primers were successfully developed, revealed that the average methylation level of 27 psoriasis scales (60.2%) is significantly higher than that of 9 normal skin samples (34.6%) (P=.013). Immunohistochemical staining revealed that HOXA5 protein was not expressed in the stratum corneum of fully developed psoriatic epidermis, but the protein was expressed in the stratum corneum of incompletely developed epidermis and normal epidermis. In conclusion, HOXA5 can be silenced in the stratum corneum of psoriasis. The silenced gene was identified by non-invasive methylation analysis of psoriatic scales.

Dual energy CT iodine map for delineating inflammation of inflammatory arthritis.

Iodine mapping is an image-processing technique used with dual-energy computed tomography (DECT) to improve iodine contrast resolution. CT, because of its high spatial resolution and thin slice reconstruction, is well suited to the evaluation of the peripheral joints. Recent developments in the treatment of inflammatory arthritis that require early diagnosis and precise therapeutic assessment encourage radiological evaluation. To facilitate such assessment, we describe DECT iodine mapping as a novel modality for evaluating rheumatoid arthritis and psoriatic arthritis of the hands and feet. KEY POINTS: • Dual-energy CT iodine mapping can delineate inflammation of peripheral inflammatory arthritis. • DECT iodine mapping has high spatial resolution compared with MRI. • DECT iodine mapping has a high iodine contrast resolution. • DECT iodine mapping may reflect therapeutic effects.

Tumor-suppressive effects of natural-type interferon-ß through CXCL10 in melanoma.

INTRODUCTION: Type 1 interferon is in widespread use as adjuvant therapy to inhibit melanoma progression. Considering the tumor-suppressive effects of local administration of interferon-ß (IFN-ß) on lymphatic metastasis, the present study was conducted to identify melanoma-suppressive molecules that are up-regulated by IFN-ß treatment of lymphatic endothelial cells. MATERIALS AND METHODS: Lymphatic endothelial cells, fibroblasts, and melanoma cells were treated with natural-type IFN-ß, and melanoma cells were treated with CXCL10. Genome-wide oligonucleotide microarray analysis was performed using lymphatic endothelial cells with or without IFN-ß treatment. Quantitative real-time reverse transcription-PCR and an enzyme-linked immunosorbent assay were performed to examine CXCL10 expression. A proliferation assay was performed to examine the effects of IFN-ß and CXCL10 in melanoma cells. RESULTS: Genome-wide microarray analyses detected CXCL10 as a gene encoding a secretory protein that was up-regulated by IFN-ß in lymphatic endothelial cells. IFN-ß treatment significantly induced CXCL10 in dermal lymphatic endothelial cells and melanoma cells that are highly sensitive to IFN-ß. CXCL10 reduced melanoma cell proliferation in IFN-ß-sensitive cells as well as resistant cells. Melanoma cells in which CXCL10 was knocked down were sensitive to IFN-ß. CXCR3-B, which encodes the CXCL10 receptor, was up-regulated in melanoma cells with high sensitivity to IFN-ß and down-regulated in melanoma cells with medium to low sensitivity. CONCLUSIONS: Our data suggest that IFN-ß suppresses proliferation and metastasis from the local lymphatic system and melanoma cells via CXCL10. Down-regulation of CXCR3-B by IFN-ß may be associated with resistance to IFN-ß.

A pediatric case of multiple palisaded encapsulated neuromas of the palms and soles.

Palisaded encapsulated neuroma (PEN) usually presents as a solitary, skin-colored papule on the face in middle-aged adults. We present a rare pediatric case of multiple PEN of the palms and soles. DNA analysis of the RET proto-oncogene in our patient showed no mutations in exons 13, 15, and 16.

High prevalence of dermatophytosis of the feet in acral melanoma of the foot.

The clinical characteristics and pathogenesis of acral melanoma of the foot (AMF) have not been sufficiently elucidated. Clinical or subclinical persistent inflammation of the feet is caused by dermatophytosis of the feet (DPF). Persistent inflammation is potentially associated with oncogenesis. Moreover, diabetes has been reported to be associated with the development of dermatophytosis and cancer. The present study aimed to elucidate the clinical association between DPF and AMF, with consideration of diabetes. The medical records of 114 Japanese patients were retrospectively examined and divided into an AMF group (n = 30) and a control group consisting of patients with foot diseases other than melanoma (n = 84). Microscopic DPF screening was performed on all patients who reported symptoms in the foot, with or without AMF. Patients underwent a microscopic test to detect the presence of dermatophytes, and the diagnosis of DPF was made based on a positive result. In the AMF group, 18 (60.0%) and eight (26.7%) patients had DPF and diabetes, respectively. Four patients (13.3%) had both DPF and diabetes. In the control group, 25 (29.8%) and 11 (13.1%) patients had DPF and diabetes, respectively. Five patients (6.0%) had both DPF and diabetes. Univariate analyses showed a significantly higher prevalence of DPF in the AMF group than in the control group (odds ratio, 3.540; p = 0.003, Pearson χ2 test). Furthermore, multivariate analyses of sex, body mass index, DPF, and diabetes revealed DPF as a significant factor associated with AMF (odds ratio, 4.285; p = 0.002, logistic regression analysis). The hyperkeratotic type of DPF was more frequently observed in patients with AMF than in control patients (odds ratio, 11.083; p < 0.001, Pearson χ2 test). In conclusion, the present study found a significantly higher prevalence of DPF, especially its hyperkeratotic type, in patients with AMF. DPF may be associated with AMF pathogenesis.

Bimekizumab Efficacy and Safety in Japanese Patients with Plaque Psoriasis in BE VIVID: A Phase 3, Ustekinumab and Placebo-Controlled Study.

INTRODUCTION: Bimekizumab treatment resulted in improved clinical outcomes in patients with moderate-to-severe plaque psoriasis in BE VIVID, a 52-week, phase 3, randomized, ustekinumab and placebo-controlled study. We present data from the BE VIVID Japan patient subpopulation. METHODS: Globally, patients were randomized to receive bimekizumab 320 mg every 4 weeks (Q4W), ustekinumab (45/90 mg weight-based at baseline and week 4, then every 12 weeks), or placebo (Q4W through week 16, then bimekizumab 320 mg Q4W). Efficacy endpoints included week 16 Psoriasis Area and Severity Index (PASI) 90 and Investigator's Global Assessment (IGA) 0/1, and other outcomes [PASI 100, PASI 75, IGA 0, Dermatology Life Quality Index (DLQI) 0/1, absolute PASI, scalp IGA, Psoriasis Symptoms and Impacts Measure (P-SIM) responses]. Safety analyses were conducted. RESULTS: There were 108 Japanese randomized patients (bimekizumab: 62; ustekinumab: 29; placebo: 17). At week 16, bimekizumab-treated patients had a higher clinical response versus ustekinumab and placebo (PASI 90: 85.5% versus 51.7% and 5.9%; IGA 0/1: 82.3% versus 48.3% and 0.0%). Over 52 weeks, improved clinical response was maintained with bimekizumab, including patients switching from placebo at week 16. Overall, the safety profile in Japanese patients was consistent with that observed in the global population. CONCLUSION: Bimekizumab resulted in improved clinical response versus ustekinumab and placebo, and was well-tolerated in Japanese patients. TRIAL REGISTRATION: NCT03370133.

Efficacy and Safety of Certolizumab Pegol in Japanese Patients with Generalized Pustular Psoriasis and Erythrodermic Psoriasis: 52-Week Results.

INTRODUCTION: We report an exploratory analysis of the efficacy and safety of certolizumab pegol (CZP) in Japanese patients with generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP) (NCT03051217). METHODS: Patients ≥ 20 years with GPP or EP were randomized 1:1 to open-label CZP 400 mg every 2 weeks (Q2W) or 200 mg Q2W (400 mg weeks 0/2/4) for 16 weeks; patients who achieved "much improved" or "very much improved" on the Global Improvement Score (GIS; for GPP) or a PASI 50 response (≥ 50% reduction from baseline Psoriasis Area and Severity Index; for EP) continued to week 52. Efficacy outcomes assessed included Clinical Global Impression of Improvement (CGI-I), Dermatology Life Quality Index (DLQI 0/1), and Itch Numeric Rating Scale (INRS 0). GIS and Japanese Dermatological Association (JDA) severity index were assessed in patients with GPP, and PASI and Physician's Global Assessment (PGA) in patients with EP. Treatment-emergent adverse events (TEAEs) were evaluated through weeks 0-52. RESULTS: Of 22 patients randomized, 19 completed week 52. At week 16, all reported outcomes improved with both CZP doses and were generally maintained through week 52. At week 52, 6/7 GPP and 12/12 EP patients achieved CGI-I response ("improved" or "remission"). Also, 4/7 GPP and 7/12 EP patients achieved DLQI 0/1; 2/7 GPP and 2/12 EP patients achieved INRS 0. Meanwhile, 6/7 patients with GPP achieved GIS response, and JDA severity index was reduced from baseline. We found that 9/12 and 5/12 patients with EP achieved PASI 90 and PGA 0/1, respectively. Overall, three serious TEAEs were reported in three CZP 400 mg Q2W-treated patients. CONCLUSION: CZP treatment over 16 weeks improved the signs and symptoms of GPP and EP, and improvements were maintained through week 52. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03051217.

Certolizumab Pegol in Japanese Patients with Moderate to Severe Plaque Psoriasis: Effect of Demographics and Baseline Disease Characteristics on Efficacy.

INTRODUCTION: We present certolizumab pegol (CZP) efficacy data across patient demographic and baseline disease characteristic subgroups from a phase 2/3 trial investigating CZP treatment in Japanese patients with moderate to severe plaque psoriasis (PSO; ClinicalTrials.gov identifier: NCT03051217). METHODS: Patients were randomised 1:2:2 to placebo once every 2 weeks (Q2W), CZP 400 mg Q2W and CZP 200 mg Q2W (400 mg weeks 0, 2 and 4) for 16 weeks. Patients who achieved ≥ 50% reduction in their baseline Psoriasis Area and Severity Index (PASI 50) score at week 16 continued therapy to week 52. PASI 75/90 (75% and 90% reduction, respectively) and Physician's Global Assessment (PGA) 0/1 responder rates at weeks 16 and 52 were reported for patient demographic and baseline disease characteristic subgroups, including body mass index (BMI), PASI, disease duration and prior biologic use. Non-responder imputation was used. RESULTS: Of the randomised patients, 2/26 patients in the placebo group, 47/53 patients in the CZP 400 mg Q2W group and and 39/48 patients in the CZP 200 mg Q2W group completed week 52. In the subgroups evaluated, week 16 efficacy was generally maintained through week 52. At week 52, PASI 75 was achieved by 84.2, 85.7 and 80.0% of patients receiving CZP 400 mg Q2W in the low (15.0-23.7 kg/m2)/intermediate (> 23.7-27.4 kg/m2)/high (> 27.4-47.0 kg/m2) BMI subgroups, respectively, and by 77.8, 70.6 and 69.2%, respectively of patients treated with CZP 200 mg Q2W. PASI 75 at week 52 was achieved by 92.9, 75.0 and 84.2% of patients receiving CZP 400 mg Q2W in the low (12.0-18.0)/intermediate (> 18.0-27.0)/high (> 27.0-67.2) baseline PASI subgroups, respectively, and by 85.0, 58.3 and 68.8% of patients receiving CZP 200 mg Q2W, respectively. Similar responses were observed across other subgroups evaluated for both CZP doses in PASI 75/90 and PGA 0/1. CONCLUSION: Clinically meaningful improvements in signs and symptoms of PSO were maintained through week 52 for CZP dosed at 400 mg Q2W or 200 mg Q2W, across patient subgroups. In general, a numerically greater response was observed for patients receiving CZP 400 mg Q2W versus those receiving CZP 200 mg Q2W across patient subgroups. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03051217.

Certolizumab Pegol for the Treatment of Moderate to Severe Plaque Psoriasis: 16-Week Results from a Phase 2/3 Japanese Study.

INTRODUCTION: Certolizumab pegol (CZP), the Fc-free, PEGylated anti-tumor necrosis factor, is approved for the treatment of moderate to severe plaque psoriasis (PSO) in Western countries and in Japan, among other indications. METHODS: We report results from the first 16 weeks of a 52-week phase 2/3 trial of CZP in Japanese patients with PSO. Patients ≥ 20 years with PSO ≥ 6 months (Psoriasis Area and Severity Index [PASI] ≥ 12, body surface area affected ≥ 10%, and Physician's Global Assessment [PGA] ≥ 3 on a 5-point scale) were randomized 2:2:1 to CZP 400 mg every 2 weeks (Q2W), CZP 200 mg Q2W (400 mg weeks 0/2/4), or placebo Q2W. Outcomes assessed to week 16: PASI 75, PASI 90, PGA 0/1 (Markov chain Monte Carlo), Dermatology Life Quality Index (DLQI 0/1) and Itch Numeric Rating Scale (INRS 0) (non-responder imputation), and DLQI and INRS change from baseline (last observation carried forward). Safety data were reported for patients receiving ≥ 1 dose of study medication through weeks 0-16; adverse events were evaluated using Medical Dictionary for Regulatory Activities version 18.1. RESULTS: A total of 127 patients were randomized to CZP 400 mg Q2W (N = 53), CZP 200 mg Q2W (N = 48), placebo (N = 26). Week 16 responder rates for CZP 400 mg/200 mg Q2W versus placebo were 87.1%/73.0% versus 7.9% for PASI 75; 75.7%/53.8% versus 0.2% for PASI 90; 66.7%/52.7% versus 0.0% for PGA 0/1 (all p < 0.0001 for both CZP doses versus placebo). Significant improvements in DLQI and INRS were reported at week 16 by patients receiving both CZP doses compared with placebo (p < 0.0001). Incidence of treatment-emergent adverse events within the CZP 400 mg Q2W, CZP 200 mg Q2W, and placebo groups were 326.1, 404.9, and 682.4 per 100 patient-years. No new safety signals were identified compared to previously reported data. CONCLUSION: CZP dosed at 400 mg or 200 mg Q2W was associated with improved PSO signs and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03051217.

Relationship between serum trough levels and efficacy of brodalumab from a post hoc exploratory analysis of a Japanese study in patients with plaque psoriasis.

Previous clinical studies have shown that efficacy and serum brodalumab levels are dose dependent in patients with psoriasis receiving the same dose of brodalumab during the study. This study aimed to investigate the association between dosage, serum levels, and efficacy of brodalumab in Japanese patients with plaque psoriasis with dosage variations during the study. This was a post hoc exploratory analysis of a 108-week, multicenter, open-label extension study, which changed into a post-marketing surveillance study following brodalumab approval in Japan. Eligible patients with plaque psoriasis (n = 129) received brodalumab 140 mg every 4 weeks on Day 1; dosage change at physician's discretion from 140 mg every 8 weeks to 210 mg every 2 weeks was permitted; patients switched to 210 mg every 2 weeks during the post-marketing surveillance study. Exploratory endpoints included serum brodalumab levels at Weeks 28 and 108, its association with Psoriasis Area and Severity Index score, and Psoriasis Area and Severity Index score in patients receiving brodalumab 210 mg every 2 weeks at end of study. Median brodalumab trough levels were significantly higher (P < 0.05) at higher vs. lower dosages at Weeks 28 (n = 126) and 108 (n = 111) except for 140 mg every 2 weeks vs. 210 mg every 2 weeks at Week 108 and higher in patients with lower Psoriasis Area and Severity Index scores-significantly different only for Psoriasis Area and Severity Index score 0 vs. >2 at Week 28 (P = 0.0153). Of 100 patients receiving 210 mg every 2 weeks at end of study, 89% had a Psoriasis Area and Severity Index score ≤2. In patients with plaque psoriasis, brodalumab efficacy may depend upon sustained serum trough levels and can be restored by using the approved dose.