Eczema Area Research Articles

Half-life-extended Monoclonal Antibody APG777 for Atopic Dermatitis: Design of the Phase 2 APEX Study

Introduction: Current treatments for moderate-to-severe atopic dermatitis (AD) include topical and systemic therapies. The latter includes monoclonal antibodies (mAbs) targeting the IL-13 pathway, which is implicated in AD pathophysiology. While currently available mAbs directed against the IL-13 pathway have demonstrated efficacy for AD, they require ongoing injections every 2 or 4 weeks. APG777 is a humanized, anti-IL-13 mAb that binds IL-13 and blocks downstream signaling mediated by the IL-13Rα1/IL-4Rα complex. APG777 contains amino acid modifications designed to extend plasma half-life through increased FcRn-mediated antibody recycling. Interim results from an ongoing phase 1 study in healthy participants suggest a favorable safety and PK/PD profile for APG777, and a half-life of approximately 75 days. Methods: APEX (NCT06395948) is a 2-part, multicenter, phase 2, randomized, double-blinded, placebo-controlled clinical trial evaluating the efficacy and safety of APG777 in adults with moderate-to-severe AD. Adults (≥18 years of age) are eligible to participate if they have a diagnosis of AD for ≥1 year prior to screening and exhibit moderate-to-severe AD (EASI ≥16, IGA ≥3, BSA ≥10%) at both screening and baseline visits. Part A of the study (proof-of-concept) is evaluating the efficacy and safety of one induction dose regimen of APG777 compared with placebo over 16 weeks; this is followed by a 36-week maintenance period. Part B (dose-regimen finding) will evaluate different dose regimens of APG777 compared with placebo over 16 weeks followed by a 36-week maintenance period. Participants completing the maintenance period of Part A or B of the study will be eligible to enroll in a separate long-term extension study or enter the post-treatment follow-up period (up to 52 weeks). The primary outcome measure for the study is the percentage change from baseline to week 16 in the Eczema Area and Severity Index (EASI). The APEX study is currently enrolling.

Efficacy and Safety of Ruxolitinib Cream by Anatomic Region in Children Aged 2 to 11 Years With Atopic Dermatitis: Results From TRuE-AD3

Atopic dermatitis (AD) is a chronic, pruritic inflammatory skin disease. Ruxolitinib (Janus kinase [JAK]1/JAK2 inhibitor) cream has demonstrated efficacy and safety in patients aged ≥2 years with AD. In adolescents (aged ≥12 y) and adults with AD, application of ruxolitinib cream resulted in significant improvements across all anatomic regions vs vehicle. The objective of this analysis was to evaluate the efficacy and safety of ruxolitinib cream by anatomic region in the randomized, double-blind, phase 3 TRuE-AD3 study (NCT04921969). Children aged 2–11 years with AD for ≥3 months and an Investigator’s Global Assessment score of 2/3 were randomized 2:2:1 to apply 0.75% or 1.5% ruxolitinib cream twice daily (BID) or vehicle BID for 8 weeks. Efficacy was evaluated using the Eczema Area and Severity Index (EASI) subscores for head/neck, trunk, upper limbs, and lower limbs. Of 330 patients in TRuE-AD3, the mean (SD) age was 6.5 (2.9) years, and 179 patients (54.2%) were female; the mean (SD) EASI score was 8.6 (5.4). Improvements in EASI score were demonstrated with 0.75% and 1.5% ruxolitinib cream vs vehicle at first observation (Week 2), with statistically significant differences (at 0.05 alpha level and all P values below are nominal) at Week 8 in the head and neck (−0.63 [P=0.0108] and −0.70 [P=0.0011] vs −0.41), trunk (−0.98 [P=0.0310] and −1.18 [P=0.0003] vs −0.70), upper limbs (−1.81 [P<0.0001] and −2.06 [P<0.0001] vs −1.18), and lower limbs (−2.91 [P<0.0001] and −3.23 [P<0.0001] vs −1.43). Improvements in induration/papulation/edema, erythema, excoriation, and lichenification were observed for both strengths of ruxolitinib cream vs vehicle in all regions at Week 2, with statistical significance (at 0.05 alpha level) in nearly all AD signs and regions at Week 8. Ruxolitinib cream was well tolerated in both treatment groups (n=264), with 4.5% of patients experiencing application site reactions, which was similar to the frequency of application site reactions (4.3%) among patients with head/neck involvement (n=161) . In conclusion, ruxolitinib cream demonstrated significant improvements in AD vs vehicle in children with AD across anatomic regions, including on the head/neck, and was well tolerated. (Funding, Incyte Corporation)

Dupilumab Demonstrates a Higher Likelihood of Achieving Improvements in Signs, Symptoms, and Quality of Life vs. Tralokinumab at Week 16: Results from a Bucher Indirect Treatment Comparison

Background: Dupilumab and tralokinumab are biologics approved by the US Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD), aged ≥6 months and ≥12 years, respectively. Dupilumab and tralokinumab have demonstrated efficacy and safety in clinical trials. However, no direct head-to-head trials have been performed to compare the efficacy of dupilumab vs tralokinumab. The Bucher indirect treatment comparison (ITC) is a robust, placebo-adjusted, and accepted method to evaluate the relative efficacy of drugs in the absence of direct comparisons. The objective of this analysis was to report results from a Bucher ITC comparing the efficacy of dupilumab+topical corticosteroid (TCS) vs tralokinumab+TCS at Week 16. Methods: The placebo-adjusted Bucher ITC included published data from the two similarly designed phase 3 trials, LIBERTY AD CHRONOS (NCT02260986) and ECZTRA 3 (NCT03363854). For both studies, data from the 16-week period were used, employing non-responder imputation, with the following doses: 300mg dupilumab every 2 weeks (q2w)+TCS or placebo+TCS, and 300mg tralokinumab q2w+TCS or placebo+TCS. The evaluated endpoints included the proportions of patients achieving an Investigator’s Global Assessment score 0/1 (IGA 0/1; clear/almost clear), 75% and 90% improvements from baseline in Eczema Area and Severity Index (EASI-75 and EASI-90), ≥4-point improvement from baseline in the Peak Pruritus Numerical Rating Scale score (PP-NRS >4), and ≥4-point improvement from baseline in the Dermatology Life Quality Index (DLQI >4). The Bucher ITC with the frequentist approach was performed using R software (v 4.20; netmeta package) with a fixed-effect model. Results were reported as odds ratio (OR) with 95% confidence interval (CI). Results: A total of 801 patients (LIBERTY AD CHRONOS: placebo+TCS: 315; dupilumab+TCS: 106; ECZTRA 3: placebo+TCS: 127; tralokinumab+TCS: 253) were included in the Bucher ITC. Baseline disease characteristics indicated comparable severity between the two trial populations based on IGA and PP-NRS. However, CHRONOS showed slightly higher baseline EASI scores (median [Q1, Q3] score 30.9 [22.3, 41.6] vs. ECZTRA 3: 24.7 [18.4, 35.9]), while ECZTRA 3 showed slightly higher DLQI scores (median [Q1, Q3] score 18.0 [12.0, 23.0] vs. CHRONOS: 13.5 [8.0, 20.0]). Patients treated with dupilumab+TCS had a significantly higher likelihood of achieving IGA 0/1 (OR=2.49, 95%CI 1.24–5.00), EASI-75 (OR=3.21, 95%CI 1.66–6.19), EASI-90 (OR=2.92, 95%CI 1.41–6.02), PP-NRS ≥4 (OR=3.62, 95%CI 1.87–7.00), and DLQI ≥4 (OR=2.16, 95%CI 1.03–4.54) at Week 16 vs those treated with tralokinumab+TCS. Conclusions: A placebo-adjusted Bucher ITC showed that the likelihood of achieving improvements in signs, symptom, and quality of life is significantly higher for patients treated with dupilumab+TCS vs tralokinumab+TCS at Week 16.

Switching from Dupilumab to Upadacitinib in Adults and Adolescents with Moderate-to-Severe Atopic Dermatitis and Inadequate Response to Dupilumab: Efficacy and Safety Results from the Phase 3b/4 LEVEL UP Study

Atopic dermatitis (AD) is a chronic skin disease characterized by intense itch and eczematous skin lesions. Upadacitinib (UPA), a selective oral Janus kinase (JAK) inhibitor, and dupilumab (DUPI), a monoclonal antibody targeting interleukin-4 and interleukin-13 signaling, are both approved treatments for moderate-to-severe AD. LEVEL UP is a phase 3b/4 efficacy assessor blinded monotherapy study comparing UPA to DUPI for treatment of moderate-to-severe AD in adults and adolescents over a 16-week period (Period 1). Patients not achieving ≥75% improvement in the Eczema Area and Severity Index (EASI 75) from baseline at Week 16 entered an additional 16-week extension phase (Period 2). In Period 2, patients either continued/escalated to UPA 30 mg (UPA/UPA 30) or switched from DUPI to UPA 15 mg (DUPI/UPA), with the potential to escalate to 30 mg based on clinical response. Efficacy for skin and itch outcomes in Period 2 were assessed using observed case analysis while on treatment, without statistical comparisons. Here we report efficacy and safety results for the DUPI/UPA switch group. A total of 355 patients who did not achieve EASI 75 at Week 16 entered Period 2 of the study (DUPI/UPA, N=208). At Week 32, response rates in the DUPI/UPA group were: 79.6%, 58.7%, and 19.9% achieving EASI 75, EASI 90, and EASI 100, respectively; 60.2% achieving WP-NRS improvement ≥4 among those with baseline WP-NRS ≥4; 37.0% achieving WP-NRS 0/1 among those with baseline WP-NRS >1; and 26.8% simultaneously achieving EASI 90 and WP-NRS 0/1 by Week 32. Clinically meaningful outcomes were also observed at an earlier visit (Week 20). No new safety signals through Week 32 were identified compared to the established safety profile of UPA. Most patients with an inadequate response to DUPI at Week 16 experienced clinically meaningful improvements in skin clearance and itch at 4 weeks post-switch to UPA, with additional patients achieving these outcomes by 16 weeks post-switch. These findings suggest that switching from DUPI to UPA is an effective treatment strategy for patients who do not meet moderate or optimal treatment targets with DUPI.

Achievement of No-to-minimal Itch and Sleep Improvement with Tapinarof Cream 1% Once Daily in Two Pivotal Phase 3 Trials in Adults and Children Down to 2 Years of Age with Atopic Dermatitis

Introduction: Itch frequently causes sleep disturbance in patients with atopic dermatitis (AD). The gold-standard Peak Pruritus Numerical Rating Scale (PP-NRS) improvement from baseline is 4 points; however, more stringent outcomes include achieving no-to-minimal itch (PP-NRS ≤1). Tapinarof cream 1% once daily (QD) demonstrated superior efficacy, including itch reduction, versus vehicle and was well tolerated in adults and children down to 2 years of age with AD in the ADORING 1 and 2 pivotal phase 3 trials. Here we present highly stringent itch outcomes and sleep improvement with tapinarof from these trials. Methods: In ADORING 1 and 2, patients with a Validated Investigator Global Assessment for Atopic Dermatitis™ score ≥3 (moderate or severe), Eczema Area and Severity Index score ≥6, and body surface area involvement of 5–35% were randomized to tapinarof cream or vehicle QD for 8 weeks. Stringent PP-NRS assessments were analyzed post hoc and included achieving no‑to‑minimal itch (PP-NRS ≤1) or PP-NRS score <2. Mean weekly PP-NRS scores were assessed on an 11-point scale (0 indicates “no itch” and 10 is “worst imaginable itch”). The Patient Oriented Eczema Measure (POEM) question 2 evaluated sleep disturbance on a 5-point scale (0 indicates “no days” and 4 is “every day”); outcomes were pooled and stratified by age. Results: 407 and 406 patients were randomized in ADORING 1 and 2. Mean baseline scores were similar across ADORING 1 and 2 treatment groups: PP-NRS, 6.7 and 6.8; pooled POEM sleep disturbance scores, 2.0 (aged ≥12 years) and 2.4 (<12 years), respectively. Statistically significant achievement of no-to-minimal itch (PP-NRS ≤1), PP-NRS <2, and improvement in sleep were achieved with tapinarof versus vehicle as early as Week 1, the first assessment, and continued through Week 8. Stringent itch outcomes were achieved with tapinarof versus vehicle at Week 8: no-to-minimal itch, 31.4% versus 17.4% (P=0.0072) and 33.0% versus 14.0% (P=0.0003); and PP-NRS <2, 48.1% versus 28.4% (P=0.0006) and 46.8% versus 19.6% (P<0.0001) in ADORING 1 and 2, respectively. Sleep scores improved with tapinarof versus vehicle at Week 8: –1.4 versus –0.8 (≥12 years); –1.7 versus –1.0 (<12 years; both P<0.0001). Conclusion: Tapinarof cream 1% QD demonstrated early, significant, and meaningful achievement of no-to-minimal itch and improvement of sleep in adults and children down to 2 years of age with AD.

Long-Term Maintenance of Optimal Treatment Targets for Skin and Itch Outcomes With Upadacitinib in Moderate-to-Severe Atopic Dermatitis: 140-Week Results From the Phase 3 Measure Up 1 and 2 Studies

Introduction: Despite undergoing prolonged systemic therapy, many patients with moderate-to-severe atopic dermatitis (AD) do not achieve optimal targets for skin and itch outcomes as defined by Aiming High in Eczema/AD (AHEAD) recommendations (eg, ≥90% improvement from baseline in Eczema Area and Severity Index [EASI 90] and Worst Pruritus Numerical Rating Scale [WP-NRS] score of 0/1 [no/minimal itch]). We evaluated long-term maintenance of optimal treatment targets with upadacitinib, an oral selective JAK inhibitor approved for moderate-to-severe AD in adolescents and adults. Methods: This 140-week interim analysis included adolescents and adults with moderate-to-severe AD who were randomized at baseline to upadacitinib 15 mg (UPA15) or 30 mg (UPA30) in the ongoing, phase 3, double-blind Measure Up 1 and 2 studies. Assessments included the proportion of patients (at the population level) who maintained EASI 90, WP-NRS 0/1, or simultaneous achievement of EASI 90 + WP-NRS 0/1 responses from week 16 (end of the placebo-controlled period) onwards. Data are reported as observed cases with no imputation for missing data. Results: Among patients who achieved EASI 90 at week 16 (UPA15, n=298; UPA30, n=384), EASI 90 was maintained by 79.8% (UPA15) and 83.7% (UPA30) at week 52, 76.7% (UPA15) and 83.0% (UPA30) at week 100, and 74.0% (UPA15) and 84.2% (UPA30) at week 140. Of patients achieving WP-NRS 0/1 at week 16 (UPA15, n=193; UPA30, n=281), WP-NRS 0/1 was maintained by 69.4% (UPA15) and 72.0% (UPA30) at week 52, 65.6% (UPA15) and 68.4% (UPA30) at week 100, and 62.3% (UPA15) and 66.0% (UPA30) at week 140. Of patients simultaneously achieving EASI 90 + WP-NRS 0/1 at week 16 (UPA15, n=156; UPA30, n=243), maintenance was achieved by 68.1% (UPA15) and 70.8% (UPA30) at week 52, 62.7% (UPA15) and 66.5% (UPA30) at week 100, and 58.7% (UPA15) and 64.4% (UPA30) at week 140. Among patients who did not maintain optimal outcomes, most still achieved clinically meaningful responses. Conclusion: Most patients maintained optimal skin and itch outcomes through 140 weeks of upadacitinib treatment, demonstrating its potential to provide sustained long-term disease control in atopic dermatitis.

Effect of house dust mite sublingual immunotherapy in patients with adult atopic dermatitis with rhinitis.

Aim: Whether house dust mite (HDM) sublingual immunotherapy (SLIT) is effective for the skin symptoms of adult atopic dermatitis (AD) is unclear.Methods: HDM SLIT was added to conventional AD treatment for 10 HDM-sensitized AD patients with rhinitis for 2years.Results: Seven out of ten enrolled patients completed the study. Eczema Area and Severity Index score was significantly reduced when comparing before treatment and at 24months follow-up. CD203c ratio in the basophil activation test using HDM extract, skin prick test with HDM extract and Dermatophagoides pteronyssinus/Dermatophagoides farinae specific-IgG4 tended to improve when comparing before treatment and after treatment.Conclusion: HDM SLIT might be a therapeutic option for AD patients with rhinitis who are sensitized to HDM.

Efficacy and safety of tozorakimab in moderate-to-severe atopic dermatitis: A Phase 2a randomized controlled trial (FRONTIER-2).

Atopic dermatitis (AD) is a chronic, inflammatory skin disease characterized by intense pruritus and eczematous lesions. Tozorakimab is a high-affinity human monoclonal antibody that neutralizes interleukin-33, a broad-acting alarmin cytokine that is over-expressed in keratinocytes of patients with AD. This Phase 2a study (FRONTIER-2; NCT04212169) evaluated the safety and efficacy of tozorakimab in adults with moderate-to-severe AD. FRONTIER-2 was a randomized, placebo-controlled, parallel-group, double-blind study conducted from 9 December 2019 to 20 September 2022 at 32 centres across six countries. Patients were randomized 3:1:1:3 to receive placebo, tozorakimab 60 mg, tozorakimab 300 mg or tozorakimab 600 mg by subcutaneous injection once every 4 weeks for four doses. The primary endpoint was percentage change from baseline to Week 16 in the Eczema Area and Severity Index (EASI) score in patients treated with tozorakimab versus placebo. Secondary outcomes included EASI-75 responders (patients achieving ≥75% reduction from baseline in EASI score), Investigator's Global Assessment (IGA) responders (patients achieving an IGA score of 0 or 1), pharmacokinetics, immunogenicity and safety. Overall, 148 patients were randomized. There was no statistically significant difference in the primary endpoint (60 mg difference of 1.3 [90% confidence interval (CI): -13.7, 16.2], p = 0.888; 300 mg: difference of 5.9 [90% CI: -10.4, 22.1], p = 0.549; 600 mg: difference of - 1.7 [90% CI: -13.4, 10.0], p = 0.807). The proportion of EASI-75 and IGA 0/1 responders at Week 16 was numerically higher in the tozorakimab 600 mg group than in the placebo group (EASI-75: 18.2% vs. 7.1%, p = 0.094; IGA 0/1: 9.1% vs. 1.8%, p = 0.113). Serum pharmacokinetics were dose-dependent, immunogenicity incidence was low and tozorakimab was well tolerated. FRONTIER-2 did not show a statistically significant difference in the primary endpoint for tozorakimab compared with placebo. However, numerical increases in responder rates were observed.

Rocatinlimab Improves Patient-Reported Outcomes in Adults with Moderate-to-Severe Atopic Dermatitis: Results from a Double-Blind Placebo-Controlled Phase2b Study.

In adults with moderate-to-severe atopic dermatitis (AD), rocatinlimab demonstrated significant and progressive improvement in clinical measures of disease severity compared with placebo. This post hoc analysis of a phase2b study was undertaken to understand the disease burden and to assess the impact of rocatinlimab on patient-reported outcomes (PROs). This analysis used baseline data from a multicenter, randomized, double-blind study of adults with moderate-to-severe AD, who completed a Worst Pruritus numerical rating scale (NRS), Sleep Disturbance NRS, and the Dermatology Life Quality Index (DLQI). A mixed model for repeated measures was used to estimate changes in PRO scores from baseline; scores were also compared with clinically meaningful change benchmarks. The analysis included 267 subjects, mean (SD) age 37.9 (14.7) years, 40.8% female; 55.1% grade3 and 44.9% grade4 Investigator Global Assessment for AD. Mean (SD) scores were: Worst Pruritus NRS 7.5 (1.9), Sleep Disturbance NRS 5.5 (2.9), DLQI total score 12.6 (7.1). Worst Pruritus and Sleep NRS scores had low positive correlations with SCORing AD (SCORAD) score (r = 0.44, r = 0.45 respectively) and negligible correlations with Eczema Area and Severity Index (EASI) score and area affected (r < 0.30). DLQI score varied by sex, study country, race, age, longer disease duration, disease severity (EASI and SCORAD), presence of asthma, and Worst Pruritus NRS, Sleep disturbance NRS, and DLQI scores. Rocatinlimab showed benefit on all three PROs, with significant improvements from baseline at the end of the double-blind period (week18) and active treatment extension (week36). Benefits were maintained over 20weeks' post-treatment follow-up. The benefit of rocatinlimab treatment on PROs is rapid and maintained for at least 20weeks following treatment completion. This analysis demonstrates the importance of characterizing the burden of moderate-to-severe AD from the patient's perspective, alongside clinical disease measures, to develop a fuller picture of treatment benefit. ClinicalTrials.gov identifier, NCT03703102.

Durable improvements in atopic dermatitis in the head and neck and across other anatomic regions with rocatinlimab

In a randomized phase 2b trial (NCT03703102) for adult patients with moderate-to-severe atopic dermatitis (AD), treatment with the T cell rebalancing anti-OX40 receptor antibody rocatinlimab (AMG 451/KHK4083) led to significant improvements in clinical measurements versus placebo including whole-body Eczema Area and Severity Index (EASI) score. AD manifestations can impact variable anatomic regions, and involvement of the head and neck, a sensitive, hard-to-treat area, can negatively impact quality of life. In this post hoc analysis, we investigated response to rocatinlimab treatment across anatomic regions, including the head and neck. Least squares mean change from baseline to Week 56 in EASI score was analyzed by anatomic region (head and neck, trunk, upper extremities, or lower extremities) for patients with baseline moderate-to-severe AD in the respective anatomic region, using mixed models for repeated measures. Rocatinlimab groups were compared with placebo at Week 16. The proportion of patients achieving at least 75% reduction from baseline in EASI (EASI-75) was calculated. Probability of relapsing in EASI-75 during the off-treatment follow-up period (Weeks 36–56) was estimated using a Kaplan − Meier approach. At Week 16, decrease from baseline in mean EASI score was greater with all rocatinlimab regimens versus placebo across all anatomic regions for patients with baseline moderate-to-severe AD in the respective region (all P < 0.001). EASI scores continued to improve on treatment after Week 16 and were maintained during the off-treatment period across all regions. Among patients with baseline moderate-to-severe AD in the head and neck (n = 219; rocatinlimab, n = 174; placebo, n = 45), mean difference (rocatinlimab vs placebo) at Week 16 in LS mean percent change in head and neck EASI score ranged from − 30.4% to − 42.6% across treatment regimens. In patients who received rocatinlimab from the start of the trial, 47% − 71% achieved EASI-75 in the head and neck at Week 36. Among EASI-75 responders at Week 36, the probability of relapsing in EASI-75 in any region was low (< 25% in the head and neck) 20 weeks after treatment discontinuation until Week 56.Rocatinlimab treatment led to durable improvements in AD across multiple anatomic regions, including the sensitive head and neck region.Graphical abstract

Efficacy and Safety of Lebrikizumab in Atopic Dermatitis: A Systematic Review and Meta-analysis

Background: Atopic Dermatitis (AD) is a long-lasting dermatological condition that leads to skin irritation and inflammation. In cases of severe cases of AD biological therapy may be warranted. In this systematic review and meta-analysis, we aim to assess the efficacy and safety of Lebrikizumab, an IL-13 immunomodulator. Methodology: A systematic search was used in the following databases Medline, Scopus, Clinical Trials.gov registry (CT.gov), EBSCO, Science Direct, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar. The efficacy of Lebrikizumab was evaluated by using some measures such as Investigator’s Global Assessment (IGA), Body Surface Area (BSA), and Eczema Area and Severity Index (EASI). The measures namely serious adverse events (SAEs), and non-serious adverse events (NSAEs) were used to assess the safety. The risk of bias was determined by the Revised Cochrane risk of bias tool. Results: Four randomized controlled trials (RCTs) were included in our meta-analysis with a total of 1,686 patients who had taken lebrikizumab (n =1,168) compared with placebo (n= 518). The total analysis demonstrated a decrease in the area and severity of eczema as measured by EASI when using lebrikizumab, this decrease was statistically significant compared to placebo (mean difference (MD): -25.60, 95% CI [-38.01, -13.18], P &lt; 0.0001), statistically significant enhancement in the Change of BSA with lebrikizumab compared to placebo (MD: -9.81, 95% CI [-15.39, -4.23], P &lt; 0.0006), and significant enhancement in the EASI 75 score with lebrikizumab compared to placebo (Risk Ratio (RR):2.60, 95% CI [2.17, 3.13], P &lt; 0.00001). Lebrikizumab did not correlate significantly with the incidence of NSAEs and SAEs as concluded by the pooled analysis of safety. Conclusion: Lebrikizumab has demonstrated promise as a treatment option for AD. It has shown significant effectiveness across various measures and has exhibited a favourable safety profile. Future research is required to evaluate long-term safety and efficacy.

Treatment of atopic dermatitis with abrocitinib in real practice in Spain: efficacy and safety results from a 24-week multicenter study.

Abrocitinib, a selective JAK 1 inhibitor, was recently approved in Europe. Despite its approval, real-world data on its efficacy and safety in treating moderate-to-severe atopic dermatitis (AD) remains limited. This study aimed to evaluate the short-term effectiveness and safety of abrocitinib in a real-life setting for patients with moderate-to-severe AD. We conducted a retrospective multicenter study involving adult patients with moderate-to-severe AD who started abrocitinib treatment between May 1, 2023, and September 30, 2023, in 15 Spanish hospitals. Treatment doses were 100 or 200 mg daily, based on clinical assessment. Data collection included patient demographics, AD history, comorbidities, previous treatments, and disease severity indicators such as SCORing atopic dermatitis (SCORAD), Eczema Area and Severity Index (EASI), body surface area, and Peak Pruritus NRS scores at baseline, 4, 12, and 24 weeks. Quality of life was measured using the Dermatology Life Quality Index (DLQI), and safety was assessed by monitoring adverse reactions and various biochemical parameters. The cohort comprised 76 patients with an average age of 33.93 years; 57.89% were male. Before abrocitinib, 36.84% were naïve to advanced therapies. The baseline mean scores were SCORAD 47.04, EASI 21.79, and DLQI 15.01. At Week 24, there were significant improvements: EASI was reduced to 2.81, and 70.58% of the patients achieved EASI 75. However, 18.42% discontinued treatment mainly due to inefficacy or adverse effects. The safety profile was favorable, with 22.37% reporting mild adverse events (AEs) and one serious case of cutaneous lymphoma. This first Spanish series assessing abrocitinib in real-world conditions reveals a significant improvement in AD symptoms and quality of life in a range of severity and prior treatment failures. Abrocitinib was well-tolerated, with few serious AEs, highlighting its potential as an effective treatment option for AD.

Phase 2b randomized clinical trial of amlitelimab, an anti-OX40 ligand antibody, in patients with moderate-to-severe atopic dermatitis

Amlitelimab, a fully human nondepleting monoclonal antibody targeting OX40 ligand on antigen-presenting cells, could prevent T-cell-driven inflammation seen in atopic dermatitis (AD). This trial evaluated the efficacy and safety of amlitelimab in adults with AD. In this 2-part, phase 2b, randomized, double-blinded placebo-controlled trial (NCT05131477), patients received subcutaneous amlitelimab every 4 weeks at doses of 250 mg with 500-mg loading dose, 250 mg, 125 mg, or 62.5 mg, or placebo for 24 weeks in Part 1 (1:1:1:1:1 randomization). In Part 2, clinical responders were reallocated 3:1 to withdraw amlitelimab or continue the previous dose regimen for 28 weeks. The primary end point was percent change in Eczema Area and Severity Index (EASI) from baseline to Week 16. 390 and 190 patients enrolled in Part 1 and Part 2, respectively. Significant percent change decreases in EASI were observed with amlitelimab vs. placebo (P<.001). Clinical responses at Week 24 (Investigator Global Assessment 0/1 and/or EASI-75) were maintained at Week 52 in patients continuing or withdrawn from amlitelimab. In patients maintaining clinical response at Week 52 while off-treatment, >80% had serum amlitelimab concentrations below a 4-μg/mL threshold for several weeks prior to Week 52. Reductions in AD-related biomarkers during Part 1 were maintained through Part 2. Amlitelimab was well tolerated over 52 weeks. Amlitelimab treatment significantly reduced clinical and biomarker responses, and was well tolerated in adults with AD through Week 52. Sustained responses were observed in the majority of patients after amlitelimab withdrawal for 28 weeks.

Cost-Effectiveness Study of Difamilast 1% for the Treatment of Atopic Dermatitis in Adult Japanese Patients.

Difamilast has proven to be an effective treatment for the treatment of atopic dermatitis (AD) in Japan, but its cost-effectiveness remains unknown. Therefore, the objective of the current study was to determine the cost-effectiveness of difamilast 1% compared with delgocitinib 0.5% in Japanese adult patients with moderate-to-severe AD and compared with placebo in Japanese adult patients with all-severity AD from a Japanese public health-care perspective. The analysis was conducted using a cost-effectiveness model from the Japanese public health-care perspective. This model had four health states ("clear," "mild," "moderate," and "severe") defined according to the Eczema Area and Severity Index score. The time horizon of the analysis was 1year. Because the analysis period was short, no discount rate was applied. The proportions of patients previously estimated by the anchored matching-adjusted indirect comparison were implemented in the model. The model was further populated with data from the literature. The main model outcomes were quality-adjusted life-years (QALY), costs, and outcomes, including the incremental cost-effectiveness ratio. All prices were stated in JPY at the price level from 2018 April to 2019 March. One-way sensitivity analysisand probabilistic sensitivity analysis (PSA) were performed to assess the robustness of the results. In the base case, the cost-effectiveness of difamilast 1% compared with delgocitinib 0.5% and placebo was JPY 827,054/QALY and JPY 1,518,657/QALY, respectively. The PSA showed that the cost-effectiveness of difamilast 1% compared with delgocitinib 0.5% and placebo had a 66.6% and 99.6% probability of being below the JPY 5 million/QALY threshold, respectively. The results suggest that difamilast 1% is a more cost-effective treatment option compared with delgocitinib 0.5% in Japanese adult patients with moderate-to-severe AD and compared with placebo in adult patients with all-severity AD from a Japanese public health-care perspective.

Efficacy and Safety of Upadacitinib Versus Dupilumab Treatment for Moderate to Severe Atopic Dermatitis in Four Body Regions: Analysis From the Heads-Up Study.

Upadacitinib has demonstrated high and rapid rates of efficacy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) as assessed by the Eczema Area and Severity Index (EASI). This post hoc analysis assessed the EASI response in four anatomical regions for patients with moderate-to-severe AD treated with upadacitinib compared to dupilumab over 24 weeks. Data from patients randomised 1:1 to receive upadacitinib 30 mg extended-release tablet orally once daily or dupilumab 300 mg by subcutaneous injection every 2 weeks after a loading dose of 600 mg in the Heads Up study were analysed for achievement of ≥75%, ≥90%, or 100% reduction of EASI in four body regions: 1) head and neck, 2) trunk (including genitals), 3) upper limbs, and 4) lower limbs (including buttocks) at each study visit through week 24. Patient response data from the Head and Neck Patient Global Impression of Severity (HN-PGIS) were also analysed at each study visit for comparison of upadacitinib to dupilumab. Greater proportions of patients treated with upadacitinib versus dupilumab achieved skin clearance rates of ≥75% (EASI 75) at week 1 and higher clearance rates of ≥90% (EASI 90) or 100% (EASI 100) by week 4 or earlier in all four body regions. This difference was maintained at each visit through week 24 for both EASI 90 and EASI 100. Patient responses on the HN-PGIS indicated that a greater proportion of patients (nominal p-value <0.05) treated with upadacitinib compared to dupilumab reported that AD symptoms in the head and neck region were absent or minimal as early as week 1. Compared to dupilumab, upadacitinib treatment provided higher rates of rapid, sustained efficacy for the head and neck, trunk, upper limbs, and lower limbs for the treatment of moderate-to-severe AD as measured by the EASI and supported by patient responses.

Fecal microbiota transplantation against moderate-to-severe atopic dermatitis: A randomized, double-blind controlled explorer trial.

Fecal microbiota transplantation (FMT) is a novel treatment for inflammatory diseases. Herein, we assess its safety, efficacy, and immunological impact in patients with moderate-to-severe atopic dermatitis (AD). In this randomized, double-blind, placebo-controlled clinical trial, we performed the efficacy and safety assessment of FMT for moderate-to-severe adult patients with AD. All patients received FMT or placebo once a week for 3 weeks, in addition to their standard background treatments. Patients underwent disease severity assessments at weeks 0, 1, 2, 4, 8, 12, and 16, and blood and fecal samples were collected for immunologic analysis and metagenomic shotgun sequencing, respectively. Safety was monitored throughout the trial. Improvements in eczema area and severity index (EASI) scores and percentage of patients achieving EASI 50 (50% reduction in EASI score) were greater in patients treated with FMT than in placebo-treated patients. No serious adverse reactions occurred during the trial. FMT treatment decreased the Th2 and Th17 cell proportions among the peripheral blood mononuclear cells, and the levels of TNF-α, and total IgE in serum. By contrast, the expression levels of IL-12p70 and perforin on NK cells were increased. Moreover, FMT altered the abundance of species and functional pathways of the gut microbiota in the patients, especially the abundance of Megamonas funiformis and the pathway for 1,4-dihydroxy-6-naphthoate biosynthesis II. FMT was a safe and effective therapy in moderate-to-severe adult patients with AD; the treatment changed the gut microbiota compositions and functions.

Dupilumab is Efficacious in Young Children with Atopic Dermatitis Regardless of Type2 Comorbidities.

Patients with atopic dermatitis (AD) often have other comorbid type2 inflammatory conditions. The aim of this study was to evaluate the impact of type2 comorbidities on the response to and safety of dupilumab in young children with AD. LIBERTY AD PRESCHOOL partB was a randomized, placebo-controlled trial in children aged 6months to 5years with moderate-to-severe AD. In this posthoc analysis, patients were stratified by the presence or absence of caregiver-reported selected type2 comorbidities at baseline: asthma, allergic rhinitis (AR), and food allergies (FAs). At week16, significantly more patients receiving dupilumab versus placebo, with or without asthma and AR, achieved an Investigator's Global Assessment (IGA) score of 0/1 and a ≥ 75% improvement in Eczema Area and Severity Index (all p < 0.05). Significantly more patients receiving dupilumab versus placebo with FAs and numerically more patients without FAs achieved an IGA score of 0/1 (p = 0.0007 and p = 0.06). Numerically more patients receiving dupilumab versus placebo with asthma and significantly more patients without asthma achieved a ≥ 4-point reduction in the weekly average of daily score on the Worst Scratch/Itch Numeric Rating Scale (WSI-NRS) (p = 0.6 and p < 0.0001). Additionally, significantly more patients receiving dupilumab versus placebo with or without AR (p = 0.008 and p < 0.0001) and with or without FAs (p = 0.0002 and p = 0.004) achieved a ≥ 4-point reduction in the weekly average of daily score on the WSI-NRS. Overall safety was consistent with the known dupilumab safety profile. Dupilumab treatment improves AD signs and symptoms in children aged 6months to 5years with and without type2 comorbidities such as asthma, AR, and FAs. ClinicalTrials.gov registration number NCT03346434. Do type 2 comorbidities impact the response to dupilumab in children with atopic dermatitis? (MP4 103,451 KB).

Long-term efficacy and safety of stapokibart for moderate-to-severe atopic dermatitis: 52-week results from a phase 3 trial.

Management of moderate-to-severe atopic dermatitis (AD) needs long-term therapy. Stapokibart is a humanized monoclonal antibody targeting interleukin-4 receptor α subunit (IL-4Rα), a shared receptor for IL-4 and IL-13 which are key pathogenic drivers of AD. In a pivotal phase 3 trial (NCT05265923), significant higher proportions of adult AD patients receiving stapokibart than placebo achieved ≥75% improvement from baseline in Eczema Area and Severity Index (EASI-75; 66.9% vs. 25.8%) and Investigator's Global Assessment (IGA) score of 0/1 with ≥2-point reduction (44.2% vs. 16.1%) at Week 16. Herein, we report long-term (52 weeks) efficacy and safety of stapokibart from this trial. After 16-week double-blind treatment completed, patients in both stapokibart and placebo groups entered a 36-week maintenance treatment period and received stapokibart 300 mg every 2 weeks. Concomitant use of topical medications for AD was permitted throughout the maintenance period. Of 476 patients entering maintenance period, 430 completed the treatment. At Week 52, EASI-75 was achieved in 92.5% of patients continuing stapokibart and 88.7% of those switching from placebo to stapokibart, respectively; an IGA score of 0 or 1 with a ≥2-point reduction was achieved in 67.3% and 64.2% of patients, respectively; a ≥4-point reduction in weekly average of daily Peak Pruritus Numerical Rating Scale (PP-NRS) was achieved in 67.3% and 60.5% of patients, respectively. Over the 52-week treatment period, 88.1% of patients reported treatment-emergent adverse events, most were mild or moderate. Long-term treatment with stapokibart demonstrated a sustained efficacy and favorable safety profile in adults with moderate-to-severe AD.

The regulatory T cell-selective interleukin-2 receptor agonist rezpegaldesleukin in the treatment of inflammatory skin diseases: two randomized, double-blind, placebo-controlled phase 1b trials

Regulatory T cell (Treg) impairment is implicated in the pathogenesis of chronic inflammatory diseases, but relatively little is known about the therapeutic potential of Treg restoration. Here we present clinical evidence for the Treg-selective interleukin-2 receptor agonist rezpegaldesleukin (REZPEG) in two randomized, double-blind, placebo-controlled Phase 1b trials in patients with moderate-to-severe atopic dermatitis (AD) (NCT04081350) or chronic plaque psoriasis (PsO) (NCT04119557). Key inclusion criteria for AD included an Eczema Area and Severity Index (EASI) score ≥ 16 and a validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) ≥ 3, and for PsO included a Psoriasis Area and Severity Index (PASI) score of ≥ 12 and a static Physician’s Global Assessment (sPGA) score of ≥ 3. REZPEG is safe and well-tolerated and demonstrates consistent pharmacokinetics in participants receiving subcutaneous doses of 10 to 12 µg/kg or 24 µg/kg once every 2 weeks for 12 weeks, meeting the primary and secondary objectives, respectively. AD patients receiving the higher dose demonstrate an 83% improvement in EASI score after 12 weeks of treatment. EASI improvement of ≥ 75% (EASI-75) and vIGA-AD responses are maintained for 36 weeks after treatment discontinuation in 71% and 80% of week 12 responders, respectively. These exploratory clinical improvements are accompanied by sustained increases in CD25bright Tregs. REZPEG thus represents a homeostatic approach to cutaneous disease therapy and holds clinical potential in providing long-term, treatment-free disease control.

Upadacitinib in Adolescents With Moderate to Severe Atopic Dermatitis

The Measure Up 1, Measure Up 2, and AD Up studies demonstrated the efficacy and adverse events of upadacitinib through 52 weeks in adults and adolescents with atopic dermatitis (AD); however, longer-term outcomes (longer than 1 year) in adolescents have not previously been available. To evaluate the efficacy and adverse events of upadacitinib in adolescent patients with moderate to severe AD through 76 weeks. The Measure Up 1, Measure Up 2, and AD Up trials are ongoing double-blind, placebo-controlled phase 3 randomized clinical trials including adolescents (aged 12 to 17 years) with moderate to severe AD. Data were collected from August 2018 to April 2022, and data were analyzed from June 2022 to September 2023. Adolescents were randomized 1:1:1 to receive once-daily oral upadacitinib, 15 mg; upadacitinib, 30 mg; or placebo, either alone (Measure Up 1 and Measure Up 2 trials) or with topical corticosteroids (AD Up). At week 16, placebo-treated patients were rerandomized to receive upadacitinib, 15 mg, or upadacitinib, 30 mg, daily. Coprimary end points assessing efficacy included achievement of 75% reduction or more in the Eczema Area and Severity Index Score (EASI-75) from baseline, Validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score of clear (0) or almost clear (1) with 2 grades or more of improvement, and Worst Pruritus Numerical Rating Scale (WP-NRS) improvement of 4 points or greater through week 76 for participants with a WP-NRS score of 4 points or higher at baseline. From all studies, 542 adolescents were included; of these, 284 (52.4%) were female. At week 76, among patients in the Measure Up 1, Measure Up 2, and AD Up trials, EASI-75 was achieved by 89.1%, 84.4%, and 87.8% of adolescents taking upadacitinib, 15 mg, respectively, and by 96.1%, 93.6%, and 82.7% of adolescents taking upadacitinib, 30 mg, indicating maintenance or improvement of EASI-75 across 76 weeks with upadacitinib. Efficacy measured by achievement of vIGA-AD score of 0 or 1 and WP-NRS improvement of 4 points or more from baseline was similarly maintained or improved through week 76 for adolescents taking upadacitinib, 15 mg or 30 mg. Long-term outcomes in Measure Up 1, Measure Up 2, and AD Up participants were consistent with the known adverse event profile of upadacitinib (herpetic infection: 4.0, 1.9, and 1.1 events per 100 patient-years, respectively; creatine kinase elevation: 11.6, 11.0, and 7.1 events per 100 patient-years); no new signals were observed with either dose. In this study assessing 3 randomized clinical trials, long-term treatment of adolescents with moderate to severe AD with upadacitinib demonstrated a favorable benefit-risk profile, with sustained efficacy responses through 76 weeks. Measure Up 1 trial: ClinicalTrials.gov Identifier: NCT03569293; Measure Up 2 trial: NCT03607422; AD Up trial: NCT03568318.