Peak Pruritus Numerical Rating Scale Research Articles

Anti-Interleukin Biologics for the treatment of the Atopic March Diseases

The atopic march refers to the natural history of allergic disorders as they develop from infancy to childhood. Classically, the atopic march begins with atopic dermatitis (AD), followed by food allergy, advancing to asthma, allergic rhinitis (AR), and finally to the fifth member eosinophilic esophagitis. The pathogenesis of the atopic march is complex, and involves genetic, immunological, and environmental factors. T helper type 2 (Th2) lymphocytes, and epithelial cells play a key role in the pathogenesis of the diseases in the atopic march. Th2 cells secrete cytokines, such as interleukin-5 (IL-5), IL-4, and IL-13, whereas, epithelial cell injury release alarmin cytokines, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP). Th2 cells and alarmin cytokines play an important role in the development of eczematous skin lesions, airway inflammation and remodeling, and oesophageal mucosal inflammation. Treatment of eosinophilic asthma and associated comorbid disorders is challenging, and requires a precision targeted approach with biologics. Dupilumab is a fully humanized IgG4 monoclonal antibody to the IL-4Rα, which mediates signaling to both IL-4 and IL-13, and blocks their immunopathological effects. Dupilumab is the only biologic that has been approved for the treatment of eosinophilic asthma, AD, and eosinophilic esophagitis. In patients with eosinophilic asthma treatment with dupilumab has been shown to improve asthma control, reduce exacerbations, and improve lung function. In patients with atopic dermatitis dupilumab has been demonstrated to improve the Eczema Area Severity Index (EASI) score, Investigator’s Global Assessment (IGA) response, SCORing Atopic Dermatitis (SCORAD) score, and the Peak Pruritus Numerical Rating (PNR) scale. Lebrikizumab and Tralokinumab (anti-IL-13) failed to show the expected results for the treatment of asthma, astoundingly, in several clinical trials they have been shown to significantly improvement EASI score, IGA response, SCORAD score, PNR scale, sleep architecture, and Dermatology Life Quality Index (DLQI). They have been granted First Tract Designation, and European Commission regulatory approval, respectively. Tezepelumab (anti-TSLP) is approved for the treatment of eosinophilic asthma, and has been shown to significantly reduce exacerbations, and improve asthma control, lung function, and HLQoL. However, tezepelumab did not meet the endpoints in phase II for the treatment of AD. Keywords: Atopic March; Atopic Dermatitis; Eosinophilic Asthma; Interleukin; Dupilumab; Tralokinumab

Efficacy of biologics and oral small molecules for atopic dermatitis: a systematic review and meta-analysis

Background As new targeted therapies continue to emerge for atopic dermatitis (AD), comparisons between agents are necessary to inform clinical decision-making. Objectives Assess the efficacy of biologics and oral small molecules on the clinical signs, symptoms, and quality of life in AD. Methods A systematic literature review identified phase II and III randomized clinical trials of biologics and oral small molecules in AD. Clinical benefit was assessed for three outcome measures: Eczema Area and Severity Index (EASI), Dermatology Life Quality Index (DLQI), and Peak Pruritus Numerical Rating Scale (PP-NRS) by performing a meta-analysis using the inverse variance heterogeneity model ((IVhet)). Results The highest achievement of 75% reduction in EASI was seen with the higher dose of upadacitinib (30 mg) followed by abrocitinib and lebrikizumab, which outperformed dupilumab. Similarly, the highest proportion achieving at least a 4-point reduction of PP-NRS was seen with lebrikizumab followed by upadacitinib and abrocitinib which had greater reduction of itch than dupilumab. Abrocitinib had the greatest improvement in DLQI. Conclusions Upadacitinib, abrocitinib, and lebrikizumab had greater improvement of clinical signs, symptoms, and quality of life in AD compared to dupilumab and other targeted therapies.

Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis

Dupilumab subcutaneous injection is approved for treating moderate-to-severe atopic dermatitis (AD) in adolescents, but there has been too little research on an efficacious systemic oral treatment with a favorable benefit-risk profile for adolescents with moderate-to-severe AD. To investigate the efficacy and safety of oral abrocitinib plus topical therapy in adolescents with moderate-to-severe AD. The phase 3, randomized, double-blind, placebo-controlled study JADE TEEN was conducted in countries of the Asia-Pacific region, Europe, and North America in patients aged 12 to 17 years with moderate-to-severe AD and an inadequate response to 4 consecutive weeks or longer of topical medication or a need for systemic therapy for AD. The study was conducted between February 18, 2019, and April 8, 2020. The data were analyzed after study completion. Patients were randomly assigned 1:1:1 to receive once-daily oral abrocitinib, 200 mg or 100 mg, or placebo for 12 weeks in combination with topical therapy. Coprimary end points were achievement of an Investigator's Global Assessment (IGA) response of clear (0) or almost clear (1) with improvement of 2 or more grades from baseline (IGA 0/1) and 75% or greater improvement from baseline in Eczema Area and Severity Index (EASI-75) response at week 12. Key secondary end points included 4-point or greater improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 12. Adverse events (AEs) were monitored. This study included 285 adolescents with moderate-to-severe AD (145 boys [50.9%] and 140 girls [49.1%]), of whom 160 (56.1%) were White and 94 (33.0%) were Asian; the median age was 15 years (interquartile range 13-17 years). Substantially more patients treated with abrocitinib (200 mg or 100 mg) vs placebo achieved an IGA response of 0/1 (46.2%; 41.6% vs 24.5%; P < .05 for both), EASI-75 (72.0%; 68.5% vs 41.5%; P < .05 for both), and PP-NRS4 (55.4%; 52.6% vs 29.8%; P < .01 for 200 mg vs placebo) at week 12. Adverse events were reported for 59 (62.8%), 54 (56.8%), and 50 (52.1%) patients in the 200 mg, 100 mg, and placebo groups, respectively; nausea was more common with abrocitinib, 200 mg (17 [18.1%]) and 100 mg (7 [7.4%]). Herpes-related AEs were infrequent; 1 (1.1%), 0, and 2 (2.1%) patients had serious AEs. This randomized clinical trial found that oral abrocitinib combined with topical therapy was significantly more effective than placebo with topical therapy in adolescents with moderate-to-severe AD, with an acceptable safety profile. ClinicalTrials.gov identifier: NCT03796676.

27603 Rapid itch relief with abrocitinib predicts later skin clearance: A post hoc analysis vs dupilumab and placebo in JADE COMPARE

Background: Rapid itch response is a desirable treatment goal for atopic dermatitis (AD). In JADE-COMPARE, more patients had clinically meaningful itch relief (≥4-point improvement in Peak Pruritus Numerical Rating Scale [PP-NRS4]) at week 2 with abrocitinib 200 mg (49.1%) vs dupilumab (26.4%) and placebo (13.8%) and with abrocitinib 100 mg (31.8%) vs placebo (all comparisons, P≤0.0002). We investigated itch response from days 2-15 and relationships between week 2 PP-NRS4 response and week 12 response of ≥90% improvement in Eczema Area and Severity Index (EASI-90).

27571 Dupilumab provides clinically meaningful responses in adults with moderate-to-severe atopic dermatitis (AD): Results from LIBERTY AD CHRONOS study

Background: AD, a common chronic skin condition, has substantial impact on health-related quality of life (HRQoL). Stringent regulatory endpoints of Investigator Global Assessment score 0/1 and 75% reduction in Eczema Area and Severity Index (EASI-75) capture the AD skin lesion component, without encompassing all clinical endpoints. More inclusive tools are often needed to assess clinically meaningful responses in AD patients. We assess the effect of 52-week dupilumab treatment on a composite endpoint incorporating improvement in AD signs (EASI-75), symptoms (Peak Pruritus Numerical Rating Scale[PP-NRS] score≤4), and HRQoL (Dermatology Life Quality Index[DLQI]≤5) in adult AD patients.

Dupilumab in Adults with Moderate-to-Severe Atopic Dermatitis and Prior Use of Systemic Non-Steroidal Immunosuppressants: Analysis of Four Phase3 Trials.

IntroductionDupilumab is approved as first-line systemic treatment for adults/adolescents with moderate-to-severe atopic dermatitis (AD) in Europe and elsewhere owing to its favourable benefit–risk profile. However, systemic non-steroidal immunosuppressants (NSISS) are often used as first-line therapy in clinical practice. Impact of prior therapy with NSISS on dupilumab’s treatment effect vs. control has not been described previously. This study assessed dupilumab’s efficacy vs. control in patients with moderate-to-severe AD, comparing treatment effect in patients with/without prior systemic NSISS therapy, in four phase 3 trials.MethodsThis post hoc analysis included 1553 patients randomized to placebo or dupilumab (300 mg q2w) as monotherapy for 16 weeks, or with concomitant topical corticosteroids (TCS) for 16/52 weeks, from four randomized, double-blind, placebo-controlled, phase 3 trials. Patients were stratified by prior use of systemic NSISS and dupilumab-treated patients were analysed against control groups (treated with placebo or placebo + TCS).ResultsDupilumab-treated patients, regardless of prior treatment with NSISS, achieved a significantly higher percentage reduction from baseline in Eczema Area and Severity Index (EASI), SCORing Atopic Dermatitis (SCORAD), Dermatology life Quality Index (DLQI), and Patient-Oriented Eczema Measure (POEM) vs. control; significantly more achieved EASI score ≤ 7, Peak Pruritus Numerical Rating Scale ≤ 4, POEM ≤ 7, and DLQI ≤ 5 by week 4. These rapid, significant improvements were seen with or without concomitant TCS and sustained through end-of-treatment.ConclusionsDupilumab treatment (monotherapy or + TCS) provides rapid, significant, sustained improvements in signs, symptoms, and quality of life in patients with moderate-to-severe AD compared with control, regardless of prior systemic NSISS use.Clinical Trial RegistrationLIBERTY AD SOLO 1: ClinicalTrials.gov identifier NCT02277743, EudraCT 2014-001198-15. LIBERTY AD SOLO 2: ClinicalTrials.gov identifier NCT02277769, EudraCT 2014-002619-40. LIBERTY AD CHRONOS: ClinicalTrials.gov identifier NCT02260986, EudraCT 2013-003254-24. LIBERTY AD CAFÉ: ClinicalTrials.gov identifier NCT02755649, EudraCT 2015-002653-35.Graphic Supplementary InformationThe online version contains supplementary material available at 10.1007/s13555-021-00558-0.

Dupilumab treatment induced similar improvements in signs, symptoms, and quality of life in adults with moderate-to-severe atopic dermatitis with baseline Eczema Area and Severity Index Score

In multiple phase 3 trials, dupilumab improved signs, symptoms (including pruritus), and quality-of-life (QoL) in adults with moderate-to-severe atopic dermatitis (AD). In Italy, dupilumab received innovation status but is currently only reimbursed by the National Health Service for adults with Eczema Area Severity Index (EASI) scores ≥24. This analysis assesses disease burden and dupilumab efficacy in adults with EASI scores above and below this threshold. This post-hoc analysis included 299 adults pooled from two, randomized, placebo-controlled, phase 3 trials, LIBERTY AD CAFÉ (NCT02755649) and LIBERTY AD CHRONOS (NCT02260986), who received the approved dupilumab regimen (300 mg every 2 weeks) or placebo, with concomitant topical corticosteroids. EASI, Peak Pruritus Numerical Rating Scale (PP-NRS), and Dermatology Life Quality Index (DLQI) were assessed in patients with EASI scores ≥20 to <24 and ≥24 at week 16. At baseline, EASI was weakly correlated with PP-NRS and DLQI (Spearman's correlation coefficient: 0.22 and 0.29, respectively). At week 16, in both the EASI<24 and EASI≥24 populations, respectively, significantly more patients vs. control achieved: ≥50% improvement in EASI (95.5% vs. 55.6%; 80.6% vs. 33.1%); ≥3-point improvement in PP-NRS (68.4% vs. 35.3%; 55.3% vs. 17.7%); and ≥4-point improvement in DLQI (83.3% vs. 43.8%; 84.2% vs. 41.9%); from baseline. Dupilumab was generally well tolerated with an acceptable safety profile. Dupilumab treatment improves signs, symptoms, and QoL in moderate-to-severe AD adults with EASI<24, who can present with high disease burden. Opportunity may exist to use additional parameters to define disease severity and access to new therapies.

Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis

BackgroundThe oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.MethodsIn a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator’s Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index–75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16.ResultsA total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P<0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P<0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively.ConclusionsIn this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.)

Disease burden and treatment history among adults with atopic dermatitis receiving systemic therapy: baseline characteristics of participants on the EUROSTAD prospective observational study

Background Insights into the real-world treatment paradigm and long-term burden of atopic dermatitis (AD) are needed to inform clinical and health policy decisions. Methods The prospective, observational EUROSTAD study enrolled adults with moderate-to-severe AD starting or switching systemic therapy (51 sites in 10 European countries). We report the baseline characteristics, treatment patterns, and outcomes of these patients using descriptive statistics. Results A 12-month enrollment period of EUROSTAD was completed and 308 patients were enrolled: average age 37 years, AD duration 25 years, 43% were female. Most patients reported use of systemic therapy (93%) and ≥1 atopic comorbidity (82%). Mean [standard deviation] disease severity/burden measures were high: Investigator’s Global Assessment (3.1 [0.8]), Eczema Area and Severity Index (16.2 [10.9]), Peak Pruritus Numerical Rating Scale (5.5 [2.5]), sleep impairment Visual Analog Scale (49.8 [31.6]) scores, and time lost from work (4.1 [13.7] days/year) or usual activities (16.8 [38.7] days/year). Most patients showed borderline or clinical levels of anxiety (59%) and/or depression (63%) using the Hospital Anxiety and Depression Scale. Conclusions Adults with moderate-to-severe AD starting/switching systemic treatment enrolled in EUROSTAD have a high burden of longstanding disease despite continuous use of topical drugs, emollients, and systemic therapies.

Efficacy of Dupilumab on Different Phenotypes of Atopic Dermatitis: One-Year Experience of 221 Patients.

Background: The clinical features of adult-onset atopic dermatitis (AD) are heterogeneous and the diagnosis can be a challenge. A new biologic drug (dupilumab) has been approved for moderate to severe AD in adult patients. The efficacy and safety have been demonstrated in clinical trials, but these studies do not reflect conditions in daily practice and do not consider the different clinical manifestations of AD. Objectives: Analyzing the dupilumab activity in a real-world setting and comparing its efficacy on different AD phenotypes. Methods: We retrospectively evaluated 221 AD patients treated with dupilumab, stratified into six clinical phenotypes: classic, generalized eczema inflammatory and lichenoid patterns, prurigo, nummular eczema, and erythroderma. At baseline and at weeks 4, 16, and 52, the disease severity was assessed through the Eczema Area and Severity Index (EASI) and the quality of life was assessed through the Dermatology Life Quality Index (DLQI) questionnaire, Peak Pruritus Numerical Rating Scale (itch NRS), and Peak Sleep NRS. Results: We found a significant improvement after 16 weeks of treatment (p < 0.0001) in all six phenotypes for all the assessed scores mentioned above, persisting up to week 52. The best improvement was seen in the more severe phenotypes, particularly the erythrodermic one. Conclusions: The present study confirmed the efficacy and safety of dupilumab in the treatment of severe AD. Its strength was in the stratification of AD patients in six different phenotypes based on their clinical presentation, all of whom markedly improved in terms of both clinically evident and reported symptoms, as well as their quality of life.

Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial

Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis. In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060. Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported. Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis. Pfizer.

Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic Dermatitis

Abrocitinib, an oral, once-daily Janus kinase 1 selective inhibitor, was effective and well tolerated in a phase 3 monotherapy trial of patients with moderate-to-severe atopic dermatitis (AD). To investigate the efficacy and safety of abrocitinib in adolescents and adults with moderate-to-severe AD in an identically designed trial. This phase 3, double-blinded, placebo-controlled, parallel-group randomized clinical trial included patients 12 years or older with a clinical diagnosis of moderate-to-severe AD for at least 1 year and inadequate response to topical medications given for at least 4 weeks within 6 months. Patients were enrolled from 115 centers in Australia, Bulgaria, Canada, China, Czechia, Germany, Hungary, Japan, South Korea, Latvia, Poland, United Kingdom, and the United States from June 29, 2018, to August 13, 2019. Data were analyzed from September 13 to October 25, 2019. Patients were randomly assigned (2:2:1) to receive once-daily oral abrocitinib in 200- or 100-mg doses or placebo for 12 weeks. The coprimary end points were the proportion of patients achieving Investigator Global Assessment (IGA) response (ie, clear [0] or almost clear [1], with improvement of ≥2 grades) and the proportion of patients achieving at least 75% improvement in Eczema Area and Severity Index score (EASI-75) at week 12. Key secondary end points included the proportion of patients achieving a Peak Pruritus Numerical Rating Scale (PP-NRS) response (ie, improvement of ≥4 points) at week 12. Other secondary end points included the proportion of patients achieving at least 90% improvement in EASI score (EASI-90). Safety was assessed via adverse events and laboratory monitoring. A total of 391 patients (229 male [58.6%]; mean [SD] age, 35.1 [15.1] years) were included in the analysis; of these, 155 received abrocitinib, 200 mg/d; 158, abrocitinib, 100 mg/d; and 78, placebo. Among patients with available data at week 12, greater proportions of patients in the 200- and 100-mg abrocitinib groups vs the placebo group achieved IGA (59 of 155 [38.1%] and 44 of 155 [28.4%] vs 7 of 77 [9.1%]; P < .001) and EASI-75 (94 of 154 [61.0%] and 69 of 155 [44.5%] vs 8 of 77 [10.4%]; P < .001), greater estimated proportions achieved PP-NRS (55.3% [95% CI, 47.2%-63.5%] and 45.2% [95% CI, 37.1%-53.3%] vs 11.5% [95% CI, 4.1%-19.0%]; P < .001), and/or greater proportions achieved EASI-90 (58 of 154 [37.7%] and 37 of 155 [23.9%] vs 3 of 77 [3.9%]) responses. Adverse events were reported for 102 patients (65.8%) in the 200-mg group, 99 (62.7%) in the 100-mg group, and 42 (53.8%) in the placebo group; serious adverse events were reported for 2 patients (1.3%) in the 200-mg group, 5 (3.2%) in the 100-mg group, and 1 (1.3%) in the placebo group. Decreases in platelet count (2 [1.3%]) and laboratory values indicating thrombocytopenia (5 [3.2%]) were reported in the 200-mg group. Monotherapy with once-daily oral abrocitinib was effective and well tolerated in adolescents and adults with moderate-to-severe AD. ClinicalTrials.gov Identifier: NCT03575871.

Treatment of Recalcitrant Prurigo Nodularis with Dupilumab

Objectives: Prurigo nodularis (PN) is a disease of aberrant and recalcitrant itching which is difficult to effectively manage. There are no current FDA-approved therapies for PN. The current topical and systemic medications used for this condition provide less than optimal efficacy for the majority of patients with this condition and often have unacceptable side effects. We report 4 patients who were effectively treated with dupilumab (Dupixent) for the treatment of recalcitrant PN.Methods: Four patients were treated successfully with dupilumab, a systemic biologic agent that is not immunosuppressive (Dupixent; Sanofi-Regeneron). Patients were treated with dupilumab monotherapy, without the use of other systemic immunosuppressing agents. The peak pruritus numerical rating scale (NRSi) was used to evaluate patients at weeks 0 and 4. Results: Dupilumab therapy results in a dramatic reduction in NRSi scores by week 4 and that result continues throughout the duration of therapy. This reduction in itch is seen with continuous therapy.Conclusion: Dupilumab therapy appears effective in reducing the overall itch severity in patients with PN. The usage of dupilumab as a monotherapy shows promise in the treatment of PN. The therapeutic response to dupilumab seen in PN suggests that the pathogenesis of PN may overlap with that of atopic dermatitis.

Clinical Response and Quality of Life in Patients with Severe Atopic Dermatitis Treated with Dupilumab: A Single-Center Real-Life Experience.

Dupilumab is an anti-interleukin-4 receptor monoclonal antibody that was recently approved for the treatment of atopic dermatitis (AD). In this single-center retrospective study, clinical baseline data of 117 severe AD patients treated with dupilumab were collected. At baseline and at weeks 4 and 16, disease severity was assessed through the Eczema Area and Severity Index (EASI) and quality of life through the Dermatology Life Quality Index (DLQI) questionnaire, Patient-Oriented Eczema Measure (POEM), Hospital Anxiety and Depression Scale (HADS), Peak Pruritus Numerical Rating Scale (NRS-itch), and VAS-sleep. Response to dupilumab was defined as an improvement of ≥75% in EASI from baseline (EASI75). At multivariate analysis, AD onset before 18 years [OR, 2.9; 95% CI, 1.2–7.2; p = 0.0207] and absence of hypereosinophilia [OR, 2.24; 95% CI, 1.03–4.86; p = 0.0412] were identified as significant predictive parameters for response to dupilumab in terms of EASI75 at week 4 but not at week 16. Significant reductions in EASI, DLQI, POEM, HADS, NRS-itch, and VAS-sleep were found between week 4 versus baseline (p < 0.0001 for all) and week 16 versus baseline (p < 0.0001 for all). Early AD onset and absence of hypereosinophilia may be suggested as predictive markers of early response to dupilumab. We confirmed the efficacy and safety of this agent along with the improvement of life quality in severe AD patients.

Dupilumab treatment results in early and sustained improvements in itch in adolescents and adults with moderate to severe atopic dermatitis: Analysis of the randomized phase 3 studies SOLO 1 and SOLO 2, AD ADOL, and CHRONOS

Pruritus (itch) is a cardinal symptom in atopic dermatitis (AD). To evaluate the timing and effect of dupilumab on itch. Analysis of data from 1505 patients with moderate to severe AD included in 4 randomized controlled studies, treated for up to 52weeks. Adults received dupilumab 300mg every 2weeks or placebo monotherapy (SOLO 1: NCT02277743; SOLO 2: NCT02277769), with concomitant topical corticosteroids (CHRONOS: NCT02260986); adolescents (≥12 to <18y) were treated with dupilumab monotherapy every 2weeks (200mg for baseline weight of <60kg; 300mg for baseline weight of ≥60kg) or placebo (AD ADOL: NCT03054428). Dupilumab showed significant rapid improvements from baseline in daily Peak Pruritus Numerical Rating Scale scores versus placebo, by day 2 in adults and day 5 in adolescents. At treatment end, dupilumab vs placebo/control had greater least-squares mean percent change from baseline in the weekly average of Peak Pruritus Numerical Rating Scale scores: SOLO -47.5% vs -20.5%; AD-ADOL -47.9% vs -19.0%; CHRONOS -57.3% vs -30.9% (P<.0001 for all). Short duration of monotherapy trials (16weeks). Across 4 randomized trials, dupilumab treatment showed rapid and sustained improvements in the magnitude of itch, starting with first dose; responses progressively increased and were sustained through to the end of treatment, up to 1year.

Validation of the Peak Pruritus Numerical Rating Scale

Validation of the Peak Pruritus Numerical Rating Scale

162 Biomarkers CCL17/TARC and Total IgE Do Not Predict Clinical Response to Dupilumab in Atopic Dermatitis (AD): a Post hoc Analysis of Pooled Phase 3 Data (SOLO 1 & 2)

Dupilumab (DUP), a fully human IL-4Rα mAb, inhibits signaling of IL-4/IL-13, key drivers of Type 2/Th2 immune diseases such as AD/asthma. CCL17 (TARC) and IgE production are enhanced by IL-4/IL-13 and correlate with AD severity. This pooled post hoc analysis reports the relationship between baseline (BL) serum CCL17 and total IgE levels and DUP treatment effect in adults with moderate-to-severe AD in 2 identical double-blind, placebo (PBO)-controlled phase 3 trials (SOLO 1: NCT02277743, N=671; SOLO 2: NCT02277769, N=708). Patients (pts; N=1,379) were randomized (1:1:1) to subcutaneous 300 mg DUP weekly (qw), every 2 weeks (q2w), or PBO for 16 weeks (W). CCL17 and total IgE were measured in serum samples collected between BL and W16 using commercial assays. Efficacy analyses by BL CCL17 tertiles (≤1115; >1115 to ≤4300; and >4300 pg/mL) and total IgE subgroups (<150 kU/L and ≥150 kU/L) were performed for % changes from BL in Eczema Area and Severity Index (EASI) and peak pruritus Numerical Rating Scale (NRS). On study entry, pts with low BL CCL17 (≤1115 pg/mL; n=457) or IgE concentrations (<150 kU/L; n=220) had numerically lower BL EASI and pruritus NRS scores than pts with high CCL17 (>4300 pg/mL; n=457) or IgE levels (≥150 kU/L; n=1158). Both DUP dose regimens significantly reduced EASI and pruritus NRS scores from BL at W16 vs PBO in pts with high, mid, or low BL CCL17 or high or low IgE levels (all P<0.0001 vs PBO, except pruritus in the low IgE group [P=0.002/P=0.006; qw/q2w]). The most common adverse events with DUP vs PBO were injection-site reactions and conjunctivitis. BL levels of CCL17 and IgE did not predict DUP treatment response (% reductions in EASI and pruritus NRS), although the smaller n of the low IgE group and lower BL disease activity in the low CCL17 and IgE groups may affect the power of this analysis.

Peak Pruritus Numerical Rating Scale: psychometric validation and responder definition for assessing itch in moderate-to-severe atopic dermatitis.

SummaryBackgroundModerate‐to‐severe atopic dermatitis (AD) is a chronic disease characterized by intense, persistent and debilitating itch, resulting in sleep deprivation, signs of anxiety and depression, impaired quality of life and reduced productivity. The Peak Pruritus Numerical Rating Scale (NRS) was developed and validated as a single‐item, patient‐reported outcome (PRO) of itch severity.ObjectivesTo describe the content validity and psychometric assessment (test–retest reliability, construct validity, known‐groups validity, sensitivity to change) of the Peak Pruritus NRS, and to derive empirically a responder definition to identify adults with a meaningful change in itch.MethodsContent validity was assessed through in‐depth patient interviews. Psychometric assessments used data from phase IIb and phase III dupilumab clinical trials and included test–retest reliability, construct validity, known‐groups validity and sensitivity to change in patients with moderate‐to‐severe AD.ResultsInterview participants indicated that the Peak Pruritus NRS was a relevant, clear and comprehensive assessment of itch severity. Peak Pruritus NRS scores showed large, positive correlations with existing PRO measures of itch, and weak or moderate correlations with clinician‐reported measures assessing objective signs of AD. Peak Pruritus NRS score improvements were highly correlated with improvements in other itch PROs, and moderately correlated with improvements in clinician‐reported measures assessing objective signs of AD. The most appropriate threshold for defining a clinically relevant, within‐person response was ≥ 2–4‐point change in the Peak Pruritus NRS.ConclusionsThe Peak Pruritus NRS is a well‐defined, reliable, sensitive and valid scale for evaluating worst itch intensity in adults with moderate‐to‐severe AD.

692 Real-world effectiveness of dupilumab based on Investigator Global Assessment (IGA) and peak Pruritus Numerical Rating Scale (PNRS) scores

The real-world effectiveness of dupilumab in AD based on the IGA and PNRS measures was assessed via Modernizing Medicine’s Electronic Medical Assistant dermatology-specific medical records for patients age≥18, ≥1 dupilumab prescription between 01APR17-30NOV17 and with recorded IGA and PNRS scores ≤3months pre- and ≥4months post- dupilumab initiation. Pre- vs. post-dupilumab improvements in IGA and PNRS were evaluated in patients with baseline IGA≥3 and PNRS≥3 (moderate-to-severe AD), respectively. Of 211 and 89 patients with recorded IGA and PNRS scores, respectively, 187(88%) with IGA≥3 and 61(69%) with PNRS≥3 were analyzed. Mean (SD) age was 42.3(±17.3) and 46.9(±16.8) years, 51% were male in both groups, and 44% and 43% were White, in the IGA≥3 and PNRS≥3 groups, respectively. Treatments 1-year pre-dupilumab for IGA≥3 and PNRS≥3 were, respectively: topical corticosteroids 69% and 85%, topical calcineurin inhibitors 19% and 25%, oral/injectable steroids 39% and 59%, systemic immunosuppressants 25% and 31%, phototherapy 11% and 8%, PDE-4 inhibitors 27% and 25%. Baseline IGA distribution was: 35% for IGA3, 54% for IGA4 and 11% for IGA5. Post-dupilumab, in IGA≥3 32% of patients achieved IGA0-1; 58% and 79% achieved IGA improvements ≥2-points and ≥1-point, respectively. Baseline PNRS distribution for patients with PNRS≥3 was: 47% for PNRS3-6, 53% for PNRS7-10. Post-dupilumab, in PNRS≥3 PNRS improved by [mean (SD),%change] -3.6(±3.5),-54% (p<.0001); 66% had ≥3-point PNRS improvement. A majority of moderate-to-severe AD patients treated with dupilumab in routine clinical practice achieved clinically meaningful improvements in AD signs and itch. Improvements observed in real-world clinical practice were comparable to those seen in dupilumab trials.

Dupilumab in Moderate-to-Severe Atopic Dermatitis With or Without Comorbid Asthma: Pooled Analysis of 2 Randomized Phase 3 Trials (LIBERTY AD SOLO 1 & 2)

Dupilumab, a fully human anti-IL-4Rα mAb, inhibits signaling of IL-4 and IL-13, key drivers of type 2/Th2 immune diseases. Dupilumab is approved by the FDA with or without topical corticosteroids for treatment of adults with moderate-to-severe AD. We report on efficacy and safety of dupilumab in adults with moderate-to-severe AD with or without comorbid patient-reported asthma in two pooled phase 3 monotherapy trials (LIBERTY AD SOLO 1&2: NCT02277743; NCT02277769). Patients were randomized (1:1:1) to subcutaneous dupilumab 300mg every 2 weeks (q2w; n=457) or weekly (qw; n=462), or placebo (n=460) for 16 weeks. Endpoints included proportion of patients with Investigator’s Global Assessment (IGA) 0/1, ≥75% improvement in Eczema Area and Severity Index (EASI-75), and peak pruritus Numerical Rating Scale (NRS) improvement ≥4. Safety was assessed. Baseline characteristics were consistent across groups and between patients with (dupilumab q2w: 49%/qw: 46%, placebo: 45%) or without comorbid asthma. At Week 16, more patients with comorbid asthma receiving dupilumab 300mg q2w/qw achieved IGA 0/1 (34.1%/31.9% vs 9.3%), EASI-75 (50.0%/47.4% vs 13.7%), and peak pruritus NRS improvement ≥4 (37.9%/37.8% vs 9.3%) versus placebo (p<0.0001 for all). Patients without comorbid asthma showed similar results. Treatment groups (dupilumab q2w/qw, placebo) had similar rates of adverse events (69%/67%, 69%). Injection-site reactions and conjunctivitis were more frequent in dupilumab-treated patients. This subgroup analysis shows that dupilumab-treated patients with and without comorbid asthma have comparable/significant improvement in AD signs and symptoms. Future studies in AD patients with symptomatic comorbid asthma will help assess the potential benefit of dupilumab in both conditions.