Itch control is an important treatment goal for patients with atopic dermatitis (AD). According to the treat-to-target framework, optimal treatment goals in AD were defined for various disease domains (e.g., achievement of Eczema Area and Severity Index [EASI] ≤ 7, Peak Pruritus Numeric Rating Scale [PP-NRS] ≤ 4, and Dermatology Life Quality Index [DLQI] ≤ 5) to be achieved after 6 months and sustained thereafter.
Methods
In this post hoc analysis of LIBERTY AD CHRONOS (NCT02260986), we report the proportion of patients achieving an optimal itch response with or without an optimal response in signs (EASI ≤ 7) and quality of life (DLQI ≤ 5), after 24 and 52 weeks of treatment with dupilumab.
Results
The majority of patients (69 of 90; 76.7%) had an optimal itch response at week 24 as measured by treat-to-target goal PP-NRS ≤ 4; this proportion was sustained at week 52 (64 of 79; 81.0%). Using SCORing Atopic Dermatitis (SCORAD) Pruritus Visual Analog Scale (VAS) < 4 as validation, the majority of patients (76/89; 85.4%) had an optimal itch response at week 24, and this proportion was also sustained at week 52 (69 of 79; 87.3%). Around 70% of patients with an optimal itch response according to PP-NRS or SCORAD Pruritus VAS also had optimal response in EASI and DLQI at weeks 24 and 52.
Conclusion
Dupilumab provided optimal itch response and further optimal treatment response in signs and quality of life at week 24, sustained up to 52 weeks, in the majority of patients. Graphical Abstract available for this article.
Poster at ISAD 2024; October 24–26, 2024, Doha, Qatar (P4.10#446).
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Key Summary Points
Why carry out this study?
Itch control is an important treatment goal in patients with moderate-to-severe atopic dermatitis (AD). Treat-to-target goals help evaluate treatment success in AD signs, itch, and quality of life (QoL)
This post hoc analysis analyzed the proportion of patients achieving optimal itch response along with optimal response in signs and QoL with dupilumab according to the treat-to-target goals
What was learned from the study?
Most patients achieved optimal itch response with dupilumab at week 24 and 52, with the majority of these patients also demonstrating optimal response in signs and QoL
These findings demonstrate that dupilumab can be used to target itch in AD with optimal outcomes, including comprehensive improvements in signs and QoL
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Introduction
Moderate-to-severe atopic dermatitis (AD) is a chronic, relapsing, type 2 inflammatory skin condition, characterized by signs and symptoms (intense itch, pain). Severe itch can have a profound effect on patients, causing sleep loss and psychological disorders such as anxiety and depression, and consequently has a negative impact on their quality of life (QoL) [1‐4]. Itch control is thus an important treatment goal for patients.
In patients with AD, itch is mainly driven by key type 2 inflammatory cytokines, interleukin (IL)-4, IL-13, and IL-31 [2, 5]. The presence of IL-4 is required for the expression of the “itch cytokine” IL-31, making IL-4 an upstream cytokine in IL-31 production [3, 6]. IL-4 also potentiates the interaction between IL-31 and its receptor IL-31R [7]. IL-4 and IL-13 maintain an inflammatory state in the skin and also downregulate skin barrier proteins leading to enhanced skin barrier dysfunction and increased itch [3, 4, 8]. Furthermore, IL-4 and IL-13 activate sensory neurons and lower the sensitivity threshold of sensory nerves for several itch-related factors, including IL-31 [1, 3, 5, 8].
Dupilumab, a systemic treatment for moderate-to-severe AD, is a human monoclonal antibody that inhibits signaling of both IL-4 and IL-13, key and central drivers of type 2 inflammation in multiple diseases [1‐3, 9, 10].
The treat-to-target (T2T) framework has been proposed to guide systemic treatment decisions in clinical practice and is thus likely to be aligned with real-world goals regarding disease control. Treatment success in AD according to T2T is achieved when optimal targets for various disease domains are attained after 6 months and 1 year. Optimal itch response was defined as Peak Pruritus Numeric Rating Scale (PP-NRS) ≤ 4; optimal disease signs response as Eczema Area and Severity Index (EASI) ≤ 7; and optimal QoL response as Dermatology Life Quality Index (DLQI) ≤ 5 [11‐13].
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This post hoc analysis of the LIBERTY AD CHRONOS study reports the proportion of patients achieving optimal itch response with or without optimal response in signs and QoL, after 24 and 52 weeks of treatment with dupilumab.
Methods
Study Design
This was a post hoc analysis from LIBERTY AD CHRONOS (NCT02260986), a 1-year, randomized, double-blind, placebo-controlled, phase 3 study [14]. Full study design, and efficacy and safety outcomes of LIBERTY AD CHRONOS have been previously reported [14]. In total, 740 adult patients with moderate-to-severe AD and inadequate response to topical corticosteroids (TCS) were randomized (3:1:3) to subcutaneous dupilumab 300 mg every week (N = 319), dupilumab 300 mg every 2 weeks (N = 106), or placebo (N = 315), plus concomitant TCS. To align with the approved dosing in adults with AD, only patients who had received dupilumab 300 mg every 2 weeks plus TCS were included in this analysis.
Outcomes
The study outcomes were measures of optimal response achieved at week 24 and week 52, as defined by the T2T framework [11‐13]: optimal itch response (PP-NRS ≤ 4), optimal disease signs response (EASI ≤ 7), and optimal QoL response (DLQI ≤ 5). SCORing Atopic Dermatitis (SCORAD) Pruritus Visual Analog Scale (VAS) < 4 as an additional itch outcome measure was used to confirm the T2T optimal itch response.
Statistical Analyses
These post hoc analyses were descriptive. All observed values at each timepoint were used for the analysis, with no imputation of missing data. Percentages of evaluable patients are reported for each outcome.
Ethical Approval
This study (LIBERTY AD CHRONOS) was done in accordance with the provisions of the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines (version R1), and applicable regulatory requirements. All patients provided signed written informed consent. The protocol and all relevant study forms were approved by all relevant institutional review boards and an independent ethics committee. An independent data monitoring committee monitored patient safety. This clinical trial was prospectively registered at ClinicalTrials.gov with the identifier number NCT02260986.
Results
A total of 106 patients who received dupilumab 300 mg every 2 weeks plus TCS were included in the analysis. Full baseline demographics and clinical characteristics have been previously reported [14]. At baseline, mean (standard deviation [SD]) PP-NRS was 7.4 (1.66), mean (SD) EASI was 33.6 (13.30), mean (SD) DLQI was 14.5 (7.31), and mean (SD) SCORAD Pruritus VAS was 7.5 (1.86). At baseline, 77 of 106 patients (72.6%) had severe itch, defined as a PP-NRS score ≥ 7.
The proportion of patients with an optimal itch response, as measured by PP-NRS ≤ 4, increased over time from week 4 onwards (Fig. 1). The majority of patients (69 of 90; 76.7%) had an optimal itch response at week 24; this proportion was sustained at week 52 (64 of 79; 81.0%) (Fig. 1). Most patients with an optimal PP-NRS itch response also had optimal EASI and DLQI responses. At week 24, 51 of the 69 (73.9%) patients with an optimal itch response also had EASI ≤ 7 and DLQI ≤ 5. At week 52, 44 of the 64 (68.8%) patients with an optimal itch response also had EASI ≤ 7 and DLQI ≤ 5.
Fig. 1
Proportion of patients achieving optimal itch response (PP-NRS ≤ 4). Percentages are calculated from N. Brackets represent proportion of patients with optimal itch response PP-NRS ≤ 4 (blue columns). Solid colors represent patients who achieved DLQI ≤ 5; shading represents patients who did not achieve DLQI ≤ 5. DLQI Dermatology Life Quality Index, EASI Eczema Area and Severity Index, PP-NRS Peak Pruritus Numeric Rating Scale
To further validate the results, we also used SCORAD Pruritus VAS < 4 as an additional optimal itch response outcome, which increased over time from week 4 onwards (Fig. 2). The majority of patients (76 of 89; 85.4%) had an optimal itch response at week 24; this proportion was sustained at week 52 (69 of 79; 87.3%) (Fig. 2). Most patients with an optimal SCORAD Pruritus VAS itch response also had optimal EASI and DLQI responses. At week 24, 55 of the 76 (72.4%) patients with an optimal SCORAD itch response also had EASI ≤ 7 and DLQI ≤ 5. At week 52, 48 of the 69 (69.6%) patients with an optimal SCORAD itch response also had EASI ≤ 7 and DLQI ≤ 5.
Fig. 2
Proportion of patients achieving optimal itch response (SCORAD Pruritus VAS < 4). Percentages are calculated from N. Brackets represent proportion of patients with optimal itch response SCORAD Pruritus VAS < 4 (blue columns). Solid colors represent patients who achieved DLQI ≤ 5; shading represents patients who did not achieve DLQI ≤ 5. DLQI Dermatology Life Quality Index, EASI Eczema Area and Severity Index, SCORAD SCORing Atopic Dermatitis, VAS Visual Analog Scale
Of the 77 patients with severe itch (PP-NRS ≥ 7) at baseline, 47 of 65 patients (72%) had an optimal itch response (PP-NRS ≤ 4) at week 24; this proportion was sustained at week 52 (47/59; 80%), similar to the overall patient population.
Safety was consistent with the known dupilumab safety profile [14].
Discussion
The T2T goals for treatment success, including optimal targets for various disease domains (i.e., signs, symptoms, and QoL) to be achieved at 6 months and reassessed at 1 year, capture both clinicians’ and patients’ perspectives on disease control, allowing patient involvement in decisions related to treatment approach and optimization [11‐13]. The findings of our post hoc analysis of dupilumab are in line with the T2T criteria. The proportion of patients with optimal response in itch, signs, and QoL increased over time, with optimal itch response observed as early as week 4 in most patients. Dupilumab met the optimal 6-month T2T goals in the majority of patients at or before week 24, and at week 52, achieving the long-term T2T milestone. The results were consistent using PP-NRS ≤ 4 and SCORAD Pruritus VAS < 4 as optimal itch response targets.
Itch is a key feature of type 2 inflammation in AD; therefore, itch control is a cornerstone of comprehensive disease control in AD, including signs and QoL improvements. Toward this goal, achieving optimal itch response is critical. Dupilumab’s dual inhibition of IL-4 and IL-13 signaling achieved optimal itch response in most patients, clinically confirming the upstream actions and pivotal multidimensional roles (itch, inflammation, skin barrier) of these cytokines in the itch pathway. Both cytokines, IL-4 and IL-13, influence downstream mediators such as IL-31 and impair skin barrier function; however, blocking their signaling with dupilumab leads to the restoration of the skin barrier [15]. Furthermore, our results are in line with previous findings indicating that improvements in itch have been associated with improvements in QoL [16]. Limitations included the post hoc nature of the analysis, the focus on the dupilumab treatment arm for this specific analysis, and the potential for bias due to the use of observed values without imputation of missing data. Despite these limitations, the findings provide valuable insights into optimal treatment outcomes with dupilumab in patients with moderate-to-severe AD.
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Conclusion
Our analysis shows low disease activity with dupilumab treatment, with optimal response in itch and QoL in combination with AD signs after 24 weeks, sustained up to 1 year, in the majority of patients. Patients with severe itch at baseline achieved optimal itch responses similar to the overall population.
Acknowledgements
The authors would like to thank Purvi Kobawala Smith, MS, MPH, of Regeneron Pharmaceuticals Inc., and Robert McDonald, PhD, of Sanofi, for their contributions to the manuscript, and also the participants of the study.
Medical Writing/Editorial Assistance
Medical writing/editorial assistance was provided by Léa Meyer, PhD, of Excerpta Medica, and was funded by Sanofi and Regeneron Pharmaceuticals Inc., according to the Good Publication Practice guidelines.
Declarations
Conflict of Interest
Sonja Ständer has received research grants from Almirall, Galderma, Sanofi, and Trevi Therapeutics; has served as a consultant for AbbVie, Almirall, Amgen, Beiersdorf, BMS, Clexio, Galderma, Kiniksa, Klinge Pharma, KliRNA, P.G. Unna Academy, Pfizer, Sanofi, and Vifor; has served in advisory boards for AbbVie, Almirall, Celldex, Galderma, Lilly, P.G. Unna Akademie e. V., Pfizer, Regeneron Pharmaceuticals Inc., Sanofi, and Vifor; has served as a speaker for AbbVie, Almirall, Amgen, Beiersdorf, Focus Insight, FOMF, GCI Health, Galderma, LEO Pharma, Lilly, L’Oréal, MEDahead, Medicinske Tidsskrifter, Novartis, P.G. Unna Academy, Pfizer, Sanofi, STREAMED UP, touchIME, UCB, and Vifor; and is an Editorial Board member of Dermatology and Therapy. Sonja Ständer was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Gil Yosipovitch has served as an advisory board member for AbbVie, Almirall, Amgen, Arcutis, Celldex, Eli Lilly, Escient Health, Galderma, GSK, LEO Pharma, Merck, Novartis, Pfizer, Pierre Fabre, Regeneron Pharmaceuticals Inc., Sanofi, and Vifor; has received grants/research funding from Eli Lilly, Escient, Galderma, Kiniksa, LEO Pharma, Novartis, Pfizer, Sanofi Celldex, and Sanofi-Regeneron Pharmaceuticals Inc.; has been an investigator for Galderma, Regeneron Pharmaceuticals Inc., and Sanofi; and is an Editorial Board member of Dermatology and Therapy. Gil Yosipovitch was not involved in the selection of peer reviewers for the manuscript nor any of the subsequent editorial decisions. Brian S. Kim is a co-founder of Alys Pharmaceuticals and Neurommune Therapeutics; and has been a consultant for AbbVie, Abrax Japan, Almirall, Alys Pharmaceuticals, Cara Therapeutics, Clexio Biosciences, Eli Lilly, Escient Pharmaceuticals, Evommune, Galderma, Neurommune Therapeutics, Novartis, Pfizer, RecensMedical, Regeneron Pharmaceuticals Inc., Sanofi, and Septerna. Martin Steinhoff has received grants by AbbVie, Almirall, Avon, Galderma, Kiniksa, LEO Pharma, Lilly, L’Oréal, Maruho, Mitsubishi, Novartis, Pfizer, Sanofi, and Toray; has served in advisory boards for AbbVie, Alfasigma, Algorithm, Allergan, Almirall, Anacor, Avon, Bayer Health, Beiersdorf, BMS, Celgene, Chugai, Ducray, Galderma, Genentech, GSK, Kiniksa, LEO Pharma, Lilly, Maruho, MenloTX, Mitsubishi, Novartis, Pfizer, Pierre Fabre, Regeneron Pharmaceuticals Inc., Salix, Sanofi, Toray, Vertex, and ZymoGenetics; has been an investigator for AbbVie, Alfasigma, Almirall, Avon, BMS, Celgene, Ducray, Galderma, GSK, LEO Pharma, Lilly, L’Oréal, Maruho, MenloTX, Mitsubishi, Novartis, Pfizer, Pierre Fabre, Regeneron Pharmaceuticals Inc., Sanofi, Toray, Vertex, and ZymoGenetics; and has been a speaker for AbbVie, Algorithm, Almirall, Anacor, Allergan, Avon, Bayer Health, Beiersdorf, BMS, Celgene, Chugai, Ducray, Galderma, Genentech, LEO Pharma, Lilly, L’Oréal, Maruho, MenloTX, Novartis, Qatar Pharma, Pfizer, Pierre Fabre, Regeneron Pharmaceuticals Inc., Sanofi, and ZymoGenetics. April Armstrong has been an investigator and/or consultant for AbbVie, BMS, Dermavant, Dermira, Janssen, LEO Pharma, Lilly, Modernizing Medicine, Ortho Dermatologics, Regeneron Pharmaceuticals Inc., Sanofi, Science 37, and UCB. Franz J. Legat has received consulting fees and/or honoraria for lectures, presentations, speaker’s bureaus, manuscript writing or education events; participated on advisory boards; and/or served as an investigator for AbbVie, Almirall, Amgen, Celgene, DS Biopharma, Eli Lilly and Company, Galderma, Incyte, Janssen Cilag, Kiniksa Pharmaceuticals, LEO Pharma, Menlo Therapeutics, Novartis, Pelpharma, Pfizer, Sanofi, Trevi Therapeutics, and Vifor Pharma. Kenji Kabashima has received honoraria for lectures from Eli Lilly, Japan Tobacco, LEO Pharma, Maruho, Mitsubishi Tanabe Pharma, and Procter & Gamble; and has received research grants from Kyoto Hakko Kirin, Mitsubishi Tanabe Pharma, and Ono Pharmaceutical. Takeshi Nakahara has received laboratory funds from Maruho; and speaker fees from Maruho and Sanofi. Atsuyuki Igarashi has received research grants from AbbVie, Eli Lilly, Japan Tobacco, Novartis, Sanofi, and Torii Pharmaceutical; consultant fee from Japan Tobacco and Maruho; and honoraria for lectures from Maruho and Sanofi. Amy H. Praestgaard and Mike Bastian are employees of Sanofi and may hold stock and/or stock options in the company. Tien V. Nguyen is an employee and shareholder of Regeneron Pharmaceuticals Inc.
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Ethical Approval
This study (LIBERTY AD CHRONOS) was done in accordance with the provisions of the Declaration of Helsinki, International Conference on Harmonisation Good Clinical Practice guidelines (version R1), and applicable regulatory requirements. All patients provided signed written informed consent. The protocol and all relevant study forms were approved by all relevant institutional review boards and an independent ethics committee. An independent data monitoring committee monitored patient safety. This clinical trial was prospectively registered at ClinicalTrials.gov with the identifier number NCT02260986.
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Optimal Itch Response in Adults Treated with Dupilumab for Moderate-to-Severe Atopic Dermatitis
Verfasst von
Sonja Ständer
Gil Yosipovitch
Brian S. Kim
Martin Steinhoff
April Armstrong
Franz J. Legat
Kenji Kabashima
Takeshi Nakahara
Atsuyuki Igarashi
Amy H. Praestgaard
Tien V. Nguyen
Mike Bastian
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