Abstract
Introduction
Efficacy of upadacitinib has been assessed in trials including Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 assessed efficacy of upadacitinib 30 mg and upadacitinib 15 mg against placebo, while Heads Up assessed efficacy of upadacitinib 30 mg in a head-to-head trial against dupilumab 300 mg. A head-to-head trial of upadacitinib 15 mg against dupilumab 300 mg has not been conducted. Network meta-analysis has shown that upadacitinib 30 mg and upadacitinib 15 mg are among the most efficacious targeted systemic therapies, but prior indirect comparisons have not evaluated more stringent outcomes.
Methods
A population-adjusted indirect comparison was conducted using post hoc individual patient data from Measure Up 1 and 2 and Heads Up to estimate how upadacitinib 15 mg would have performed if included in Heads Up by adjusting for patient-level covariates. Absolute response rates at weeks 4, 16, and 24 were estimated for the following outcomes: no/minimal itch [Worst Pruritus Numerical Rating Scale (WP-NRS) score of 0/1], Eczema Area and Severity Index (EASI) score of ≤ 3 (EASI ≤ 3), 100% improvement in EASI (EASI 100), both ≥ 90% improvement in EASI (EASI 90) and WP-NRS 0/1, both EASI ≤ 3 and WP-NRS 0/1, and both EASI 100 and WP-NRS 0/1. The analysis was conducted on adult patients, aligned with the intention-to treat population for the clinical trials, and used non-responder imputation.
Results
Across all outcomes assessed, the estimated absolute response rates were greatest for upadacitinib 30 mg, followed by upadacitinib 15 mg and then dupilumab. This pattern was observed at week 4, week 16, and week 24.
Conclusions
For adults with moderate-to-severe AD, upadacitinib 30 mg appears to be the most efficacious treatment in attaining more stringent and composite outcomes across multiple timepoints, followed by upadacitinib 15 mg and then dupilumab 300 mg.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Why carry out this study? |
There are multiple treatment options for atopic dermatitis, but relatively few head-to-head randomized controlled trials have compared treatments with one another. |
Prior head-to-head randomized controlled trials have not assessed more stringent endpoints, which have been found to be associated with improved patient outcomes and have been highlighted as optimal targets for treat-to-target recommendations. |
The study used population-adjusted indirect comparison to estimate how upadacitinib 15 mg would have performed if included in a head-to-head trial that had assessed efficacy of upadacitinib 30 mg against dupilumab 300 mg. |
What was learned from the study? |
Across all outcomes and timepoints assessed, the estimated absolute response rates were greatest for upadacitinib 30 mg, followed by upadacitinib 15 mg and then dupilumab. |
Upadacitinib 30 mg appears to be the most efficacious treatment in attaining independent and simultaneous achievement of more stringent skin and itch outcomes for adults with moderate-to-severe atopic dermatitis, followed by upadacitinib 15 mg and then dupilumab 300 mg. |
Introduction
Randomized controlled trials represent the gold standard of establishing efficacy of treatments, but for diseases where there are multiple treatment options, such as atopic dermatitis, randomized controlled trials comparing treatments with one another may be few. Indirect treatment comparisons may be used to evaluate therapeutic options in these situations.
Upadacitinib and dupilumab are two treatment options for atopic dermatitis. Upadacitinib is an oral, small-molecule Janus kinase inhibitor that has greater inhibitory potency for JAK1 than for JAK2, JAK3, or tyrosine kinase 2 [1]. Upadacitinib is metabolized in the liver, primarily via the CYP3A4 pathway and excreted predominantly unchanged in the urine and feces [2]. Dupilumab is a subcutaneously administered human monoclonal antibody that inhibits interleukin-4 and interleukin-13 signaling [3]. Dupilumab is metabolized into peptides and amino acids through catabolism [4]. Common adverse events for upadacitinib include acne, upper respiratory tract infection, nasopharyngitis, headache, plasma creatine phosphokinase elevation, atopic dermatitis (AD) worsening, nausea, and oral herpes; for dupilumab, common adverse events include conjunctivitis, allergic conjunctivitis, exacerbation of AD, nasopharyngitis, headache, fatigue, allergic rhinitis, cough, diarrhea, vascular disorders, injection-site reactions, non-skin infections, herpes viral infections, and upper respiratory tract infection [5, 6]. Both upadacitinib and dupilumab have been found to be well tolerated with a favorable benefit–risk profile compared with placebo [1, 3]. Efficacy of upadacitinib in treating atopic dermatitis has been assessed in trials, including Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and Measure Up 2 assessed efficacy of upadacitinib 30 mg and upadacitinib 15 mg against placebo, while Heads Up assessed efficacy of upadacitinib 30 mg in a head-to-head trial against dupilumab 300 mg. A head-to-head trial of upadacitinib 15 mg against dupilumab 300 mg, though, has not been conducted. Network meta-analysis has shown that upadacitinib 30 mg and upadacitinib 15 mg are among the most efficacious targeted systemic therapies, [7, 8] but prior indirect comparisons have not looked at stricter outcomes such as complete skin clearance and itch resolution.
This analysis builds on prior indirect comparisons in that it uses individual patient-level data for all treatment arms assessed across multiple trials to compare upadacitinib and dupilumab on more stringent skin and itch outcomes. This analysis aims to use indirect comparison to compare upadacitinib and dupilumab on stringent and composite measures of skin clearance and itch resolution to estimate how upadacitinib 15 mg would perform compared to dupilumab 300 mg.
Methods
This analysis is a post hoc analysis of clinical trial data. The analysis used individual patient data from three clinical trials: Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and Measure Up 2 were replicate multicenter, randomized, double-blind, placebo-controlled phase 3 trials with co-primary endpoints of achievement of at least 75% improvement in Eczema Area and Severity Index (EASI) score from baseline and achievement of a validated Investigator’s Global Assessment for Atopic Dermatitis (vIGA-AD) response (defined as a vIGA-AD score of 0, clear or 1, almost clear with ≥ 2 grades of reduction from baseline) at week 16. Patients were eligible on the basis of age (adolescents aged 12–17 years or adults aged 18–75 years) and disease criteria (moderate to severe AD [≥10% of body surface affected by AD, EASI score of ≥ 16, vIGA-AD score of ≥ 3, Worst Pruritus Numerical Rating Scale (WP-NRS) score of ≥ 4]) [1]. Heads Up was a head-to-head, multicenter, randomized, double-blinded, double-dummy, active-controlled phase 3b clinical trial which compared the safety and efficacy of upadacitinib 30 mg with dupilumab 300 mg. Patients were eligible on the basis of age (adults ages 18–75) and disease criteria (moderate-to-severe AD defined as ≥ 10% of body surface area affected by AD, EASI ≥ 16, vIGA-AD ≥ 3, and WP-NRS ≥ 4 at baseline) [9].
This analysis uses a population-adjusted indirect comparison, using covariate adjustment as a treatment effect calibration to estimate how upadacitinib 15 mg would have performed in a head-to-head comparison with dupilumab 300 mg. This study uses an “anchored” population adjustment because both studies have upadacitinib 30 mg as a common comparator. The theoretical basis of this analysis is laid out by Zhang et al. (2009) [10]; the covariate-adjustment method, an individual patient data calibration method mentioned in National Health and Care Excellence (NICE) guidance, was applied [11]. A logistic regression model was fit to the Measure Up 1 and Measure Up 2 pooled data to understand the relationship between upadacitinib 30 mg and upadacitinib 15 mg for each outcome, adjusting for patient-level baseline covariates (age, gender, race, country, previous use of systemic therapy, disease duration, vIGA-AD, and EASI). Using this estimated relationship, the differential between upadacitinib 30 mg and upadacitinib 15 mg was applied to the Heads Up data to estimate how upadacitinib 15 mg would have performed if included in Heads Up.
Prespecified efficacy outcomes included the achievement of no/minimal itch (WP-NRS 0/1), EASI score of ≤ 3 (EASI ≤ 3), 100% improvement in EASI (EASI 100), both EASI ≤ 3 and WP-NRS 0/1 simultaneously (EASI ≤ 3 & WP-NRS 0/1), both ≥ 90% improvement in EASI (EASI 90) and WP-NRS 0/1 simultaneously (EASI 90 & WP-NRS 0/1), and both EASI 100 and WP-NRS 0/1 simultaneously (EASI 100 & WP-NRS 0/1). Predicted differences were used to estimate absolute response rates at weeks 4, 8, 12, 16, and 24. The analysis included adult patients across all studies and used non-responder imputation.
This study did not require institutional review board approval as it did not access identifiable patient information or have direct interaction with patients. This post hoc analysis used data from previously conducted studies and did not contain data from any new studies with human participants or animals performed by any of the authors.
Results
Across all outcomes assessed at week 4, the estimated absolute response rates were greatest for upadacitinib 30 mg, followed by upadacitinib 15 mg and then dupilumab (Fig. 1). Numerical differences between upadacitinib 15 mg and dupilumab 300 mg were most pronounced on the achievement of EASI ≤ 3, WP-NRS 0/1, and EASI 90 & WP-NRS 0/1; differences favoring upadacitinib 15 mg over dupilumab 300 mg were statistically significant on these outcomes (Fig. 2).
Estimated absolute response rates increased for all treatment arms over time, though the rank order remained consistent throughout: upadacitinib 30 mg, followed by upadacitinib 15 mg, and then dupilumab (see Supplementary Table 1). At week 16, the primary endpoint time point of these trials, a > 15 percentage-point difference was observed with upadacitinib 30 mg over dupilumab across all outcomes (Fig. 3). Statistically significant differences favoring upadacitinib 15 mg over dupilumab were observed for EASI ≤ 3, EASI 100, and EASI 100 & WP-NRS 0/1 (Fig. 4). These patterns also held at week 24, with statistically significant differences between upadacitinib 15 mg and dupilumab observed for EASI 100 and EASI 100 & WP-NRS 0/1 (Figs. 5 and 6).
Discussion
For diseases where there are multiple treatment options, as is the case with AD, head-to-head randomized controlled trials comparing treatments with one another may be few. Indirect treatment comparisons are valuable to provide evidence in the absence of multiple head-to-head trials. However, because they have not been frequently reported, prior indirect comparisons have not been conducted on the more stringent endpoints assessed here.
More stringent outcomes have been found to be associated with improved patient outcomes, including the achievement of both skin and itch resolution [12]. Developing treat-to-target recommendations supports stringent outcomes as optimal targets, highlighting the importance of both clinician- and patient-reported measures such as skin and itch assessments to inform disease management [13]. These indirect comparisons can enrich shared decision-making discussions between patients and physicians with evidence on these optimal treatment targets.
Indirect comparisons of treatments for moderate-to-severe AD have been conducted using network meta-analysis [7, 8, 14, 15].Previous analyses evaluated skin and itch improvement separately across various immunomodulatory treatments. Due to limited data availability, prior assessments have focused primarily on stringent skin improvement outcomes, specifically EASI 90 and vIGA-AD 0/1. Consequently, the indirect comparison of simultaneous achievement of both skin and itch improvement was not compared indirectly. This analysis partially fills this evidence gap by providing indirect comparison results on these novel stringent endpoints. Although the analysis presented here is limited to upadacitinib (15 mg and 30 mg) and dupilumab, the rank order and temporal dynamics of these treatments are generally consistent with prior indirect comparisons, with greater degrees of skin and itch efficacy observed with upadacitinib compared with dupilumab, and with the highest degrees of efficacy observed with upadacitinib 30 mg.
Limitations
Outside of a head-to-head clinical trial comparing upadacitinib 15 mg with dupilumab 300 mg, having individual patient data for all treatment options in an indirect treatment comparison is the next best option. This analysis was limited to select upadacitinib and dupilumab trials because individual patient-level data were not available for all AD immunomodulatory treatment trials. Covariate adjustment was used to account for imbalances across the included trials, and while this approach has both published theoretical underpinnings and applications, it assumes potential imbalances are sufficiently addressed by the baseline covariates included in the statistical model. Other indirect comparison approaches (such as network meta-analysis) were infeasible because the outcomes of interest are not commonly or consistently reported across AD immunomodulatory treatment trials. Pending future reporting of these stringent outcomes, other indirect comparison approaches may be employed and can complement these findings with the inclusion of additional treatments.
Conclusions
For adults with moderate-to-severe AD, upadacitinib 30 mg appears to be the most efficacious treatment in attaining independent and simultaneous achievement of more stringent skin and itch outcomes across multiple timepoints over 24 weeks, followed by upadacitinib 15 mg and then dupilumab 300 mg.
Data Availability
AbbVie is committed to responsible data sharing regarding the clinical trials it sponsors. This includes access to anonymized, individual, and trial-level data (analysis datasets), as well as other information (e.g., protocols, clinical study reports, or analysis plans), as long as the trials are not part of an ongoing or planned regulatory submission. This includes requests for clinical trial data for unlicensed products and indications. These clinical trial data can be requested by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal, Statistical Analysis Plan (SAP), and execution of a Data Sharing Agreement (DSA). Data requests can be submitted at any time after approval in the USA and Europe and after acceptance of this manuscript for publication. The data will be accessible for 12 months, with possible extensions considered. For more information on the process or to submit a request, visit the following link: https://vivli.org/ourmember/abbvie/ then select “Home”.
References
Guttman-Yassky E, Teixeira HD, Simpson EL, et al. Once-daily upadacitinib versus placebo in adolescents and adults with moderate-to-severe atopic dermatitis (measure up 1 and measure up 2): results from two replicate double-blind, randomised controlled phase 3 trials. The Lancet. 2021;397(10290):2151–68.
Padda IS, Bhatt R, Patel P, et al. Upadacitinib. [Updated 2024 Jun 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK572088/
Silverberg JI, Yosipovitch G, Simpson EL, et al. 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. J Am Acad Dermatol. 2020;82(6):1328–36.
Gade A, Ghani H, Patel P, et al. Dupilumab. [Updated 2024 Feb 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK585114/
Davis DMR, Drucker AM, Alikhan A, et al. Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies. J Am Acad Dermatol. 2024;90(2):e43–56.
Guidelines, AAD. AAD guidelines of care for the management of atopic dermatitis in adults with phototherapy & systemic therapies. Mendeley Data. 2023. https://doi.org/10.17632/s72kbfrfcv.1.
Silverberg JI, Hong HC, Thyssen JP, et al. Comparative efficacy of targeted systemic therapies for moderate to severe atopic dermatitis without topical corticosteroids: systematic review and network meta-analysis. Dermatol Ther (Heidelb). 2022;12(5):1181–96.
Silverberg JI, Hong HC, Calimlim BM, et al. Comparative efficacy of targeted systemic therapies for moderate-to-severe atopic dermatitis without topical corticosteroids: an updated network meta-analysis. Dermatol Ther (Heidelb). 2023;13(10):2247–2264.
Blauvelt A, Teixeira HD, Simpson EL, et al. Efficacy and safety of upadacitinib vs dupilumab in adults with moderate-to-severe atopic dermatitis: a randomized clinical trial. JAMA Dermatol. 2021;157(9):1047–55.
Zhang Z. Covariate-adjusted putative placebo analysis in active-controlled clinical trials. Stat Biopharm Res. 2009;1(3):279–90.
Phillippo D, Ades T, Dias S, Palmer S, Abrams KR, Welton NJ. NICE DSU Technical Support Document 18: Methods for population-adjusted indirect comparisons in submissions to NICE: NICE Decision Support Unit; 2016. http://www.nicedsu.org.uk/Populationadjusted-ICs-TSD(3026862).htm, pg 6–7.
Reich K, de Bruin-Weller MS, Deleuran M, et al. Higher levels of response on clinical atopic dermatitis severity measures are associated with meaningful improvements in patient-reported symptom and quality of life measures: integrated analysis of three upadacitinib phase 3 trials. J Eur Acad Dermatol Venereol. 2023. https://doi.org/10.1111/jdv.18995.
Silverberg JI, Gooderham M, Katoh N, et al. Optimizing the management of atopic dermatitis with a new minimal disease activity concept and criteria and consensus-based recommendations for systemic therapy. Revolutionizing Atopic Dermatitis; 2022; Virtual Conference 2022.
Drucker AM, Ellis AG, Bohdanowicz M, et al. Systemic immunomodulatory treatments for patients with atopic dermatitis: a systematic review and network meta-analysis. JAMA Dermatol. 2020. https://doi.org/10.1001/jamadermatol.2020.0796.
Silverberg JI, Thyssen JP, Fahrbach K, et al. Comparative efficacy and safety of systemic therapies used in moderate-to-severe atopic dermatitis: a systematic literature review and network meta-analysis. J Eur Acad Dermatol Venereol. 2021;35(9):1797–810.
Funding
Financial support for the study was provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. All authors contributed to the development of the publication and maintained control over the final content. Funding for the journal’s Rapid Service Fee was provided by AbbVie.
Author information
Authors and Affiliations
Contributions
April W. Armstrong, H. Chih-Ho Hong, Brian Caimlim, Marric G. Buessing, Marjorie M. Crowell, and Jonathan I. Silverberg contributed to the study conception and design. Data preparation and analysis were performed by Marric Buessing and Marjorie Crowell. The first draft of the manuscript was written by Marric Buessing, Marjorie Crowell, and Brian Calimlim, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
Corresponding author
Ethics declarations
Conflict of Interest
April Armstrong has served as a research investigator, scientific advisor, or speaker to AbbVie, Amgen, Almirall, Arcutis, ASLAN, Beiersdorf, BI, BMS, EPI, Incyte, Leo, UCB, Janssen, Lilly, Mindera, Nimbus, Novartis, Ortho, Sun, Dermavant, Dermira, Sanofi, Takeda, Organon, Regeneron, Pfizer, and Ventyx. H. Chih-Ho Hong has served as an investigator, speaker, advisor and/or consultant for Abbvie, Amgen, Arcutis, Bausch Health, Boehringer-Ingelheim, Bristol Meyers Squibb, Celgene, Cutanea, Dermira, Dermavant, DS Biopharma, Eli Lilly, Evelo Biosciences, Galderma, GSK, Incyte, Janssen, Leo Pharma, Medimmune, Merck, Mirimar, Novartis, Pfizer, Regeneron, Sanofi-Genzyme, Roche, and UCB. Brian Calimlim is a full-time employee of AbbVie and may hold AbbVie stock and/or stock options and patents. Marric Buessing and Marjorie Crowell are employees of Medicus Economics LLC, which was paid fees by AbbVie to conduct the research in the manuscript. Jonathan Silverberg reports personal fees from Abbvie, Afyx, Arena, Asana, BioMX, Bluefin, Bodewell, Boehringer-Ingelheim, Celgene, Dermavant, Dermira, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Kiniksa, Leo, Luna, Menlo, Novartis, Pfizer, RAPT, Regeneron, and Sanofi-Genzyme; institution received grants from Galderma.
Ethical Approval
This study did not require institutional review board approval as it did not access identifiable patient information or have direct interaction with patients. This post hoc analysis used data from previously conducted studies and did not contain data from any new studies with human participants or animals performed by any of the authors.
Additional information
Prior Presentation: This manuscript is based on work that has been previously presented at RAD Virtual, 10 December 2023: https://djbpnesxepydt.cloudfront.net/radv/Dec2023Posters/524_Indirect-Comparison-on-Stringent-Endpoints_Armstrong-et-al_Poster_1701987797470.pdf.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
About this article
Cite this article
Armstrong, A.W., Hong, H.CH., Calimlim, B.M. et al. Efficacy of Upadacitinib and Dupilumab on Achieving Stringent and Composite Skin and Itch Outcomes: an Indirect Comparison of Adults with Moderate-to-Severe Atopic Dermatitis. Dermatol Ther (Heidelb) (2024). https://doi.org/10.1007/s13555-024-01240-x
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s13555-024-01240-x