Elsevier

The Lancet

Volume 397, Issue 10290, 5–11 June 2021, Pages 2169-2181
The Lancet

Articles
Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial

https://doi.org/10.1016/S0140-6736(21)00589-4Get rights and content

Summary

Background

Systemic therapies are typically combined with topical corticosteroids for the management of moderate-to-severe atopic dermatitis. Upadacitinib is an oral Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2 that is being tested for atopic dermatitis. We aimed to assess the efficacy and safety of upadacitinib plus topical corticosteroids compared with placebo for the treatment of moderate-to-severe atopic dermatitis.

Methods

In this randomised, double-blind, placebo-controlled, phase 3 trial (AD Up) adults (aged 18–75 years) and adolescents (aged 12–17 years) with chronic atopic dermatitis that was moderate to severe (≥10% of body surface area affected, Eczema Area and Severity Index [EASI] score of ≥16, validated Investigator's Global Assessment for atopic dermatitis [vIGA-AD] score of ≥3, and weekly average Worst Pruritus Numerical Rating Scale score of ≥4 at baseline) were enrolled at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, the Middle East, North America, and Oceania. Patients were randomly assigned (1:1:1) to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo once daily, all in combination with topical corticosteroids for 16 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity, geographical region, and age. Study investigators, study site personnel, and patients were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved at least a 75% reduction in EASI score from baseline (EASI-75) and the proportion of patients who had achieved a vIGA-AD response (defined as a vIGA-AD score of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement from baseline) at week 16. Efficacy was analysed in the intention-to-treat population and safety was analysed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03568318, and is active, but not recruiting.

Findings

Between Aug 9, 2018, and Dec 20, 2019, 901 patients were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304). At week 16, the proportion of patients who had achieved EASI-75 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (194 [65%] of 300 patients) and the upadacitinib 30 mg plus topical corticosteroids group (229 [77%] of 297 patients) than the placebo group (80 [26%] of 304 patients; adjusted difference in EASI-75 response rate vs placebo, 38·1% [95% CI 30·8–45·4] for the upadacitinib 15 mg group and 50·6% [43·8–57·4] for the upadacitinib 30 mg group; p<0·0001 for both doses). The proportion of patients who had achieved a vIGA-AD response at week 16 was significantly higher in the upadacitinib 15 mg plus topical corticosteroid group (119 [40%] patients) and upadacitinib 30 mg plus topical corticosteroid group (174 [59%] patients) than the placebo group (33 [11%] patients; adjusted difference in vIGA-AD response vs placebo, 28·5% [22·1–34·9] for the upadacitinib 15 mg group and 47·6% [41·1–54·0] for the upadacitinib 30 mg group; p<0·0001 for both doses). During the double-blind period, upadacitinib 15 and 30 mg were well tolerated in combination with topical corticosteroids. The most frequently reported treatment-emergent adverse events (≥5% in any treatment group) were acne, nasopharyngitis, upper respiratory tract infection, oral herpes, elevation of blood creatine phosphokinase levels, headache, and atopic dermatitis. The incidence of acne was higher in the upadacitinib 15 mg (30 [10%] of 300 patients) and upadacitinib 30 mg (41 [14%] of 297 patients) groups than the placebo group (six [2%] of 304 patients). The incidence of adverse events leading to discontinuation of study drug (four [1%] patients in the upadacitinib 15 mg plus topical corticosteroids group, four [1%] patients in the upadacitinib 30 mg plus topical corticosteroids group, and seven [2%] patients in the placebo plus topical corticosteroids group) and serious adverse events (seven [2%] patients, four [1%] patients, and nine [3%] patients) were similar among treatment groups. No deaths were reported in any treatment group.

Interpretation

Upadacitinib plus topical corticosteroids was well tolerated and superior to placebo plus topical corticosteroids. Upadacitinib as combination therapy had a positive benefit–risk profile in adults and adolescents with moderate-to-severe atopic dermatitis.

Funding

AbbVie.

Introduction

Atopic dermatitis, also known as atopic eczema, is the major cause of skin-related disability globally,1 and is characterised by recurrent eczematous lesions and intense itch (pruritus).2 The understanding of atopic dermatitis pathophysiology has evolved from early concepts that atopic dermatitis lesions were T-helper-2 (Th2) cell-driven in the acute phase, shifting to Th1 cell-driven in the chronic phase, to current understanding that atopic dermatitis lesions are associated with broad and progressive immune activation involving Th2, Th17, Th1, and Th22 pathways as lesions progress from acute to chronic.3 For many patients with moderate-to-severe atopic dermatitis, systemic therapy in addition to topical corticosteroids has been typically recommended to control symptoms.4 This combined treatment framework is based largely on the poor efficacy of systemic therapies used as monotherapy observed to date. Use of systemic immunosuppressive treatments such as ciclosporin A, azathioprine, and oral corticosteroids is restricted because of the risk of adverse events and the potential for cumulative toxicity, which is reflected by the high proportion of patients who discontinue treatment in clinical practice due to side-effects.5, 6 Less than half of patients given the anti-interleukin (IL)-4 receptor α monoclonal antibody dupilumab achieve clear or almost clear skin after 16 weeks of monotherapy treatment with maximal response achieved after week 8.7 The addition of topical corticosteroids to dupilumab increases the response rate compared with that observed for monotherapy by approximately 10–20%.7, 8 Similarly, the addition of topical corticosteroids to tralokinumab, an anti-IL-13 monoclonal antibody, or baricitinib, a selective Janus kinase 1 (JAK1) and JAK2 inhibitor, increased response rates by approximately 20–30% compared with that observed with either drug as monotherapy.9, 10, 11, 12

Research in context

Evidence before this study

Upadacitinib is an oral selective Janus kinase (JAK) inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, which is approved in the USA, Europe, and other countries to treat moderately or severely active rheumatoid arthritis and is under investigation for atopic dermatitis and other immune-mediated inflammatory conditions. Results from a phase 2b study (NCT02925117) showed that monotherapy with upadacitinib is well tolerated and effective in treating patients with moderate-to-severe atopic dermatitis. For many patients with moderate-to-severe atopic dermatitis, systemic therapy in addition to topical corticosteroids is recommended to control symptoms. This combination treatment framework is largely based on the poor efficacy of systemic therapies as monotherapy observed to date. Use of systemic immunosuppressive treatments are limited by the risk of adverse events and the potential for cumulative toxicity. We searched ClinicalTrials.gov for clinical trials done on or before Nov 5, 2020, using the search terms “TCS” and “combination” with “interventional phase 3 studies in atopic dermatitis”. Our search yielded ten studies: one study was not yet recruiting, two studies did not have published results, one study was done in children, three studies were in adults who were not adequately controlled with or had contraindications for ciclosporin A, and three studies were in a population similar to that of AD Up (adolescents or adults with moderate-to-severe atopic dermatitis). In the LIBERTY AD CHRONOS study, the addition of topical corticosteroids to dupilumab, an anti-interleukin (IL)-4 receptor α monoclonal antibody, increased the response rate compared with that for dupilumab monotherapy by approximately 10–20% in patients with moderate-to-severe atopic dermatitis. Similarly in the ECZTRA 3 and BREEZE-AD7 studies, the addition of topical corticosteroids to tralokinumab, an anti-IL-13 monoclonal antibody, or baricitinib, a selective JAK1 and JAK2 inhibitor, increased response rates by approximately 20–30% when compared with either drug as monotherapy.

Added value of this study

This study provides evidence for the safety and efficacy of upadacitinib in combination with topical corticosteroids, which is the current treatment framework for moderate-to-severe atopic dermatitis. Upadacitinib 15 mg and 30 mg plus topical corticosteroids were superior to placebo plus topical corticosteroids for the coprimary endpoints and all key secondary endpoints, with upadacitinib 30 mg plus topical corticosteroids showing numerically better results than upadacitinib 15 mg plus topical corticosteroids for all. A substantial proportion of patients achieved the stringent endpoint of at least a 90% improvement in Eczema Area and Severity Index score from baseline at week 16 in both upadacitinib groups (15 mg or 30 mg plus topical corticosteroids); 63% of patients in the upadacitinib 30 mg plus topical corticosteroids group achieved this endpoint, demonstrating a depth of response that has not previously been reported in studies of other atopic dermatitis therapies. Both doses of upadacitinib were well tolerated in combination with topical corticosteroids and no new important safety signals were observed beyond the known safety profile of upadacitinib in patients with rheumatoid arthritis; however, more patients given upadacitinib reported acne than did patients given placebo in this study. No patients had active tuberculosis, lymphoma, adjudicated gastrointestinal perforations, or adjudicated venous thromboembolisms.

Implications of all the available evidence

The results of this study support the potential of upadacitinib as a treatment option for adults and adolescents with moderate-to-severe atopic dermatitis. The magnitude of the clinical responses observed were generally similar to those observed for upadacitinib monotherapy, which might indicate that the incremental benefit of adding topical corticosteroids to upadacitinib is minimal compared with upadacitinib as monotherapy. A substantial proportion of patients were able to discontinue topical corticosteroids while maintaining a strong treatment response at week 16, suggesting that upadacitinib therapy could align with steroid-sparing treatment goals. These results challenge the current standard of care that asserts combination therapy with topical corticosteroids is essential to optimise outcomes.

There is a need for additional atopic dermatitis treatment options that can provide clinical responses (ie, Investigator's Global Assessment [IGA] of 0 [clear] or 1 [almost clear] with ≥2 grades of improvement and ≥75% improvement in Eczema Area and Severity Index score from baseline [EASI-75]) in more patients and more extensive (ie, at least a 90% reduction in EASI score [EASI-90] and at least a 100% reduction in EASI score [EASI-100]) and more rapid responses. The efficacy of dupilumab and other targeted therapies directed against specific cytokine pathways might be lower than therapies that inhibit multiple inflammatory pathways involved in atopic dermatitis. Many of the proinflammatory cytokines implicated in the pathophysiology of atopic dermatitis use JAK1 to mediate their effects, which include Th2 axis activation (IL-4, IL-13, and thymic stromal lymphopoietin), epidermal thickening and skin barrier dysfunction (IL-4, IL-13, IL22, and interferon-γ), and itch (IL–4, IL-13, IL-31, and thymic stromal lymphopoietin).13

Upadacitinib is an oral selective JAK inhibitor with greater inhibitory potency for JAK1 than JAK2, JAK3, or tyrosine kinase 2, and is approved in the USA, Europe, and other countries to treat moderately or severely active rheumatoid arthritis, and is under investigation for the treatment of atopic dermatitis and other immune-mediated inflammatory conditions.14 Upadacitinib was designed to occupy the so-called closed glycine-rich P-loop of JAK1 (as opposed to the more open confirmation of JAK2) via tight van der Waals interactions using its small and highly polar trifluoroethyl group, which confers increased metabolic stability and membrane permeability.14, 15 Results from a phase 2b study16 and contemporaneous phase 3 studies17 demonstrated that monotherapy with once-daily upadacitinib 15 mg or 30 mg is an effective and well tolerated treatment option for patients with moderate-to-severe atopic dermatitis. Since systemic atopic dermatitis treatments are often prescribed in combination with topical corticosteroids, it is important to assess the safety and efficacy of combination therapy for any new systemic atopic dermatitis treatment. Considering that treatment practices for atopic dermatitis vary with respect to topical corticosteroids use, here, we report the primary results from a phase 3 trial of upadacitinib in combination with topical corticosteroids in adults and adolescents with moderate-to-severe atopic dermatitis.

Section snippets

Study design and participants

AD Up (NCT03568318) was a randomised, double-blind, placebo-controlled, phase 3 trial done at 171 clinical centres across 22 countries in the Asia-Pacific region, Europe, Middle East, North America, and Oceania. The study consisted of a main study and an adolescent substudy (for which data acquisition is ongoing; results will be reported elsewhere). The main study consisted of a 35-day screening period and 16-week double-blind treatment period, followed by a 120-week blinded extension period

Results

Between Aug 9, 2018, and Dec 20, 2019, 1160 patients were screened, of whom 901 (785 adults and 116 adolescents) were randomly assigned to receive upadacitinib 15 mg plus topical corticosteroids (n=300), upadacitinib 30 mg plus topical corticosteroids (n=297), or placebo plus topical corticosteroids (n=304; figure 2). 287 (96%) of 300 patients in the upadacitinib 15 mg plus topical corticosteroids group, 287 (97%) of 297 patients in the upadacitinib 30 mg plus topical corticosteroids group, and

Discussion

Upadacitinib 15 mg plus topical corticosteroids and upadacitinib 30 mg plus topical corticosteroids were superior to placebo plus topical corticosteroids for the coprimary endpoints. Although no statistical comparisons were done between the upadacitinib 15 mg and 30 mg groups, the number of responders in the upadacitinib 30 mg plus topical corticosteroids group was consistently numerically higher than that in the upadacitinib 15 mg plus topical corticosteroids group for all key endpoints. The

Data sharing

AbbVie is committed to responsible data sharing regarding the clinical trials we sponsor. This includes access to anonymised, individual, and trial-level data (analysis datasets), as well as other information (eg, protocols and clinical study reports), 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. This clinical trial data can be requested by any qualified researchers who

Declaration of interests

KR has served as an adviser, paid speaker, or has participated in clinical trials sponsored by AbbVie, Affibody, Almirall, Amgen, Avillion, Biogen, Bausch Health (Valeant), Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Centocor, Covagen, Dermira, Forward Pharma, Fresenius, Galapagos, GlaxoSmithKline, Janssen, Kyowa Kirin, LEO Pharma, Lilly, Medac, Merck, Novartis, Miltenyi Biotec, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Sun Pharma, Takeda, UCB, and XenoPort. HDT, JZ,

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