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Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results from a randomized, placebo-controlled trial
Journal Pre-proof Upadacitinib in Adults With Moderate-to-Severe Atopic Dermatitis: 16-Week Results From a Randomized, Placebo-Controlled Trial Emma Guttman-Yassky, MD, Diamant Thaçi, MD, Aileen L. Pangan, MD, H. Chih-ho Hong, MD, Kim A. Papp, MD, Kristian Reich, MD, Lisa A. Beck, MD, Mohamed-Eslam F. Mohamed, PhD, Ahmed A. Othman, PhD, Jaclyn K. Anderson, DO, Yihua Gu, MS, Henrique D. Teixeira, PhD, Jonathan I. Silverberg, MD PII:
S0091-6749(19)31608-2
DOI:
https://doi.org/10.1016/j.jaci.2019.11.025
Reference:
YMAI 14280
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 22 May 2019 Revised Date:
17 October 2019
Accepted Date: 1 November 2019
Please cite this article as: Guttman-Yassky E, Thaçi D, Pangan AL, Hong HC-h, Papp KA, Reich K, Beck LA, Mohamed M-EF, Othman AA, Anderson JK, Gu Y, Teixeira HD, Silverberg JI, Upadacitinib in Adults With Moderate-to-Severe Atopic Dermatitis: 16-Week Results From a Randomized, PlaceboControlled Trial, Journal of Allergy and Clinical Immunology (2019), doi: https://doi.org/10.1016/ j.jaci.2019.11.025. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.
Guttman-Yassky 1
1 2
Upadacitinib in Adults With Moderate-to-Severe Atopic Dermatitis: 16-Week Results
3
From a Randomized, Placebo-Controlled Trial
4 5
Emma Guttman-Yassky, MD,1 Diamant Thaçi, MD,2 Aileen L. Pangan, MD,3 H. Chih-ho Hong,
6
MD,4 Kim A. Papp, MD,5 Kristian Reich, MD,6 Lisa A. Beck, MD,7 Mohamed-Eslam F.
7
Mohamed, PhD,8 Ahmed A. Othman, PhD,8* Jaclyn K. Anderson, DO,3 Yihua Gu, MS,9
8
Henrique D. Teixeira, PhD,3 Jonathan I. Silverberg, MD10
9
*At the time of this research.
10
1
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;
11
2
Institute and Comprehensive Center Inflammation Medicine, University of Lübeck, Lübeck,
12
Germany; 3Immunology Clinical Development, AbbVie Inc., North Chicago, IL, USA;
13
4
14
Medical Research, Surrey, BC, Canada; 5Probity Medical Research and K Papp Clinical
15
Research, Waterloo, ON, Canada; 6Translational Research in Inflammatory Skin Diseases,
16
Institute for Health Services Research in Dermatology and Nursing, University Medical Center
17
Hamburg-Eppendorf, and Skinflammation® Center, Hamburg, Germany; 7Department of
18
Dermatology, University of Rochester Medical Center, Rochester, NY, USA; 8Clinical
19
Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA; 9Data and
20
Statistical Sciences, AbbVie Inc., North Chicago, IL, USA; 10Department of Dermatology, The
21
George Washington University School of Medicine and Health Sciences, Washington, DC, USA
22
Department of Dermatology and Skin Science, University of British Columbia and Probity
Guttman-Yassky 2
23
Corresponding author:
24
Emma Guttman-Yassky, MD, PhD
25
Icahn School of Medicine at Mount Sinai
26
5 East 98th Street
27
New York, NY 10029 USA
28
Telephone: +1 212-241-9728/3288
29
Fax: +1 212-876-8961
30
[email protected]
31 32
Funding: AbbVie funded the study, contributed to the design of the study and was involved in
33
the collection, analysis, and interpretation of the data and in the writing, review, and approval of
34
the publication. The corresponding author had full access to all the data in the study and had final
35
responsibility for the decision to submit for publication.
36 37
Contributors
38
Study design: Emma Guttman-Yassky, Diamant Thaçi, Aileen L. Pangan, Mohamed-Eslam F.
39
Mohamed, Ahmed A. Othman, Jaclyn K. Anderson, Yihua Gu, Henrique D. Teixeira, Jonathan I.
40
Silverberg
41
Acquisition of data: Emma Guttman-Yassky, H. Chih-ho Hong, Kim A. Papp, Kristian Reich,
42
Lisa A. Beck, Jaclyn K. Anderson, Henrique D. Teixeira
43
Statistical analysis: Yihua Gu
Guttman-Yassky 3
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Analysis and interpretation of data: Emma Guttman-Yassky, Diamant Thaçi, Aileen L. Pangan,
45
H. Chih-ho Hong, Kim A. Papp, Kristian Reich, Lisa A. Beck, Mohamed-Eslam F. Mohamed,
46
Ahmed A. Othman, Jaclyn K. Anderson, Yihua Gu, Henrique D. Teixeira, Jonathan I. Silverberg
47
Writing of the manuscript: Emma Guttman-Yassky, Aileen L. Pangan, Mohamed-Eslam F.
48
Mohamed, Jaclyn K. Anderson, Henrique D. Teixeira
49
Critical revision of the manuscript for important intellectual content: Emma Guttman-Yassky,
50
Diamant Thaçi, Aileen L. Pangan, H. Chih-ho Hong, Kim A. Papp, Kristian Reich, Lisa A. Beck,
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Mohamed-Eslam F. Mohamed, Ahmed A. Othman, Jaclyn K. Anderson, Yihua Gu, Henrique D.
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Teixeira, Jonathan I. Silverberg
53
Declaration of Interests
54
EG: employee, Mount Sinai; research/consultant, AbbVie, Anacor, AnaptysBio, Asana
55
Biosciences, Botanix, Celgene, DBV, Dermira, DS Biopharma, Escalier, Galderma, Glenmark,
56
Innovaderm, Janssen, Kyowa Kirin, Leo Pharma, Lilly, MedImmune/AstraZeneca, Mitsubishi
57
Tanabe, Novan, Novartis, Pfizer, Promius, Ralexar, Regeneron, Sanofi Aventis, Stiefel/GSK,
58
UCB, Vitae
59
DT: advisor/speaker/consultant, AbbVie, Almirall, Amgen, Asana Biosciences, Biogen Idec,
60
Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dignity, GSK, Janssen-Cilag, Kyowa
61
Kirin, Leo Pharma, Lilly, Maruho, Merck Sharp & Dohme, Novartis, Regeneron, Sandoz,
62
Sanofi-Aventis, Pfizer, UCB; research, AbbVie, Celgene, Novartis
63
HH: research/consultant/advisor, AbbVie, Amgen, Celgene, Dermavant, DS Biopharma,
64
Galderma, GSK, Janssen, Leo Pharma, Lilly, MedImmune, Novartis, Pfizer, Regeneron, Roche,
65
Sanofi-Genzyme, UCB
Guttman-Yassky 4
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KP: advisor/speaker/consultant/steering committee/research, AbbVie, Akros, Allergan, Amgen,
67
Anacor, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers
68
Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Forward Pharma, Galderma,
69
Genentech, Gilead, GSK, InflaRx GmbH, Janssen, Kyowa-Hakko Kirin, Leo Pharma, Lilly,
70
MedImmune, Meiji Seika Pharma, Merck (MSD), Merck-Serono, Mitsubishi Pharma, Moberg
71
Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis Genzyme, Takeda, UCB,
72
Valeant/Bausch Health
73
KR: advisor/speaker/research, AbbVie, Affibody, Almirall, Amgen, Biogen, Boehringer
74
Ingelheim, Celgene, Centocor, Covagen, Forward Pharma, Fresenius Medical Care, GSK,
75
Janssen-Cilag, Kyowa Kirin, Leo, Lilly, Medac, Merck Sharp & Dohme, Novartis, Miltenyi
76
Biotec, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Takeda, UCB, Valeant,
77
Xenoport
78
LB: consultant, AbbVie, Asana Biosciences, AstraZeneca, Boehringer Ingelheim, Celgene, GSK,
79
Leo Pharma, Lilly, Novan, Novartis, Realm Therapeutics, Regeneron, Sanofi; research,
80
Regeneron, AbbVie, Realm Therapeutics; stock, Pfizer, Medtronics
81
JS: advisor/speaker/consultant, AbbVie, Asana, Dermavant, Galderma, GlaxoSmithKline,
82
Glenmark, Kiniksa, Leo, Lilly, Menlo, Novartis, Pfizer, Realm, Regeneron-Sanofi; research,
83
GSK
84
AP, MM, JA, YG, HT: employee/stock, AbbVie
85
AO: former employee/stock, AbbVie
Guttman-Yassky 5
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Abstract
87
Background: Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic
88
skin lesions.
89
Objective: This study evaluated the safety and efficacy of multiple doses of the selective Janus
90
kinase 1 inhibitor upadacitinib in patients with moderate-to-severe atopic dermatitis.
91
Methods: In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion
92
of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting),
93
adults with moderate-to-severe disease and inadequate control by topical treatment were
94
randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-
95
daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary endpoint was
96
percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy
97
was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all
98
randomized patients who received study medication, based on actual treatment.
99
Results: Patients (N=167) enrolled from November 21, 2016, to April 20, 2017. All were
100
randomized and analyzed for efficacy (each upadacitinib group, n=42; placebo, n=41); 166 were
101
analyzed for safety (each upadacitinib group, n=42; placebo, n=40). The mean (standard error)
102
primary efficacy endpoint was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib
103
7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P=0.03, <0.001, and
104
<0.001). Serious adverse events occurred in 4.8% [2/42], 2.4% [1/42], 0% [0/42] of upadacitinib
105
groups (vs 2.5% [1/40] for placebo).
106
Conclusion: A dose-response relationship was observed for upadacitinib efficacy; the 30-mg
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once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.
Guttman-Yassky 6
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Clinical Implication: The favorable benefit/risk profile of upadacitinib supported initiation of
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phase 3 trials in atopic dermatitis.
110 111
Capsule Summary: This study is the first to demonstrate the robust efficacy of the JAK-1
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selective inhibitor upadacitinib in patients with moderate-to-severe atopic dermatitis that could
113
not be controlled with topical therapy.
114
Keywords: atopic dermatitis; randomized clinical trial; eczema; efficacy; Janus kinase; placebo-
115
controlled; upadacitinib; safety
116
Guttman-Yassky 7
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Abbreviations List
118
AD=atopic dermatitis
119
AE=adverse event
120
ALT=alanine aminotransferase
121
AST=aspartate aminotransferase
122
BSA=body surface area
123
DLQI=The Dermatology Life Quality Index
124
EASI 90=≥90% improvement in Eczema Area and Severity Index
125
IGA 0/1=Investigator Global Assessment of 0 or 1
126
IL=interleukin
127
JAK=Janus kinase
128
NRS=numeric rating scale
129
POEM=Patient-Oriented Eczema Measure
130
QD=once daily
131
QoL=quality of life
132
SCORAD=SCORing Atopic Dermatitis
133
STAT=signal transducer and activator of transcription
134
Th=T helper
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TYK2=tyrosine kinase 2
Guttman-Yassky 8
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Introduction
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Atopic dermatitis (AD) is a common inflammatory skin disease characterized by recurrent
138
eczematous lesions,1 which are associated with intense pruritus that greatly interferes with
139
quality of life (QoL) and sleep,2 particularly in those with moderate-to-severe disease (16%–71%
140
of patients across different ages and regions).3 AD in adults may persist from childhood4or may
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begin or reoccur in adulthood.5 Corticosteroids are an orally administered systemic treatment
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widely used for patients with AD,6 but there is risk of exposure-associated adverse effects with
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long-term and short-term use.7 In some countries, cyclosporine A is approved for use for patients
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with severe AD but generally as short-term rescue therapy (≤1 year) because of cumulative
145
nephrotoxicity. The paucity of approved treatments has led to recommendations for use of other
146
agents not approved for AD (e.g., methotrexate and azathioprine)8 and motivated discovery and
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development of new compounds. Dupilumab, an approved injectable biologic for the treatment
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of moderate to severe AD, blocks binding of the T helper (Th) 2 cytokines interleukin (IL)-4 and
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IL-13 to IL-4 receptor α.9 Dupilumab administered every other week provided significant benefit
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compared with placebo in phase 2 and 3 trials by week 16; however, ≤40% of patients achieved
151
clear or almost clear skin (as defined by ≥90% improvement in Eczema Area and Severity Index
152
[EASI 90] or Investigator Global Assessment of 0 or 1 [IGA 0/1]).9-11 Thus, there remains a large
153
unmet need for treatments with better efficacy and a safety profile that is acceptable for long-
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term use.
155
Similar to psoriasis, AD is associated with T-cell activation in the skin and blood but is a more
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heterogeneous disease.12 In AD, the Th2 and Th22 cytokine pathways are activated, and some
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disease subtypes also appear to involve Th1 and Th17 cells.13-15 Thus, targeting multiple
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cytokine axes may be required to achieve broad efficacy.13 Many cytokines implicated in the
Guttman-Yassky 9
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pathogenesis of AD (e.g., Th2 cytokines [IL-4, IL-5, IL-13], IL-22, IL-31, IL-33, chemokines,
160
thymic stromal lymphopoietin, and interferon γ) exert their effects via intracellular signaling that
161
involves the Janus kinase (JAK) and signal transducer and activator of transcription (STAT)
162
pathways.15, 16
163
Preclinical research shows that disruption of JAK1 signaling reduces chronic itch by mechanisms
164
involving Th2 cytokines, which may also directly stimulate neurons to elicit itching17 and
165
supports a potential role for JAK inhibitors in the treatment of AD. Upadacitinib is an oral
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reversible JAK1 inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, and
167
tyrosine kinase 2 (TYK2)18 and is currently being investigated for several immune-mediated
168
inflammatory diseases. Minimizing inhibition of JAK2 and JAK3 may reduce adverse effects,
169
such as anemia and infections.19
170
The objective of this study was to evaluate the safety and efficacy of multiple doses of
171
upadacitinib versus placebo in adults with moderate-to-severe AD. Several other studies have
172
tested JAK inhibitors for the treatment of AD20; however, interpretation of the results was
173
complicated by concomitant use of topical corticosteroids (e.g., in the case of baricitinib).21 Ours
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was the first study to examine selective JAK1-inhibitor monotherapy for the treatment of AD.
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Guttman-Yassky 10
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Methods
177
Study Design
178
This is a phase 2b, double-blind, randomized, parallel-group, dose-ranging trial conducted at
179
clinical centers in Australia, Canada, Finland, Germany, Japan, Netherlands, Spain, and the
180
United States. Results from the 16-week, double-blind, randomized treatment period are reported
181
based on an interim database lock for the prespecified final efficacy analysis for this period. A
182
subsequent 72-week, double-blind, randomized withdrawal period is ongoing. The study is being
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conducted in accordance with International Council for Harmonisation Good Clinical Practice
184
guidelines and the Declaration of Helsinki. An independent ethics committee or institutional
185
review board at each study center approved the study protocol and other study-related documents
186
before procedures began. Patients provided written informed consent before beginning the study.
187 188
Patients
189
Eligible patients were 18 to 75 years old at screening, with a dermatologist-confirmed diagnosis
190
of AD according to Hanifin and Rajka criteria (≥3 of 4 major features and ≥3 of 23 minor
191
features),22 with symptoms for ≥1 year before baseline. The patients had moderate-to-severe AD,
192
defined as EASI ≥16, affected body surface area (BSA) ≥10%, and IGA ≥3, at baseline. They
193
had inadequate response to topical corticosteroids or topical calcineurin inhibitors within 1 year
194
before screening, or were patients for whom topical treatments were otherwise medically
195
inadvisable (e.g., because of important side effects or safety risks). All patients were to use an
196
additive-free bland emollient twice daily for ≥7 days before baseline and during the study
197
(details in Online Repository Methods).
Guttman-Yassky 11
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Randomization and Masking
199
An interactive response system referring to a schedule previously generated via computer by
200
statisticians from the study sponsor was used to randomize qualifying patients 1:1:1:1, stratified
201
by geographic region (United States, Puerto Rico, and Canada; European Union and Australia;
202
and Japan). Patients, investigators, and the sponsor were blinded to allocation. Each study drug
203
kit was labeled with a unique code that was linked to the randomization schedule. The placebo
204
and upadacitinib tablets were identical in appearance to maintain blinding of treatment
205
assignment.
206
Procedures
207
Patients received placebo or extended-release upadacitinib (manufactured by the study sponsor)
208
7.5, 15, or 30 mg QD by mouth. After the baseline visit, patients returned to the clinic at weeks
209
2, 4, 8, 12, and 16. Discontinuation of study drug (placebo or upadacitinib) was required if a
210
patient’s EASI worsened by ≥25% from baseline at two consecutive visits between weeks 4 and
211
12.
212
Efficacy assessments, recorded at baseline and during clinic visits at weeks 2, 4, 8, 12, and 16,
213
included EASI, IGA, pruritus numeric rating scale (NRS; weekly average of daily patient
214
assessments), SCORing Atopic Dermatitis (SCORAD),23 BSA, and Patient-Oriented Eczema
215
Measure (POEM).24 Details are in the Online Repository Methods.
216
Safety monitoring included treatment-emergent adverse events (AEs), physical examinations,
217
vital signs, and clinical laboratory assessments. AEs, vital signs, and clinical laboratory
218
assessments were recorded at each clinic visit. Physical examinations were made at baseline and
219
week 16.
Guttman-Yassky 12
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Outcomes
221
Primary and secondary outcomes were pre-specified. The primary endpoint was percentage
222
improvement from baseline at week 16 in EASI. Secondary endpoints were proportions of
223
patients achieving improvement of ≥50%/≥75%/≥90% from baseline in EASI (EASI 50/75/90) at
224
weeks 8 and 16; proportions of patients achieving IGA 0/1 at week 16; percentage improvement
225
from baseline in EASI at week 8; percentage improvement from baseline in pruritus NRS by
226
week and proportions of patients achieving pruritus NRS improvement from baseline of ≥4
227
points at each visit (among patients with baseline NRS ≥4 points); percentage improvement from
228
baseline in SCORAD at weeks 8 and 16; proportions of patients achieving ≥50%/≥75%/≥90%
229
improvement from baseline in SCORAD (SCORAD 50/75/90) at weeks 8 and 16; and change
230
from baseline in BSA at week 16. The primary and secondary variables were also analyzed for
231
all study visits at which they were assessed. Additional endpoints included percentage
232
improvement from baseline in BSA at each visit, proportions of patients achieving EASI 100 at
233
each visit, and change from baseline in POEM at weeks 4 and 16. Dermatology Life Quality
234
Index outcomes (proportion of patients achieving score 0/1 and change from baseline) were
235
defined but are not reported because of an error in the programming of the electronic device used
236
to administer the questionnaire that precluded determination of these outcomes.
237
Upadacitinib plasma concentrations were quantitated as previously described.25
238
Adverse events were coded according to Medical Dictionary for Regulatory Activities, version
239
20.0. Changes from baseline in physical examinations findings, vital signs, and clinical
240
laboratory values were recorded. Assessment of the severity of AEs and laboratory changes was
241
based on Common Terminology Criteria for Adverse Events (version 4.0) developed by the
242
National Cancer Institute.
Guttman-Yassky 13
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Statistical Analysis
244
Forty patients per treatment arm were targeted for enrollment. Assuming that improvements of
245
35%, 45%, 60%, and 70% would occur for the primary endpoint in the placebo and upadacitinib
246
7.5-, 15-, and 30-mg QD groups, respectively, with an SD of 40%, this sample size provides 99%
247
average power to detect a dose effect at a 5% level of significance (1-sided) to characterize the
248
dose-response for upadacitinib. This sample size also provided 97% power to detect a difference
249
for upadacitinib 30 mg QD compared with placebo and 78% power to detect a difference for
250
upadacitinib 15 mg QD compared with placebo at a 2-sided significance level of 5%. Between-
251
group statistical comparisons of continuous efficacy endpoints were made by analysis of
252
covariance, with stratum (geographic region), baseline value, and treatment in the model.
253
Between-group statistical comparisons of categorical efficacy endpoints were made with the
254
Cochran-Mantel-Haenszel test, adjusted for stratum (geographic region). All efficacy analyses
255
were conducted in the intention-to-treat population, comprising all randomized patients, based on
256
treatment assigned. Missing efficacy data were analyzed by last observation carried forward
257
(continuous variables) and by non-responder imputation (categorical variables). The dose-
258
response relationships among the 3 upadacitinib treatment groups and placebo group were
259
characterized for the primary endpoint using a multiple comparison procedures and modeling
260
approach that also controlled for overall type I error. Secondary endpoints and other efficacy
261
endpoints were analyzed at the nominal alpha level of 5%. Safety was analyzed in all
262
randomized patients who received ≥1 dose of study medication, based on actual treatment
263
received. A data monitoring committee oversaw unblinded safety results during the study.
264
Cardiovascular events were adjudicated by a blinded, independent adjudication committee
265
according to predefined criteria. Treatment-emergent AEs (i.e., those that occurred after starting
Guttman-Yassky 14
266
study drug through 30 days after the last dose) were summarized with descriptive statistics;
267
between-group statistical comparisons of laboratory measures were made by using a contrast
268
within a 1-way analysis of variance. Analyses were conducted with SAS version 9.4 (SAS
269
Institute, Cary, NC, USA). The study is registered with ClinicalTrials.gov, number
270
NCT02925117.
271
Guttman-Yassky 15
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Results
273
Patients
274
Between October 25, 2016, and March 16, 2017, 218 patients were assessed for eligibility, of
275
whom 167 were found eligible and enrolled to the study, and 166 received placebo or
276
upadacitinib (Figure 1). The first patient was enrolled on November 21, 2016, and the last on
277
April 20, 2017. Premature discontinuation was more common with placebo (primarily due to
278
lack of efficacy) than with upadacitinib. Patient demographic and baseline characteristics were
279
generally well balanced among treatment arms, except numerically fewer patients had an IGA of
280
4 (severe AD) in the upadacitinib 7.5- and 30-mg groups compared with the placebo and
281
upadacitinib 15-mg groups (Table I).
282
Efficacy
283
All upadacitinib doses (7.5, 15, and 30 mg) showed significantly higher mean (SE) percentage
284
improvement from baseline at week 16 in EASI versus placebo (39% [6.2%], P=0.03; 62%
285
[6.1%], P<0.001; and 74% [6.1%], P<0.001 vs 23% [6.4%], respectively), with a clear dose-
286
response relationship (Figure 2). Mean (95% CI) difference versus placebo for percentage
287
improvement from baseline at week 16 in EASI was 16% (1.4%–31%), 39% (24%–54%), and
288
51% (36%–67%), for upadacitinib 7.5, 15, and 30 mg, respectively. The dose-response
289
relationship for upadacitinib doses (7.5, 15, and 30 mg) was consistently demonstrated for this
290
endpoint in the subgroups of patients with baseline IGA of 3 (40% [8.3%], P=0.23; 63% [9.6%],
291
P=0.004; and 73% [7.6%], P<0.001 vs 27% [10%] for placebo) and baseline IGA of 4 (35%
292
[10%], P=0.19; 59% [8.3%], P<0.001; and 75% [11%], P<0.001 vs 19% [8.5%] for placebo),
293
confirming that treatment response was not affected by the numerical imbalance in baseline IGA
294
among the treatment groups. Statistical significance in favor of all upadacitinib doses in EASI
Guttman-Yassky 16
295
50, EASI 75, and EASI 90 responses was also achieved at week 16; EASI 100 was achieved by
296
2.4% (1/42; P=0.43), 9.5% (4/42; P=0.05), and 24% (10/42; P=0.001) of patients in the
297
upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus none (0/41) in the placebo group.
298
Each upadacitinib dose level was significantly superior to placebo for investigator assessment
299
(IGA 0/1) and patient assessment of pruritus (improvement in NRS and achievement of NRS
300
reduction ≥4) at week 16. Efficacy at the studied doses was generally demonstrated by week 1 to
301
4, with peak values reached and maintained after week 4 or 8 (Figure 3 and Figure E1).
302
SCORAD outcomes at weeks 8 and 16 favored upadacitinib compared with placebo, reaching
303
statistical significance for most comparisons (Figure E2). Mean percentage reductions in BSA
304
were significantly greater in all upadacitinib groups compared with placebo at every assessment
305
(weeks 2, 4, 8, 12, and 16; Figure E3), with the exception of the last assessment in the
306
upadacitinib 7.5-mg group. POEM scores at weeks 4 and 16 improved significantly more in all
307
upadacitinib groups compared with the placebo group (Figure E4).
308
Pharmacokinetics
309
Upadacitinib exposures were approximately dose proportional over the 7.5- to 30-mg dose range.
310
Upadacitinib median (interquartile range) plasma concentrations around peak and trough times
311
were consistent with exposures previously observed for the evaluated doses in healthy volunteers
312
(7.5-mg dose: 10.6 [0.8–21.0] and 2.8 [1.4–4.5] ng/mL, respectively; 15-mg dose: 32.5 [22.7–
313
39.3] and 3.6 [1.8–7.0] ng/mL; 30-mg dose: 57.0 [28.1–94.8] and 8.1 [6.6–16.6] ng/mL).26
314
Safety
315
Exposure to study drug was lower in the placebo group (Table II) because of the higher rate of
316
study discontinuation (Figure 1) in this group compared with the upadacitinib groups. AEs were
317
reported in 71% (30/42), 74% (31/42), and 79% (33/42) of patients receiving upadacitinib 7.5,
Guttman-Yassky 17
318
15, and 30 mg, respectively, versus 63% (25/40) of patients receiving placebo (Table II). The
319
most frequently reported AEs (≥10% in any group) were upper respiratory tract infection, AD
320
worsening, and acne (all reported as mild or moderate in severity). There was no relationship
321
between the dose of upadacitinib and the occurrence of particular AEs.
322
Serious AEs were infrequent and occurred in no more than two patients in any treatment group
323
(Table II). In the placebo group, a serious AE of atrial fibrillation occurred in a 71-year-old man
324
with a history of atrial fibrillation, sick sinus syndrome, hypertension, asthma,
325
emphysema/chronic obstructive pulmonary disease, obstructive sleep apnea, and smoking (30
326
years). Two patients in the upadacitinib 7.5-mg group had serious AEs: a 35-year-old man with a
327
history of repeated tooth infections experienced lower jaw pericoronitis, and a 20-year-old
328
woman experienced worsening AD (skin infection and exacerbation of AD) in the context of
329
contact dermatitis. In the upadacitinib 15-mg group, one serious AE of appendicitis was reported
330
in a 66-year-old man. No serious AEs occurred in patients allocated to upadacitinib 30 mg. All
331
serious AEs resolved with treatment in patients who received upadacitinib. The number of AEs
332
leading to discontinuation was low across the placebo and upadacitinib treatment groups (n=3,
333
n=4, n=2, and n=4 in the placebo and upadacitinib 7.5-, 15-, and 30-mg groups).
334
There were no deaths, opportunistic infections, malignancies, gastrointestinal perforations, AEs
335
of herpes zoster, renal dysfunction, active or latent tuberculosis, adjudicated cardiovascular
336
events, or thromboembolic events. Infections were more common with upadacitinib than
337
placebo, but there were few serious infections (Table II). Although 63 of 167 patients (38%) had
338
a history of asthma, no AEs of asthma exacerbation were reported during the study.
339
Mean laboratory values remained within normal ranges (Figure E5), and grade 3 and 4
340
laboratory abnormalities were uncommon (Table E1). Hepatic disorder AEs, none serious, were
Guttman-Yassky 18
341
reported in three patients during the study (Table II; alanine aminotransferase [ALT] and
342
aspartate aminotransferase [AST] increased in one patient in the placebo group [neither event
343
with grade ≥2 laboratory increase]; blood bilirubin increased in one patient in the upadacitinib
344
15-mg group [grade 2 laboratory increase]; and hepatic steatosis in another patient in the
345
upadacitinib 15-mg group [associated with grade 2 ALT increase]). All hepatic disorder AEs
346
were considered mild and resolved without dosing changes. Mean changes in ALT and AST
347
levels were similar among treatment groups, and no grade 3 or 4 ALT or AST elevations
348
occurred in patients receiving upadacitinib. All AEs of creatine phosphokinase (CPK) elevation
349
were asymptomatic in patients receiving upadacitinib and reported as mild to moderate in
350
severity (Table E1). Mean hemoglobin levels decreased more with upadacitinib compared with
351
placebo but remained at 133 to 145 g/L, which is within the normal ranges for both women and
352
men. No patients had hemoglobin abnormalities of grade ≥3. No decrease in mean absolute
353
lymphocyte counts was observed in any upadacitinib treatment group, and no patients had
354
lymphocyte abnormalities of grade ≥3. Decreases in mean neutrophil counts were small and
355
generally similar between upadacitinib and placebo. There were increases in mean
356
concentrations of low-density and high-density lipoprotein cholesterol in the upadacitinib groups
357
compared with the placebo group, but lipid ratios showed no clear pattern of change (Table E2).
358
Guttman-Yassky 19
359
Discussion
360
In this first study to investigate the efficacy and safety of the JAK1-selective inhibitor
361
upadacitinib as monotherapy for the treatment of adults with moderate-to-severe AD
362
inadequately controlled by topical medications, upadacitinib was efficacious and appeared to
363
exhibit a favorable benefit/risk profile compared with placebo. This phase 2b clinical trial
364
enrolled a population of patients with long-standing AD whose baseline severity was comparable
365
to that in the dupilumab phase 3 studies.9-11 The primary efficacy endpoint of percentage
366
improvement from baseline to week 16 in EASI and multiple other endpoints (e.g., EASI 50,
367
EASI 75, EASI 90, and IGA 0/1) were statistically significantly better at each upadacitinib dose
368
level compared with placebo, with a clear dose response. Achievement of EASI 100 was
369
significantly higher in the upadacitinib 15-mg and 30-mg groups versus placebo at week 16. We
370
also noted marked improvement from baseline at week 16 in pruritus, SCORAD, BSA, and
371
POEM with each upadacitinib dose regimen. Signs and symptoms showed rapid improvements
372
with upadacitinib compared with placebo; pruritus improved significantly at first assessment
373
(week 1), as did clinical efficacy endpoints (first assessments at week 2). The alleviation of
374
pruritus may be particularly important because itching worsens AD patients’ QoL (including loss
375
of sleep and suicidal thoughts).2 Maximal efficacy for percentage improvement in EASI, EASI
376
50, and EASI 75 was reached at week 4 and maintained through week 16. More stringently
377
defined endpoints (EASI 90 and IGA 0/1) plateaued between weeks 8 and 16, although the EASI
378
100 response was still increasing at week 16. In this phase 2b study, there were no dose-limiting
379
safety events or unexpected safety findings that would preclude further evaluation of
380
upadacitinib in AD.
Guttman-Yassky 20
381
A clear dose response was observed for the primary endpoint and a majority of secondary
382
endpoints. Upadacitinib 30 mg QD was associated with the greatest reduction in EASI and
383
appeared to present the best benefit/risk profile; the EASI 90 and IGA 0/1 results with
384
upadacitinib 30 mg (both endpoints, 50.0% at week 16) are high for a systemic monotherapy in
385
this patient population. A threshold of response, EASI 100, that had not previously been reported
386
before this study began, was defined and observed with upadacitinib. The improvement in
387
pruritus with JAK1 inhibition in this trial may have been mediated by blocking the effects of IL-
388
31 and factors that directly induce itching in sensory neurons.17 More broadly, the efficacy
389
observed in this trial may reflect the fact that JAK1 inhibition targets additional cytokine
390
pathways involved in chronic AD15 beyond just Th2 and Th22 cytokines.16 Further research may
391
reveal whether JAK1 inhibition might be beneficial in atopic diseases other than AD.
392
In this study with a limited population size that might not be representative of all potential AD
393
populations, no dose-limiting safety events nor any new safety concerns compared with the
394
ongoing upadacitinib rheumatoid arthritis phase 3 program were observed, even though safety
395
analyses were not adjusted for the greater rate of discontinuation in the placebo group. No dose
396
relationship was observed in the overall rate of AEs. Infections (but not serious infections) were
397
more common with upadacitinib compared with placebo. The events of acne, diagnosed by the
398
dermatologist investigators, were unexpected; however, as none of those AEs was serious, no
399
further details, e.g., the type of acne, are available. No deaths, herpes zoster, malignancies, or
400
thromboembolic events were reported. Dose-dependent decreases in mean hemoglobin levels
401
were small and remained within the normal ranges for women and men; no grade 3 or 4
402
decreases in hemoglobin were reported. A small number of asymptomatic CPK abnormalities
403
were observed but did not require permanent discontinuation in study drug dosing.
Guttman-Yassky 21
404
A limitation of this report is the 16-week duration of treatment. Although efficacy appeared to
405
stabilize within the 16-week period (except EASI 100, which was still increasing), the ongoing
406
72-week period of this study will provide information on longer-term efficacy and safety.
407
Another limitation is that a dose-limiting toxicity was not defined and therefore complete dose
408
ranging was not accomplished. In fact, efficacy did not plateau with the tested doses so it is
409
possible that higher doses might have produced even greater efficacy. However, unprecedented
410
efficacy in patients with atopic dermatitis was demonstrated with upadacitinib 30 mg in this
411
study, and small dose-dependent changes, not considered to be clinically meaningful, in
412
hemoglobin, neutrophils, LDL-cholesterol, and HDL-cholesterol over time were observed.
413
Overall, based on the phase 2 data, the 30-mg QD upadacitinib dose appears to have a favorable
414
benefit/risk profile in atopic dermatitis.
415
Overall, upadacitinib showed rapid clinical improvement in the primary and secondary study
416
outcomes at every dose studied, with particularly robust efficacy at the two highest doses.
417
Because of these results, upadacitinib is the first oral agent granted breakthrough therapy
418
designation by the US Food and Drug Administration for development in AD. In conclusion,
419
upadacitinib monotherapy was efficacious and demonstrated a favorable benefit/risk profile
420
compared with placebo in adults with moderate-to-severe AD and inadequate response to topical
421
treatments, supporting initiation of larger randomized, controlled, phase 3 studies to confirm its
422
potential as an effective treatment for this population.
Guttman-Yassky 22
423
Acknowledgments
424
AbbVie and the authors thank the participants in the clinical trial and all study investigators for
425
their contributions. AbbVie contributed to the design of the study and was involved in the
426
collection, analysis, and interpretation of the data and in the writing, review, and approval of the
427
publication. Statistical analysis support was provided by Su Chen, PhD, of AbbVie. Medical
428
writing support was provided by Michael J. Theisen, PhD, and Janet E. Matsuura, PhD, at
429
Complete Publication Solutions, LLC (North Wales, PA), a CHC Group company, and was
430
funded by AbbVie.
431 432
Data Sharing
433
These clinical trial data can be requested by any qualified researchers who engage in rigorous,
434
independent scientific research, and will be provided following review and approval of a
435
research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing
436
Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for
437
12 months, with possible extensions considered. For more information on the process, or to
438
submit a request, visit the AbbVie data and information sharing website:
439
https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-
440
sharing/data-and-information-sharing-with-qualified-researchers.html.
441
Guttman-Yassky 23
442
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443
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2.
Drucker AM. Atopic dermatitis: burden of illness, quality of life, and associated
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complications. Allergy Asthma Proc 2017;38:3-8. 3.
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Silverberg JI. Public health burden and epidemiology of atopic dermatitis. Dermatol Clin
Kim JP, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): a systematic review and meta-analysis. J Am Acad Dermatol 2016;75:681-7 e11.
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Lee HH, Patel KR, Singam V, Rastogi S, Silverberg JI. A systematic review and meta-
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analysis of the prevalence and phenotype of adult-onset atopic dermatitis. J Am Acad
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Dermatol 2018:[Epub ahead of print].
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Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et
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al. Consensus-based European guidelines for treatment of atopic eczema (atopic
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dermatitis) in adults and children: part II. J Eur Acad Dermatol Venereol 2018;32:850-78.
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Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, et al. Short term use of
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oral corticosteroids and related harms among adults in the United States: population
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Boguniewicz M, Fonacier L, Guttman-Yassky E, Ong PY, Silverberg J, Farrar JR. Atopic
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Thaci D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled
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by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.
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Lancet 2016;387:40-52.
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Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two
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Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, Weisman J, Pariser D, et al.
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Long-term management of moderate-to-severe atopic dermatitis with dupilumab and
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concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised,
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double-blinded, placebo-controlled, phase 3 trial. Lancet 2017;389:2287-303.
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Czarnowicki T, Malajian D, Shemer A, Fuentes-Duculan J, Gonzalez J, Suarez-Farinas
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M, et al. Skin-homing and systemic T-cell subsets show higher activation in atopic
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dermatitis versus psoriasis. J Allergy Clin Immunol 2015;136:208-11.
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Suarez-Farinas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de Guzman Strong C, et
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al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation
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compared with extrinsic atopic dermatitis. J Allergy Clin Immunol 2013;132:361-70.
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Noda S, Suarez-Farinas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, et al. The
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Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis
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with increased TH17 polarization. J Allergy Clin Immunol 2015;136:1254-64.
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Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and
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its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol
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chronic inflammatory skin disease atopic dermatitis. JAKSTAT 2013;2:e24137. 17.
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Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in
Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 2017;171:217-28 e13.
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Parmentier JM, Voss J, Graff C, Schwartz A, Argiriadi M, Friedman M, et al. In vitro and
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Charman CR, Venn AJ, Williams HC. The patient-oriented eczema measure:
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Mohamed MF, Camp HS, Jiang P, Padley RJ, Asatryan A, Othman AA.
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Mohamed MF, Zeng J, Marroum PJ, Song IH, Othman AA. Pharmacokinetics of
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Guttman-Yassky 27
Table I. Patient Demographic and Baseline Characteristics
Placebo
Upadacitinib 7.5 mg QD
Upadacitinib 15 mg QD
Upadacitinib 30 mg QD
Characteristic
(n=41)
(n=42)
(n=42)
(n=42)
Female, n (%)
17 (41)
14 (33)
12 (29)
20 (48)
39.9 (17.5)
41.5 (15.4)
38.5 (15.2)
39.9 (15.3)
White
28 (68)
24 (57)
21 (50)
23 (55)
Black or African American
6 (15)
7 (17)
10 (24)
6 (14)
Asian
7 (17)
9 (21)
9 (21)
13 (31)
Native Hawaiian or other Pacific Islander
0
2 (4.8)
1 (2.4)
0
American Indian or Alaska Native
0
0
1 (2.4)
0
0
2 (4.8)
2 (4.8)
1 (2.4)
26.2 (6.8)
27.9 (6.3)
27.4 (6.7)
27.4 (6.0)
USA/PR/Canada
29 (71)
29 (69)
29 (69)
29 (69)
EU/Australia
10 (24)
11 (26)
10 (24)
10 (24)
Japan
2 (4.9)
2 (4.8)
3 (7.1)
3 (7.1)
Duration since AD diagnosis, y, mean (SD)
26.8 (18.8)*
30.4 (18.1)
22.6 (15.8)
24.2 (13.6)
Duration of AD symptoms, y, mean (SD)
30.6 (18.6)*
33.9 (18.0)
23.6 (15.2)†
26.7 (15.7)†
14 (34)
15 (36)
11 (26)
14 (33)
0.556† (0.497)
0.575 (0.683)
0.446 (0.475)
0.518 (0.385)
Age, y, mean (SD) Race, n (%)
Hispanic or Latino ethnicity, n (%) BMI, kg/m2, mean (SD) Region, n (%)
History of asthma, n (%) Eosinophils, ×109/L, mean
Guttman-Yassky 28
Characteristic
Placebo
Upadacitinib 7.5 mg QD
Upadacitinib 15 mg QD
Upadacitinib 30 mg QD
(n=41)
(n=42)
(n=42)
(n=42)
32.6 (14.5)
31.4 (15.8)
31.4 (12.3)
28.2 (11.6)
(SD) EASI, mean (SD)‡
45.7 (22.8)
46.9 (24.9)
50.6 (21.5)
42.1 (20.4)
Moderate (IGA=3)
18 (44)
29 (69)
19 (45)
31 (74)
Severe (IGA=4)
23 (56)
13 (31)
23 (55)
11 (26)
6.5 (1.9)†
6.8 (1.8)†
6.4 (1.7)¶
6.3 (2.1)
BSA, %, mean (SD) IGA, n (%)§
Pruritus NRS, mean (SD)||
AD, atopic dermatitis; BMI, body mass index; BSA, affected body surface area; EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment; NRS, numeric rating scale; PR, Puerto Rico; QD, once daily. *Data missing for 1 patient. †
Data missing for 2 patients.
‡
Full scale ranges from 0 (none) to 72 (most severe).
§
Full scale ranges from 0 (clear) to 4 (severe).
||
Full scale ranges from 0 (no itch) to 10 (worst imaginable itch).
¶
Data missing for 5 patients.
Guttman-Yassky 29
Table II. Adverse Event Summary* Upadacitinib Upadacitinib Upadacitinib 15 mg QD 30 mg QD Placebo 7.5 mg QD Treatment-Emergent AE, n (%)
(n=40)
(n=42)
(n=42)
(n=42)
Any AE
25 (63)
31 (74)
32 (76)
33 (79)
Serious AE
1 (2.5)
2 (4.8)
1 (2.4)
0
AE leading to discontinuation of study drug
3 (7.5)
4 (9.5)
2 (4.8)
4 (9.5)
Infection
8 (20)
22 (52)
18 (43)
17 (41)
0
2 (4.8) †
1 (2.4)‡
0
1 (2.5)§
0
2 (4.8)||
0
Anemia
0
0
0
1 (2.4)
Neutropenia
0
1 (2.4)
2 (4.8)
2 (4.8)
Lymphopenia
0
0
1 (2.4)
0
URTI
4 (10)
7 (17)
5 (12)
5 (12)
Atopic dermatitis worsening
2 (5.0)
6 (14)
2 (4.8)
4 (9.5)
Acne
1 (2.5)
4 (9.5)
2 (4.8)
6 (14)
Headache
1 (2.5)
3 (7.1)
3 (7.1)
4 (9.5)
Nasopharyngitis
1 (2.5)
2 (4.8)
4 (9.5)
3 (7.1)
Blood CPK increased
2 (5.0)
0
3 (7.1)
4 (9.5)
Nausea
1 (2.5)
3 (7.1)
1 (2.4)
3 (7.1)
Diarrhea
2 (5.0)
2 (4.8)
2 (4.8)
0
Influenza
0
3 (7.1)
0
0
Oropharyngeal pain
0
3 (7.1)
0
0
Serious infection Hepatic disorder
AE in ≥5% of patients in any group
Guttman-Yassky 30
Upadacitinib Upadacitinib Upadacitinib 15 mg QD 30 mg QD Placebo 7.5 mg QD Treatment-Emergent AE, n (%) Ligament sprain
(n=40)
(n=42)
(n=42)
(n=42)
2 (5.0)
0
0
0
AE, adverse event; CPK, creatine phosphokinase; QD, once daily; URTI, upper respiratory tract infection. *Mean (SD) exposure to study drug in the placebo, upadacitinib 7.5 mg, upadacitinib 15 mg, and upadacitinib 30 mg groups was 81.6 (41.2), 101.3 (28.5), 104.2 (24.5), and 108.9 (16.4) days, respectively. †
One event each of skin infection and pericoronitis.
‡
One event of appendicitis.
§
One patient with alanine aminotransferase increased and aspartate aminotransferase increased.
||
One patient with blood bilirubin increased; one patient with hepatic steatosis.
Figure Legends Figure 1. Patient disposition with primary reasons for discontinuation of study drug. QD, once daily. *May include meeting criteria for ≥25% worsening of Eczema Area and Severity Index, resulting in discontinuation of study drug according to the protocol.
Figure 2. EASI, IGA 0/1, and pruritus NRS outcomes at week 16. EASI, Eczema Area and Severity Index; EASI 50/75/90/100, ≥50%/≥75%/≥90%/100% improvement in EASI; IGA 0/1, Investigator Global Assessment of 0 or 1; LOCF, last observation carried forward; NRI, non-
Guttman-Yassky 31
responder imputation; NRS, numeric rating scale; QD, once daily. *P≤0.001, †P≤0.01, and ‡
P≤0.05 for upadacitinib vs placebo.
Figure 3. EASI, IGA 0/1, and pruritus NRS over time. EASI, Eczema Area and Severity Index; IGA 0/1, Investigator Global Assessment of 0 or 1; LOCF, last observation carried forward; NRS, numeric rating scale; QD, once daily. *P≤0.001, †P≤0.01, and ‡P≤0.05 for upadacitinib vs placebo.
Screened n=218
Randomized N=167
Placebo n=41
Ineligible n=51 • Inclusion/exclusion criteria, 35 • Withdrew consent, 12 • Lost to follow-up, 3 • Other, 1
Upadacitinib 7.5 mg QD n=42
Upadacitinib 15 mg QD n=42
Upadacitinib 30 mg QD n=42
Treated n=42
Treated n=42
Treated n=42
Not treated n=1 Treated n=40
Discontinued n=20 • Adverse event, 2 • Lack of efficacy, 13* • Withdrew consent, 2 • Lost to follow-up, 1 • Progressive disease, 1 • Other, 1
Completed n=20
Analyzed for efficacy n=41 Analyzed for safety n=40
Discontinued n=11 • Adverse event, 2 • Lack of efficacy, 6* • Withdrew consent, 1 • Lost to follow-up, 1 • Progressive disease, 1
Completed n=31
Analyzed for efficacy n=42 Analyzed for safety n=42
Discontinued n=5 • Adverse event, 2 • Lack of efficacy, 2* • Withdrew consent, 1
Completed n=37
Analyzed for efficacy n=42 Analyzed for safety n=42
Discontinued n=4 • Adverse event, 2 • Lack of efficacy, 1* • Other, 1
Completed n=38
Analyzed for efficacy n=42 Analyzed for safety n=42
Mean ± SE Percentage Improvement (LOCF) or Percentage (95% CI) of Patients Achieving Response (NRI)
Placebo Upadacitinib 7.5 mg QD 100
Upadacitinib 15 mg QD
*
90
*
80
*
70
*
*
Upadacitinib 30 mg QD
*
†
‡
‡
*
†
40
* † ‡
*
‡
30
*
*
*
60 50
*
*
‡ ‡
20 10
0
0 Improvement in EASI (LOCF)
EASI 50 (NRI)
EASI 75 (NRI)
EASI 90 (NRI)
EASI 100 (NRI)
IGA 0/1 (NRI)
Improvement Pruritus NRS in Reduction Pruritus NRS ≥4 (LOCF) (NRI)
Mean ± SE Percentage Improvement From Baseline in EASI (LOCF)
Placebo Upadacitinib 7.5 mg QD Upadacitinib 15 mg QD Upadacitinib 30 mg QD
100 90 80 70 60 50 40 30 20 10 0
*
*
*
*
*
*
*
‡
* * * *
0
2
4
8
Week
12
* * ‡
16
Percentage (95% CI) of Patients Achieving IGA 0/1 (NRI)
Placebo Upadacitinib 7.5 mg QD Upadacitinib 15 mg QD Upadacitinib 30 mg QD
100 90 80 70 60 50 40 30 20 10 0
*
*
* †
0
*
† † 2
4
*
†
† 8
Week
12
* ‡ 16
Mean ± SE Percentage Improvement From Baseline in Pruritus NRS (LOCF)
100 90 80 70 60 50 40 30 20 10 0 –10
Placebo Upadacitinib 7.5 mg QD Upadacitinib 15 mg QD Upadacitinib 30 mg QD
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
† † † † † † † * † * † * * * *
* 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Week
S0091-6749(19)31608-2
DOI:
https://doi.org/10.1016/j.jaci.2019.11.025
Reference:
YMAI 14280
To appear in:
Journal of Allergy and Clinical Immunology
Received Date: 22 May 2019 Revised Date:
17 October 2019
Accepted Date: 1 November 2019
Please cite this article as: Guttman-Yassky E, Thaçi D, Pangan AL, Hong HC-h, Papp KA, Reich K, Beck LA, Mohamed M-EF, Othman AA, Anderson JK, Gu Y, Teixeira HD, Silverberg JI, Upadacitinib in Adults With Moderate-to-Severe Atopic Dermatitis: 16-Week Results From a Randomized, PlaceboControlled Trial, Journal of Allergy and Clinical Immunology (2019), doi: https://doi.org/10.1016/ j.jaci.2019.11.025. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the American Academy of Allergy, Asthma & Immunology.
Guttman-Yassky 1
1 2
Upadacitinib in Adults With Moderate-to-Severe Atopic Dermatitis: 16-Week Results
3
From a Randomized, Placebo-Controlled Trial
4 5
Emma Guttman-Yassky, MD,1 Diamant Thaçi, MD,2 Aileen L. Pangan, MD,3 H. Chih-ho Hong,
6
MD,4 Kim A. Papp, MD,5 Kristian Reich, MD,6 Lisa A. Beck, MD,7 Mohamed-Eslam F.
7
Mohamed, PhD,8 Ahmed A. Othman, PhD,8* Jaclyn K. Anderson, DO,3 Yihua Gu, MS,9
8
Henrique D. Teixeira, PhD,3 Jonathan I. Silverberg, MD10
9
*At the time of this research.
10
1
Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, USA;
11
2
Institute and Comprehensive Center Inflammation Medicine, University of Lübeck, Lübeck,
12
Germany; 3Immunology Clinical Development, AbbVie Inc., North Chicago, IL, USA;
13
4
14
Medical Research, Surrey, BC, Canada; 5Probity Medical Research and K Papp Clinical
15
Research, Waterloo, ON, Canada; 6Translational Research in Inflammatory Skin Diseases,
16
Institute for Health Services Research in Dermatology and Nursing, University Medical Center
17
Hamburg-Eppendorf, and Skinflammation® Center, Hamburg, Germany; 7Department of
18
Dermatology, University of Rochester Medical Center, Rochester, NY, USA; 8Clinical
19
Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, IL, USA; 9Data and
20
Statistical Sciences, AbbVie Inc., North Chicago, IL, USA; 10Department of Dermatology, The
21
George Washington University School of Medicine and Health Sciences, Washington, DC, USA
22
Department of Dermatology and Skin Science, University of British Columbia and Probity
Guttman-Yassky 2
23
Corresponding author:
24
Emma Guttman-Yassky, MD, PhD
25
Icahn School of Medicine at Mount Sinai
26
5 East 98th Street
27
New York, NY 10029 USA
28
Telephone: +1 212-241-9728/3288
29
Fax: +1 212-876-8961
30
[email protected]
31 32
Funding: AbbVie funded the study, contributed to the design of the study and was involved in
33
the collection, analysis, and interpretation of the data and in the writing, review, and approval of
34
the publication. The corresponding author had full access to all the data in the study and had final
35
responsibility for the decision to submit for publication.
36 37
Contributors
38
Study design: Emma Guttman-Yassky, Diamant Thaçi, Aileen L. Pangan, Mohamed-Eslam F.
39
Mohamed, Ahmed A. Othman, Jaclyn K. Anderson, Yihua Gu, Henrique D. Teixeira, Jonathan I.
40
Silverberg
41
Acquisition of data: Emma Guttman-Yassky, H. Chih-ho Hong, Kim A. Papp, Kristian Reich,
42
Lisa A. Beck, Jaclyn K. Anderson, Henrique D. Teixeira
43
Statistical analysis: Yihua Gu
Guttman-Yassky 3
44
Analysis and interpretation of data: Emma Guttman-Yassky, Diamant Thaçi, Aileen L. Pangan,
45
H. Chih-ho Hong, Kim A. Papp, Kristian Reich, Lisa A. Beck, Mohamed-Eslam F. Mohamed,
46
Ahmed A. Othman, Jaclyn K. Anderson, Yihua Gu, Henrique D. Teixeira, Jonathan I. Silverberg
47
Writing of the manuscript: Emma Guttman-Yassky, Aileen L. Pangan, Mohamed-Eslam F.
48
Mohamed, Jaclyn K. Anderson, Henrique D. Teixeira
49
Critical revision of the manuscript for important intellectual content: Emma Guttman-Yassky,
50
Diamant Thaçi, Aileen L. Pangan, H. Chih-ho Hong, Kim A. Papp, Kristian Reich, Lisa A. Beck,
51
Mohamed-Eslam F. Mohamed, Ahmed A. Othman, Jaclyn K. Anderson, Yihua Gu, Henrique D.
52
Teixeira, Jonathan I. Silverberg
53
Declaration of Interests
54
EG: employee, Mount Sinai; research/consultant, AbbVie, Anacor, AnaptysBio, Asana
55
Biosciences, Botanix, Celgene, DBV, Dermira, DS Biopharma, Escalier, Galderma, Glenmark,
56
Innovaderm, Janssen, Kyowa Kirin, Leo Pharma, Lilly, MedImmune/AstraZeneca, Mitsubishi
57
Tanabe, Novan, Novartis, Pfizer, Promius, Ralexar, Regeneron, Sanofi Aventis, Stiefel/GSK,
58
UCB, Vitae
59
DT: advisor/speaker/consultant, AbbVie, Almirall, Amgen, Asana Biosciences, Biogen Idec,
60
Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Dignity, GSK, Janssen-Cilag, Kyowa
61
Kirin, Leo Pharma, Lilly, Maruho, Merck Sharp & Dohme, Novartis, Regeneron, Sandoz,
62
Sanofi-Aventis, Pfizer, UCB; research, AbbVie, Celgene, Novartis
63
HH: research/consultant/advisor, AbbVie, Amgen, Celgene, Dermavant, DS Biopharma,
64
Galderma, GSK, Janssen, Leo Pharma, Lilly, MedImmune, Novartis, Pfizer, Regeneron, Roche,
65
Sanofi-Genzyme, UCB
Guttman-Yassky 4
66
KP: advisor/speaker/consultant/steering committee/research, AbbVie, Akros, Allergan, Amgen,
67
Anacor, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Boehringer Ingelheim, Bristol-Myers
68
Squibb, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Forward Pharma, Galderma,
69
Genentech, Gilead, GSK, InflaRx GmbH, Janssen, Kyowa-Hakko Kirin, Leo Pharma, Lilly,
70
MedImmune, Meiji Seika Pharma, Merck (MSD), Merck-Serono, Mitsubishi Pharma, Moberg
71
Pharma, Novartis, Pfizer, Regeneron, Roche, Sanofi-Aventis Genzyme, Takeda, UCB,
72
Valeant/Bausch Health
73
KR: advisor/speaker/research, AbbVie, Affibody, Almirall, Amgen, Biogen, Boehringer
74
Ingelheim, Celgene, Centocor, Covagen, Forward Pharma, Fresenius Medical Care, GSK,
75
Janssen-Cilag, Kyowa Kirin, Leo, Lilly, Medac, Merck Sharp & Dohme, Novartis, Miltenyi
76
Biotec, Ocean Pharma, Pfizer, Regeneron, Samsung Bioepis, Sanofi, Takeda, UCB, Valeant,
77
Xenoport
78
LB: consultant, AbbVie, Asana Biosciences, AstraZeneca, Boehringer Ingelheim, Celgene, GSK,
79
Leo Pharma, Lilly, Novan, Novartis, Realm Therapeutics, Regeneron, Sanofi; research,
80
Regeneron, AbbVie, Realm Therapeutics; stock, Pfizer, Medtronics
81
JS: advisor/speaker/consultant, AbbVie, Asana, Dermavant, Galderma, GlaxoSmithKline,
82
Glenmark, Kiniksa, Leo, Lilly, Menlo, Novartis, Pfizer, Realm, Regeneron-Sanofi; research,
83
GSK
84
AP, MM, JA, YG, HT: employee/stock, AbbVie
85
AO: former employee/stock, AbbVie
Guttman-Yassky 5
86
Abstract
87
Background: Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic
88
skin lesions.
89
Objective: This study evaluated the safety and efficacy of multiple doses of the selective Janus
90
kinase 1 inhibitor upadacitinib in patients with moderate-to-severe atopic dermatitis.
91
Methods: In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion
92
of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting),
93
adults with moderate-to-severe disease and inadequate control by topical treatment were
94
randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-
95
daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary endpoint was
96
percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy
97
was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all
98
randomized patients who received study medication, based on actual treatment.
99
Results: Patients (N=167) enrolled from November 21, 2016, to April 20, 2017. All were
100
randomized and analyzed for efficacy (each upadacitinib group, n=42; placebo, n=41); 166 were
101
analyzed for safety (each upadacitinib group, n=42; placebo, n=40). The mean (standard error)
102
primary efficacy endpoint was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib
103
7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P=0.03, <0.001, and
104
<0.001). Serious adverse events occurred in 4.8% [2/42], 2.4% [1/42], 0% [0/42] of upadacitinib
105
groups (vs 2.5% [1/40] for placebo).
106
Conclusion: A dose-response relationship was observed for upadacitinib efficacy; the 30-mg
107
once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.
Guttman-Yassky 6
108
Clinical Implication: The favorable benefit/risk profile of upadacitinib supported initiation of
109
phase 3 trials in atopic dermatitis.
110 111
Capsule Summary: This study is the first to demonstrate the robust efficacy of the JAK-1
112
selective inhibitor upadacitinib in patients with moderate-to-severe atopic dermatitis that could
113
not be controlled with topical therapy.
114
Keywords: atopic dermatitis; randomized clinical trial; eczema; efficacy; Janus kinase; placebo-
115
controlled; upadacitinib; safety
116
Guttman-Yassky 7
117
Abbreviations List
118
AD=atopic dermatitis
119
AE=adverse event
120
ALT=alanine aminotransferase
121
AST=aspartate aminotransferase
122
BSA=body surface area
123
DLQI=The Dermatology Life Quality Index
124
EASI 90=≥90% improvement in Eczema Area and Severity Index
125
IGA 0/1=Investigator Global Assessment of 0 or 1
126
IL=interleukin
127
JAK=Janus kinase
128
NRS=numeric rating scale
129
POEM=Patient-Oriented Eczema Measure
130
QD=once daily
131
QoL=quality of life
132
SCORAD=SCORing Atopic Dermatitis
133
STAT=signal transducer and activator of transcription
134
Th=T helper
135
TYK2=tyrosine kinase 2
Guttman-Yassky 8
136
Introduction
137
Atopic dermatitis (AD) is a common inflammatory skin disease characterized by recurrent
138
eczematous lesions,1 which are associated with intense pruritus that greatly interferes with
139
quality of life (QoL) and sleep,2 particularly in those with moderate-to-severe disease (16%–71%
140
of patients across different ages and regions).3 AD in adults may persist from childhood4or may
141
begin or reoccur in adulthood.5 Corticosteroids are an orally administered systemic treatment
142
widely used for patients with AD,6 but there is risk of exposure-associated adverse effects with
143
long-term and short-term use.7 In some countries, cyclosporine A is approved for use for patients
144
with severe AD but generally as short-term rescue therapy (≤1 year) because of cumulative
145
nephrotoxicity. The paucity of approved treatments has led to recommendations for use of other
146
agents not approved for AD (e.g., methotrexate and azathioprine)8 and motivated discovery and
147
development of new compounds. Dupilumab, an approved injectable biologic for the treatment
148
of moderate to severe AD, blocks binding of the T helper (Th) 2 cytokines interleukin (IL)-4 and
149
IL-13 to IL-4 receptor α.9 Dupilumab administered every other week provided significant benefit
150
compared with placebo in phase 2 and 3 trials by week 16; however, ≤40% of patients achieved
151
clear or almost clear skin (as defined by ≥90% improvement in Eczema Area and Severity Index
152
[EASI 90] or Investigator Global Assessment of 0 or 1 [IGA 0/1]).9-11 Thus, there remains a large
153
unmet need for treatments with better efficacy and a safety profile that is acceptable for long-
154
term use.
155
Similar to psoriasis, AD is associated with T-cell activation in the skin and blood but is a more
156
heterogeneous disease.12 In AD, the Th2 and Th22 cytokine pathways are activated, and some
157
disease subtypes also appear to involve Th1 and Th17 cells.13-15 Thus, targeting multiple
158
cytokine axes may be required to achieve broad efficacy.13 Many cytokines implicated in the
Guttman-Yassky 9
159
pathogenesis of AD (e.g., Th2 cytokines [IL-4, IL-5, IL-13], IL-22, IL-31, IL-33, chemokines,
160
thymic stromal lymphopoietin, and interferon γ) exert their effects via intracellular signaling that
161
involves the Janus kinase (JAK) and signal transducer and activator of transcription (STAT)
162
pathways.15, 16
163
Preclinical research shows that disruption of JAK1 signaling reduces chronic itch by mechanisms
164
involving Th2 cytokines, which may also directly stimulate neurons to elicit itching17 and
165
supports a potential role for JAK inhibitors in the treatment of AD. Upadacitinib is an oral
166
reversible JAK1 inhibitor engineered for increased selectivity for JAK1 over JAK2, JAK3, and
167
tyrosine kinase 2 (TYK2)18 and is currently being investigated for several immune-mediated
168
inflammatory diseases. Minimizing inhibition of JAK2 and JAK3 may reduce adverse effects,
169
such as anemia and infections.19
170
The objective of this study was to evaluate the safety and efficacy of multiple doses of
171
upadacitinib versus placebo in adults with moderate-to-severe AD. Several other studies have
172
tested JAK inhibitors for the treatment of AD20; however, interpretation of the results was
173
complicated by concomitant use of topical corticosteroids (e.g., in the case of baricitinib).21 Ours
174
was the first study to examine selective JAK1-inhibitor monotherapy for the treatment of AD.
175
Guttman-Yassky 10
176
Methods
177
Study Design
178
This is a phase 2b, double-blind, randomized, parallel-group, dose-ranging trial conducted at
179
clinical centers in Australia, Canada, Finland, Germany, Japan, Netherlands, Spain, and the
180
United States. Results from the 16-week, double-blind, randomized treatment period are reported
181
based on an interim database lock for the prespecified final efficacy analysis for this period. A
182
subsequent 72-week, double-blind, randomized withdrawal period is ongoing. The study is being
183
conducted in accordance with International Council for Harmonisation Good Clinical Practice
184
guidelines and the Declaration of Helsinki. An independent ethics committee or institutional
185
review board at each study center approved the study protocol and other study-related documents
186
before procedures began. Patients provided written informed consent before beginning the study.
187 188
Patients
189
Eligible patients were 18 to 75 years old at screening, with a dermatologist-confirmed diagnosis
190
of AD according to Hanifin and Rajka criteria (≥3 of 4 major features and ≥3 of 23 minor
191
features),22 with symptoms for ≥1 year before baseline. The patients had moderate-to-severe AD,
192
defined as EASI ≥16, affected body surface area (BSA) ≥10%, and IGA ≥3, at baseline. They
193
had inadequate response to topical corticosteroids or topical calcineurin inhibitors within 1 year
194
before screening, or were patients for whom topical treatments were otherwise medically
195
inadvisable (e.g., because of important side effects or safety risks). All patients were to use an
196
additive-free bland emollient twice daily for ≥7 days before baseline and during the study
197
(details in Online Repository Methods).
Guttman-Yassky 11
198
Randomization and Masking
199
An interactive response system referring to a schedule previously generated via computer by
200
statisticians from the study sponsor was used to randomize qualifying patients 1:1:1:1, stratified
201
by geographic region (United States, Puerto Rico, and Canada; European Union and Australia;
202
and Japan). Patients, investigators, and the sponsor were blinded to allocation. Each study drug
203
kit was labeled with a unique code that was linked to the randomization schedule. The placebo
204
and upadacitinib tablets were identical in appearance to maintain blinding of treatment
205
assignment.
206
Procedures
207
Patients received placebo or extended-release upadacitinib (manufactured by the study sponsor)
208
7.5, 15, or 30 mg QD by mouth. After the baseline visit, patients returned to the clinic at weeks
209
2, 4, 8, 12, and 16. Discontinuation of study drug (placebo or upadacitinib) was required if a
210
patient’s EASI worsened by ≥25% from baseline at two consecutive visits between weeks 4 and
211
12.
212
Efficacy assessments, recorded at baseline and during clinic visits at weeks 2, 4, 8, 12, and 16,
213
included EASI, IGA, pruritus numeric rating scale (NRS; weekly average of daily patient
214
assessments), SCORing Atopic Dermatitis (SCORAD),23 BSA, and Patient-Oriented Eczema
215
Measure (POEM).24 Details are in the Online Repository Methods.
216
Safety monitoring included treatment-emergent adverse events (AEs), physical examinations,
217
vital signs, and clinical laboratory assessments. AEs, vital signs, and clinical laboratory
218
assessments were recorded at each clinic visit. Physical examinations were made at baseline and
219
week 16.
Guttman-Yassky 12
220
Outcomes
221
Primary and secondary outcomes were pre-specified. The primary endpoint was percentage
222
improvement from baseline at week 16 in EASI. Secondary endpoints were proportions of
223
patients achieving improvement of ≥50%/≥75%/≥90% from baseline in EASI (EASI 50/75/90) at
224
weeks 8 and 16; proportions of patients achieving IGA 0/1 at week 16; percentage improvement
225
from baseline in EASI at week 8; percentage improvement from baseline in pruritus NRS by
226
week and proportions of patients achieving pruritus NRS improvement from baseline of ≥4
227
points at each visit (among patients with baseline NRS ≥4 points); percentage improvement from
228
baseline in SCORAD at weeks 8 and 16; proportions of patients achieving ≥50%/≥75%/≥90%
229
improvement from baseline in SCORAD (SCORAD 50/75/90) at weeks 8 and 16; and change
230
from baseline in BSA at week 16. The primary and secondary variables were also analyzed for
231
all study visits at which they were assessed. Additional endpoints included percentage
232
improvement from baseline in BSA at each visit, proportions of patients achieving EASI 100 at
233
each visit, and change from baseline in POEM at weeks 4 and 16. Dermatology Life Quality
234
Index outcomes (proportion of patients achieving score 0/1 and change from baseline) were
235
defined but are not reported because of an error in the programming of the electronic device used
236
to administer the questionnaire that precluded determination of these outcomes.
237
Upadacitinib plasma concentrations were quantitated as previously described.25
238
Adverse events were coded according to Medical Dictionary for Regulatory Activities, version
239
20.0. Changes from baseline in physical examinations findings, vital signs, and clinical
240
laboratory values were recorded. Assessment of the severity of AEs and laboratory changes was
241
based on Common Terminology Criteria for Adverse Events (version 4.0) developed by the
242
National Cancer Institute.
Guttman-Yassky 13
243
Statistical Analysis
244
Forty patients per treatment arm were targeted for enrollment. Assuming that improvements of
245
35%, 45%, 60%, and 70% would occur for the primary endpoint in the placebo and upadacitinib
246
7.5-, 15-, and 30-mg QD groups, respectively, with an SD of 40%, this sample size provides 99%
247
average power to detect a dose effect at a 5% level of significance (1-sided) to characterize the
248
dose-response for upadacitinib. This sample size also provided 97% power to detect a difference
249
for upadacitinib 30 mg QD compared with placebo and 78% power to detect a difference for
250
upadacitinib 15 mg QD compared with placebo at a 2-sided significance level of 5%. Between-
251
group statistical comparisons of continuous efficacy endpoints were made by analysis of
252
covariance, with stratum (geographic region), baseline value, and treatment in the model.
253
Between-group statistical comparisons of categorical efficacy endpoints were made with the
254
Cochran-Mantel-Haenszel test, adjusted for stratum (geographic region). All efficacy analyses
255
were conducted in the intention-to-treat population, comprising all randomized patients, based on
256
treatment assigned. Missing efficacy data were analyzed by last observation carried forward
257
(continuous variables) and by non-responder imputation (categorical variables). The dose-
258
response relationships among the 3 upadacitinib treatment groups and placebo group were
259
characterized for the primary endpoint using a multiple comparison procedures and modeling
260
approach that also controlled for overall type I error. Secondary endpoints and other efficacy
261
endpoints were analyzed at the nominal alpha level of 5%. Safety was analyzed in all
262
randomized patients who received ≥1 dose of study medication, based on actual treatment
263
received. A data monitoring committee oversaw unblinded safety results during the study.
264
Cardiovascular events were adjudicated by a blinded, independent adjudication committee
265
according to predefined criteria. Treatment-emergent AEs (i.e., those that occurred after starting
Guttman-Yassky 14
266
study drug through 30 days after the last dose) were summarized with descriptive statistics;
267
between-group statistical comparisons of laboratory measures were made by using a contrast
268
within a 1-way analysis of variance. Analyses were conducted with SAS version 9.4 (SAS
269
Institute, Cary, NC, USA). The study is registered with ClinicalTrials.gov, number
270
NCT02925117.
271
Guttman-Yassky 15
272
Results
273
Patients
274
Between October 25, 2016, and March 16, 2017, 218 patients were assessed for eligibility, of
275
whom 167 were found eligible and enrolled to the study, and 166 received placebo or
276
upadacitinib (Figure 1). The first patient was enrolled on November 21, 2016, and the last on
277
April 20, 2017. Premature discontinuation was more common with placebo (primarily due to
278
lack of efficacy) than with upadacitinib. Patient demographic and baseline characteristics were
279
generally well balanced among treatment arms, except numerically fewer patients had an IGA of
280
4 (severe AD) in the upadacitinib 7.5- and 30-mg groups compared with the placebo and
281
upadacitinib 15-mg groups (Table I).
282
Efficacy
283
All upadacitinib doses (7.5, 15, and 30 mg) showed significantly higher mean (SE) percentage
284
improvement from baseline at week 16 in EASI versus placebo (39% [6.2%], P=0.03; 62%
285
[6.1%], P<0.001; and 74% [6.1%], P<0.001 vs 23% [6.4%], respectively), with a clear dose-
286
response relationship (Figure 2). Mean (95% CI) difference versus placebo for percentage
287
improvement from baseline at week 16 in EASI was 16% (1.4%–31%), 39% (24%–54%), and
288
51% (36%–67%), for upadacitinib 7.5, 15, and 30 mg, respectively. The dose-response
289
relationship for upadacitinib doses (7.5, 15, and 30 mg) was consistently demonstrated for this
290
endpoint in the subgroups of patients with baseline IGA of 3 (40% [8.3%], P=0.23; 63% [9.6%],
291
P=0.004; and 73% [7.6%], P<0.001 vs 27% [10%] for placebo) and baseline IGA of 4 (35%
292
[10%], P=0.19; 59% [8.3%], P<0.001; and 75% [11%], P<0.001 vs 19% [8.5%] for placebo),
293
confirming that treatment response was not affected by the numerical imbalance in baseline IGA
294
among the treatment groups. Statistical significance in favor of all upadacitinib doses in EASI
Guttman-Yassky 16
295
50, EASI 75, and EASI 90 responses was also achieved at week 16; EASI 100 was achieved by
296
2.4% (1/42; P=0.43), 9.5% (4/42; P=0.05), and 24% (10/42; P=0.001) of patients in the
297
upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus none (0/41) in the placebo group.
298
Each upadacitinib dose level was significantly superior to placebo for investigator assessment
299
(IGA 0/1) and patient assessment of pruritus (improvement in NRS and achievement of NRS
300
reduction ≥4) at week 16. Efficacy at the studied doses was generally demonstrated by week 1 to
301
4, with peak values reached and maintained after week 4 or 8 (Figure 3 and Figure E1).
302
SCORAD outcomes at weeks 8 and 16 favored upadacitinib compared with placebo, reaching
303
statistical significance for most comparisons (Figure E2). Mean percentage reductions in BSA
304
were significantly greater in all upadacitinib groups compared with placebo at every assessment
305
(weeks 2, 4, 8, 12, and 16; Figure E3), with the exception of the last assessment in the
306
upadacitinib 7.5-mg group. POEM scores at weeks 4 and 16 improved significantly more in all
307
upadacitinib groups compared with the placebo group (Figure E4).
308
Pharmacokinetics
309
Upadacitinib exposures were approximately dose proportional over the 7.5- to 30-mg dose range.
310
Upadacitinib median (interquartile range) plasma concentrations around peak and trough times
311
were consistent with exposures previously observed for the evaluated doses in healthy volunteers
312
(7.5-mg dose: 10.6 [0.8–21.0] and 2.8 [1.4–4.5] ng/mL, respectively; 15-mg dose: 32.5 [22.7–
313
39.3] and 3.6 [1.8–7.0] ng/mL; 30-mg dose: 57.0 [28.1–94.8] and 8.1 [6.6–16.6] ng/mL).26
314
Safety
315
Exposure to study drug was lower in the placebo group (Table II) because of the higher rate of
316
study discontinuation (Figure 1) in this group compared with the upadacitinib groups. AEs were
317
reported in 71% (30/42), 74% (31/42), and 79% (33/42) of patients receiving upadacitinib 7.5,
Guttman-Yassky 17
318
15, and 30 mg, respectively, versus 63% (25/40) of patients receiving placebo (Table II). The
319
most frequently reported AEs (≥10% in any group) were upper respiratory tract infection, AD
320
worsening, and acne (all reported as mild or moderate in severity). There was no relationship
321
between the dose of upadacitinib and the occurrence of particular AEs.
322
Serious AEs were infrequent and occurred in no more than two patients in any treatment group
323
(Table II). In the placebo group, a serious AE of atrial fibrillation occurred in a 71-year-old man
324
with a history of atrial fibrillation, sick sinus syndrome, hypertension, asthma,
325
emphysema/chronic obstructive pulmonary disease, obstructive sleep apnea, and smoking (30
326
years). Two patients in the upadacitinib 7.5-mg group had serious AEs: a 35-year-old man with a
327
history of repeated tooth infections experienced lower jaw pericoronitis, and a 20-year-old
328
woman experienced worsening AD (skin infection and exacerbation of AD) in the context of
329
contact dermatitis. In the upadacitinib 15-mg group, one serious AE of appendicitis was reported
330
in a 66-year-old man. No serious AEs occurred in patients allocated to upadacitinib 30 mg. All
331
serious AEs resolved with treatment in patients who received upadacitinib. The number of AEs
332
leading to discontinuation was low across the placebo and upadacitinib treatment groups (n=3,
333
n=4, n=2, and n=4 in the placebo and upadacitinib 7.5-, 15-, and 30-mg groups).
334
There were no deaths, opportunistic infections, malignancies, gastrointestinal perforations, AEs
335
of herpes zoster, renal dysfunction, active or latent tuberculosis, adjudicated cardiovascular
336
events, or thromboembolic events. Infections were more common with upadacitinib than
337
placebo, but there were few serious infections (Table II). Although 63 of 167 patients (38%) had
338
a history of asthma, no AEs of asthma exacerbation were reported during the study.
339
Mean laboratory values remained within normal ranges (Figure E5), and grade 3 and 4
340
laboratory abnormalities were uncommon (Table E1). Hepatic disorder AEs, none serious, were
Guttman-Yassky 18
341
reported in three patients during the study (Table II; alanine aminotransferase [ALT] and
342
aspartate aminotransferase [AST] increased in one patient in the placebo group [neither event
343
with grade ≥2 laboratory increase]; blood bilirubin increased in one patient in the upadacitinib
344
15-mg group [grade 2 laboratory increase]; and hepatic steatosis in another patient in the
345
upadacitinib 15-mg group [associated with grade 2 ALT increase]). All hepatic disorder AEs
346
were considered mild and resolved without dosing changes. Mean changes in ALT and AST
347
levels were similar among treatment groups, and no grade 3 or 4 ALT or AST elevations
348
occurred in patients receiving upadacitinib. All AEs of creatine phosphokinase (CPK) elevation
349
were asymptomatic in patients receiving upadacitinib and reported as mild to moderate in
350
severity (Table E1). Mean hemoglobin levels decreased more with upadacitinib compared with
351
placebo but remained at 133 to 145 g/L, which is within the normal ranges for both women and
352
men. No patients had hemoglobin abnormalities of grade ≥3. No decrease in mean absolute
353
lymphocyte counts was observed in any upadacitinib treatment group, and no patients had
354
lymphocyte abnormalities of grade ≥3. Decreases in mean neutrophil counts were small and
355
generally similar between upadacitinib and placebo. There were increases in mean
356
concentrations of low-density and high-density lipoprotein cholesterol in the upadacitinib groups
357
compared with the placebo group, but lipid ratios showed no clear pattern of change (Table E2).
358
Guttman-Yassky 19
359
Discussion
360
In this first study to investigate the efficacy and safety of the JAK1-selective inhibitor
361
upadacitinib as monotherapy for the treatment of adults with moderate-to-severe AD
362
inadequately controlled by topical medications, upadacitinib was efficacious and appeared to
363
exhibit a favorable benefit/risk profile compared with placebo. This phase 2b clinical trial
364
enrolled a population of patients with long-standing AD whose baseline severity was comparable
365
to that in the dupilumab phase 3 studies.9-11 The primary efficacy endpoint of percentage
366
improvement from baseline to week 16 in EASI and multiple other endpoints (e.g., EASI 50,
367
EASI 75, EASI 90, and IGA 0/1) were statistically significantly better at each upadacitinib dose
368
level compared with placebo, with a clear dose response. Achievement of EASI 100 was
369
significantly higher in the upadacitinib 15-mg and 30-mg groups versus placebo at week 16. We
370
also noted marked improvement from baseline at week 16 in pruritus, SCORAD, BSA, and
371
POEM with each upadacitinib dose regimen. Signs and symptoms showed rapid improvements
372
with upadacitinib compared with placebo; pruritus improved significantly at first assessment
373
(week 1), as did clinical efficacy endpoints (first assessments at week 2). The alleviation of
374
pruritus may be particularly important because itching worsens AD patients’ QoL (including loss
375
of sleep and suicidal thoughts).2 Maximal efficacy for percentage improvement in EASI, EASI
376
50, and EASI 75 was reached at week 4 and maintained through week 16. More stringently
377
defined endpoints (EASI 90 and IGA 0/1) plateaued between weeks 8 and 16, although the EASI
378
100 response was still increasing at week 16. In this phase 2b study, there were no dose-limiting
379
safety events or unexpected safety findings that would preclude further evaluation of
380
upadacitinib in AD.
Guttman-Yassky 20
381
A clear dose response was observed for the primary endpoint and a majority of secondary
382
endpoints. Upadacitinib 30 mg QD was associated with the greatest reduction in EASI and
383
appeared to present the best benefit/risk profile; the EASI 90 and IGA 0/1 results with
384
upadacitinib 30 mg (both endpoints, 50.0% at week 16) are high for a systemic monotherapy in
385
this patient population. A threshold of response, EASI 100, that had not previously been reported
386
before this study began, was defined and observed with upadacitinib. The improvement in
387
pruritus with JAK1 inhibition in this trial may have been mediated by blocking the effects of IL-
388
31 and factors that directly induce itching in sensory neurons.17 More broadly, the efficacy
389
observed in this trial may reflect the fact that JAK1 inhibition targets additional cytokine
390
pathways involved in chronic AD15 beyond just Th2 and Th22 cytokines.16 Further research may
391
reveal whether JAK1 inhibition might be beneficial in atopic diseases other than AD.
392
In this study with a limited population size that might not be representative of all potential AD
393
populations, no dose-limiting safety events nor any new safety concerns compared with the
394
ongoing upadacitinib rheumatoid arthritis phase 3 program were observed, even though safety
395
analyses were not adjusted for the greater rate of discontinuation in the placebo group. No dose
396
relationship was observed in the overall rate of AEs. Infections (but not serious infections) were
397
more common with upadacitinib compared with placebo. The events of acne, diagnosed by the
398
dermatologist investigators, were unexpected; however, as none of those AEs was serious, no
399
further details, e.g., the type of acne, are available. No deaths, herpes zoster, malignancies, or
400
thromboembolic events were reported. Dose-dependent decreases in mean hemoglobin levels
401
were small and remained within the normal ranges for women and men; no grade 3 or 4
402
decreases in hemoglobin were reported. A small number of asymptomatic CPK abnormalities
403
were observed but did not require permanent discontinuation in study drug dosing.
Guttman-Yassky 21
404
A limitation of this report is the 16-week duration of treatment. Although efficacy appeared to
405
stabilize within the 16-week period (except EASI 100, which was still increasing), the ongoing
406
72-week period of this study will provide information on longer-term efficacy and safety.
407
Another limitation is that a dose-limiting toxicity was not defined and therefore complete dose
408
ranging was not accomplished. In fact, efficacy did not plateau with the tested doses so it is
409
possible that higher doses might have produced even greater efficacy. However, unprecedented
410
efficacy in patients with atopic dermatitis was demonstrated with upadacitinib 30 mg in this
411
study, and small dose-dependent changes, not considered to be clinically meaningful, in
412
hemoglobin, neutrophils, LDL-cholesterol, and HDL-cholesterol over time were observed.
413
Overall, based on the phase 2 data, the 30-mg QD upadacitinib dose appears to have a favorable
414
benefit/risk profile in atopic dermatitis.
415
Overall, upadacitinib showed rapid clinical improvement in the primary and secondary study
416
outcomes at every dose studied, with particularly robust efficacy at the two highest doses.
417
Because of these results, upadacitinib is the first oral agent granted breakthrough therapy
418
designation by the US Food and Drug Administration for development in AD. In conclusion,
419
upadacitinib monotherapy was efficacious and demonstrated a favorable benefit/risk profile
420
compared with placebo in adults with moderate-to-severe AD and inadequate response to topical
421
treatments, supporting initiation of larger randomized, controlled, phase 3 studies to confirm its
422
potential as an effective treatment for this population.
Guttman-Yassky 22
423
Acknowledgments
424
AbbVie and the authors thank the participants in the clinical trial and all study investigators for
425
their contributions. AbbVie contributed to the design of the study and was involved in the
426
collection, analysis, and interpretation of the data and in the writing, review, and approval of the
427
publication. Statistical analysis support was provided by Su Chen, PhD, of AbbVie. Medical
428
writing support was provided by Michael J. Theisen, PhD, and Janet E. Matsuura, PhD, at
429
Complete Publication Solutions, LLC (North Wales, PA), a CHC Group company, and was
430
funded by AbbVie.
431 432
Data Sharing
433
These clinical trial data can be requested by any qualified researchers who engage in rigorous,
434
independent scientific research, and will be provided following review and approval of a
435
research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing
436
Agreement (DSA). Data requests can be submitted at any time and the data will be accessible for
437
12 months, with possible extensions considered. For more information on the process, or to
438
submit a request, visit the AbbVie data and information sharing website:
439
https://www.abbvie.com/our-science/clinical-trials/clinical-trials-data-and-information-
440
sharing/data-and-information-sharing-with-qualified-researchers.html.
441
Guttman-Yassky 23
442
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443
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2.
Drucker AM. Atopic dermatitis: burden of illness, quality of life, and associated
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complications. Allergy Asthma Proc 2017;38:3-8. 3.
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Silverberg JI. Public health burden and epidemiology of atopic dermatitis. Dermatol Clin
Kim JP, Chao LX, Simpson EL, Silverberg JI. Persistence of atopic dermatitis (AD): a systematic review and meta-analysis. J Am Acad Dermatol 2016;75:681-7 e11.
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Lee HH, Patel KR, Singam V, Rastogi S, Silverberg JI. A systematic review and meta-
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analysis of the prevalence and phenotype of adult-onset atopic dermatitis. J Am Acad
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Dermatol 2018:[Epub ahead of print].
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Wollenberg A, Barbarot S, Bieber T, Christen-Zaech S, Deleuran M, Fink-Wagner A, et
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al. Consensus-based European guidelines for treatment of atopic eczema (atopic
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dermatitis) in adults and children: part II. J Eur Acad Dermatol Venereol 2018;32:850-78.
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Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, et al. Short term use of
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oral corticosteroids and related harms among adults in the United States: population
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Boguniewicz M, Fonacier L, Guttman-Yassky E, Ong PY, Silverberg J, Farrar JR. Atopic
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Thaci D, Simpson EL, Beck LA, Bieber T, Blauvelt A, Papp K, et al. Efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled
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by topical treatments: a randomised, placebo-controlled, dose-ranging phase 2b trial.
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Lancet 2016;387:40-52.
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Simpson EL, Bieber T, Guttman-Yassky E, Beck LA, Blauvelt A, Cork MJ, et al. Two
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Blauvelt A, de Bruin-Weller M, Gooderham M, Cather JC, Weisman J, Pariser D, et al.
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Long-term management of moderate-to-severe atopic dermatitis with dupilumab and
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concomitant topical corticosteroids (LIBERTY AD CHRONOS): a 1-year, randomised,
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double-blinded, placebo-controlled, phase 3 trial. Lancet 2017;389:2287-303.
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Czarnowicki T, Malajian D, Shemer A, Fuentes-Duculan J, Gonzalez J, Suarez-Farinas
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M, et al. Skin-homing and systemic T-cell subsets show higher activation in atopic
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dermatitis versus psoriasis. J Allergy Clin Immunol 2015;136:208-11.
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Suarez-Farinas M, Dhingra N, Gittler J, Shemer A, Cardinale I, de Guzman Strong C, et
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al. Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation
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compared with extrinsic atopic dermatitis. J Allergy Clin Immunol 2013;132:361-70.
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Noda S, Suarez-Farinas M, Ungar B, Kim SJ, de Guzman Strong C, Xu H, et al. The
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Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis
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Brunner PM, Guttman-Yassky E, Leung DY. The immunology of atopic dermatitis and
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its reversibility with broad-spectrum and targeted therapies. J Allergy Clin Immunol
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Bao L, Zhang H, Chan LS. The involvement of the JAK-STAT signaling pathway in
Oetjen LK, Mack MR, Feng J, Whelan TM, Niu H, Guo CJ, et al. Sensory neurons co-opt classical immune signaling pathways to mediate chronic itch. Cell 2017;171:217-28 e13.
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Parmentier JM, Voss J, Graff C, Schwartz A, Argiriadi M, Friedman M, et al. In vitro and
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Mohamed MF, Camp HS, Jiang P, Padley RJ, Asatryan A, Othman AA.
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Mohamed MF, Zeng J, Marroum PJ, Song IH, Othman AA. Pharmacokinetics of
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Guttman-Yassky 27
Table I. Patient Demographic and Baseline Characteristics
Placebo
Upadacitinib 7.5 mg QD
Upadacitinib 15 mg QD
Upadacitinib 30 mg QD
Characteristic
(n=41)
(n=42)
(n=42)
(n=42)
Female, n (%)
17 (41)
14 (33)
12 (29)
20 (48)
39.9 (17.5)
41.5 (15.4)
38.5 (15.2)
39.9 (15.3)
White
28 (68)
24 (57)
21 (50)
23 (55)
Black or African American
6 (15)
7 (17)
10 (24)
6 (14)
Asian
7 (17)
9 (21)
9 (21)
13 (31)
Native Hawaiian or other Pacific Islander
0
2 (4.8)
1 (2.4)
0
American Indian or Alaska Native
0
0
1 (2.4)
0
0
2 (4.8)
2 (4.8)
1 (2.4)
26.2 (6.8)
27.9 (6.3)
27.4 (6.7)
27.4 (6.0)
USA/PR/Canada
29 (71)
29 (69)
29 (69)
29 (69)
EU/Australia
10 (24)
11 (26)
10 (24)
10 (24)
Japan
2 (4.9)
2 (4.8)
3 (7.1)
3 (7.1)
Duration since AD diagnosis, y, mean (SD)
26.8 (18.8)*
30.4 (18.1)
22.6 (15.8)
24.2 (13.6)
Duration of AD symptoms, y, mean (SD)
30.6 (18.6)*
33.9 (18.0)
23.6 (15.2)†
26.7 (15.7)†
14 (34)
15 (36)
11 (26)
14 (33)
0.556† (0.497)
0.575 (0.683)
0.446 (0.475)
0.518 (0.385)
Age, y, mean (SD) Race, n (%)
Hispanic or Latino ethnicity, n (%) BMI, kg/m2, mean (SD) Region, n (%)
History of asthma, n (%) Eosinophils, ×109/L, mean
Guttman-Yassky 28
Characteristic
Placebo
Upadacitinib 7.5 mg QD
Upadacitinib 15 mg QD
Upadacitinib 30 mg QD
(n=41)
(n=42)
(n=42)
(n=42)
32.6 (14.5)
31.4 (15.8)
31.4 (12.3)
28.2 (11.6)
(SD) EASI, mean (SD)‡
45.7 (22.8)
46.9 (24.9)
50.6 (21.5)
42.1 (20.4)
Moderate (IGA=3)
18 (44)
29 (69)
19 (45)
31 (74)
Severe (IGA=4)
23 (56)
13 (31)
23 (55)
11 (26)
6.5 (1.9)†
6.8 (1.8)†
6.4 (1.7)¶
6.3 (2.1)
BSA, %, mean (SD) IGA, n (%)§
Pruritus NRS, mean (SD)||
AD, atopic dermatitis; BMI, body mass index; BSA, affected body surface area; EASI, Eczema Area and Severity Index; IGA, Investigator Global Assessment; NRS, numeric rating scale; PR, Puerto Rico; QD, once daily. *Data missing for 1 patient. †
Data missing for 2 patients.
‡
Full scale ranges from 0 (none) to 72 (most severe).
§
Full scale ranges from 0 (clear) to 4 (severe).
||
Full scale ranges from 0 (no itch) to 10 (worst imaginable itch).
¶
Data missing for 5 patients.
Guttman-Yassky 29
Table II. Adverse Event Summary* Upadacitinib Upadacitinib Upadacitinib 15 mg QD 30 mg QD Placebo 7.5 mg QD Treatment-Emergent AE, n (%)
(n=40)
(n=42)
(n=42)
(n=42)
Any AE
25 (63)
31 (74)
32 (76)
33 (79)
Serious AE
1 (2.5)
2 (4.8)
1 (2.4)
0
AE leading to discontinuation of study drug
3 (7.5)
4 (9.5)
2 (4.8)
4 (9.5)
Infection
8 (20)
22 (52)
18 (43)
17 (41)
0
2 (4.8) †
1 (2.4)‡
0
1 (2.5)§
0
2 (4.8)||
0
Anemia
0
0
0
1 (2.4)
Neutropenia
0
1 (2.4)
2 (4.8)
2 (4.8)
Lymphopenia
0
0
1 (2.4)
0
URTI
4 (10)
7 (17)
5 (12)
5 (12)
Atopic dermatitis worsening
2 (5.0)
6 (14)
2 (4.8)
4 (9.5)
Acne
1 (2.5)
4 (9.5)
2 (4.8)
6 (14)
Headache
1 (2.5)
3 (7.1)
3 (7.1)
4 (9.5)
Nasopharyngitis
1 (2.5)
2 (4.8)
4 (9.5)
3 (7.1)
Blood CPK increased
2 (5.0)
0
3 (7.1)
4 (9.5)
Nausea
1 (2.5)
3 (7.1)
1 (2.4)
3 (7.1)
Diarrhea
2 (5.0)
2 (4.8)
2 (4.8)
0
Influenza
0
3 (7.1)
0
0
Oropharyngeal pain
0
3 (7.1)
0
0
Serious infection Hepatic disorder
AE in ≥5% of patients in any group
Guttman-Yassky 30
Upadacitinib Upadacitinib Upadacitinib 15 mg QD 30 mg QD Placebo 7.5 mg QD Treatment-Emergent AE, n (%) Ligament sprain
(n=40)
(n=42)
(n=42)
(n=42)
2 (5.0)
0
0
0
AE, adverse event; CPK, creatine phosphokinase; QD, once daily; URTI, upper respiratory tract infection. *Mean (SD) exposure to study drug in the placebo, upadacitinib 7.5 mg, upadacitinib 15 mg, and upadacitinib 30 mg groups was 81.6 (41.2), 101.3 (28.5), 104.2 (24.5), and 108.9 (16.4) days, respectively. †
One event each of skin infection and pericoronitis.
‡
One event of appendicitis.
§
One patient with alanine aminotransferase increased and aspartate aminotransferase increased.
||
One patient with blood bilirubin increased; one patient with hepatic steatosis.
Figure Legends Figure 1. Patient disposition with primary reasons for discontinuation of study drug. QD, once daily. *May include meeting criteria for ≥25% worsening of Eczema Area and Severity Index, resulting in discontinuation of study drug according to the protocol.
Figure 2. EASI, IGA 0/1, and pruritus NRS outcomes at week 16. EASI, Eczema Area and Severity Index; EASI 50/75/90/100, ≥50%/≥75%/≥90%/100% improvement in EASI; IGA 0/1, Investigator Global Assessment of 0 or 1; LOCF, last observation carried forward; NRI, non-
Guttman-Yassky 31
responder imputation; NRS, numeric rating scale; QD, once daily. *P≤0.001, †P≤0.01, and ‡
P≤0.05 for upadacitinib vs placebo.
Figure 3. EASI, IGA 0/1, and pruritus NRS over time. EASI, Eczema Area and Severity Index; IGA 0/1, Investigator Global Assessment of 0 or 1; LOCF, last observation carried forward; NRS, numeric rating scale; QD, once daily. *P≤0.001, †P≤0.01, and ‡P≤0.05 for upadacitinib vs placebo.
Screened n=218
Randomized N=167
Placebo n=41
Ineligible n=51 • Inclusion/exclusion criteria, 35 • Withdrew consent, 12 • Lost to follow-up, 3 • Other, 1
Upadacitinib 7.5 mg QD n=42
Upadacitinib 15 mg QD n=42
Upadacitinib 30 mg QD n=42
Treated n=42
Treated n=42
Treated n=42
Not treated n=1 Treated n=40
Discontinued n=20 • Adverse event, 2 • Lack of efficacy, 13* • Withdrew consent, 2 • Lost to follow-up, 1 • Progressive disease, 1 • Other, 1
Completed n=20
Analyzed for efficacy n=41 Analyzed for safety n=40
Discontinued n=11 • Adverse event, 2 • Lack of efficacy, 6* • Withdrew consent, 1 • Lost to follow-up, 1 • Progressive disease, 1
Completed n=31
Analyzed for efficacy n=42 Analyzed for safety n=42
Discontinued n=5 • Adverse event, 2 • Lack of efficacy, 2* • Withdrew consent, 1
Completed n=37
Analyzed for efficacy n=42 Analyzed for safety n=42
Discontinued n=4 • Adverse event, 2 • Lack of efficacy, 1* • Other, 1
Completed n=38
Analyzed for efficacy n=42 Analyzed for safety n=42
Mean ± SE Percentage Improvement (LOCF) or Percentage (95% CI) of Patients Achieving Response (NRI)
Placebo Upadacitinib 7.5 mg QD 100
Upadacitinib 15 mg QD
*
90
*
80
*
70
*
*
Upadacitinib 30 mg QD
*
†
‡
‡
*
†
40
* † ‡
*
‡
30
*
*
*
60 50
*
*
‡ ‡
20 10
0
0 Improvement in EASI (LOCF)
EASI 50 (NRI)
EASI 75 (NRI)
EASI 90 (NRI)
EASI 100 (NRI)
IGA 0/1 (NRI)
Improvement Pruritus NRS in Reduction Pruritus NRS ≥4 (LOCF) (NRI)
Mean ± SE Percentage Improvement From Baseline in EASI (LOCF)
Placebo Upadacitinib 7.5 mg QD Upadacitinib 15 mg QD Upadacitinib 30 mg QD
100 90 80 70 60 50 40 30 20 10 0
*
*
*
*
*
*
*
‡
* * * *
0
2
4
8
Week
12
* * ‡
16
Percentage (95% CI) of Patients Achieving IGA 0/1 (NRI)
Placebo Upadacitinib 7.5 mg QD Upadacitinib 15 mg QD Upadacitinib 30 mg QD
100 90 80 70 60 50 40 30 20 10 0
*
*
* †
0
*
† † 2
4
*
†
† 8
Week
12
* ‡ 16
Mean ± SE Percentage Improvement From Baseline in Pruritus NRS (LOCF)
100 90 80 70 60 50 40 30 20 10 0 –10
Placebo Upadacitinib 7.5 mg QD Upadacitinib 15 mg QD Upadacitinib 30 mg QD
* * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *
† † † † † † † * † * † * * * *
* 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
Week