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August 2019 804 Volume 18 • Issue 8

Copyright © 2019 ORIGINAL ARTICLE Journal of Drugs in Dermatology
SPECIAL TOPIC

Efficacy of Dupilumab in Different Racial Subgroups of

Adults With Moderate-to-Severe Atopic Dermatitis in Three
Randomized, Placebo-Controlled Phase 3 Trials
Andrew F. Alexis MD MPH,a Marta Rendon MD,B Jonathan I. Silverberg MD,c David M. Pariser MD,D
Benjamin Lockshin MD,e Christopher E.M. Griffiths MD,f Jamie Weisman MD,g Andreas Wollenberg MD,h
Zhen Chen PhD,i John D. Davis PhD,i Meng Li PhD,j Laurent Eckert PhD,k Abhijit Gadkari PhD,i
Brad Shumel MD,i Ana B. Rossi MD,l Neil M.H. Graham MD,i Marius Ardeleanu MDi
ªDepartment of Dermatology, Mount Sinai West, New York, NY
BRendon Center for Dermatology and Aesthetic Medicine, Boca Raton, FL
c
Department of Dermatology, Preventive Medicine and Medical Social Sciences,
Northwestern University Feinberg School of Medicine, Chicago, IL
DDepartment of Dermatology, Eastern Virginia Medical School and Virginia Clinical Research, Inc., Norfolk,VA
EU.S. Dermatology Partners, Rockville, MD
f
Dermatology Centre NIHR Manchester Biomedical Research Centre, University of Manchester, Manchester, UK
g
Advanced Medical Research, PC, Atlanta, GA
h
Department of Dermatology and Allergy, Ludwig Maximilian University, Munich, Germany
IRegeneron Pharmaceuticals, Inc., Tarrytown, NY
j
Sanofi, Bridgewater, NJ
k
Sanofi, Chilly-Mazarin, France
l
Sanofi Genzyme, Cambridge, MA

ABSTRACT
Dupilumab, a monoclonal antibody that blocks the shared receptor subunit for interleukin (IL)-4 and IL-13, is currently approved for the
treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis (AD). The efficacy and safety of dupilumab for
Do Not Copy
AD among racial subgroups is unknown. This post hoc analysis from three phase 3 trials assessed the efficacy and safety of dupil-
umab vs placebo by racial subgroup (White, Asian, Black/African American). Data from LIBERTY AD SOLO 1 (NCT02277743), SOLO 2
Penalties Apply
(NCT02277769), and CHRONOS (NCT02260986) were pooled. Outcomes included mean and percent change from baseline to week
16 in the key therapeutic domains Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS), Dermatology
Life Quality Index (DLQI), and Patient-Oriented Eczema Measure, as well as Investigator’s Global Assessment and pain or discomfort
assessed by the European Quality of Life-5 Dimensions 3 level questionnaire.
A total of 2,058 patients (White n=1,429, Asian n=501, Black/African American n=128) were included in the current analysis. Baseline
demographics and disease characteristics were balanced between treatment groups and racial subgroups. In the three trials, dupilumab
significantly (P<0.0001) improved all assessed outcomes compared with placebo in the White and Asian subgroups. In the smaller
Black/African American subgroup, dupilumab significantly (P<0.0001) improved EASI endpoints and mean changes in Peak Pruritus
NRS and DLQI vs placebo, with positive numeric trends favoring dupilumab in all other endpoints.
Dupilumab was generally well tolerated, with an acceptable safety profile in all racial subgroups. Serious adverse events occurred more
frequently with placebo; treatment discontinuations due to adverse events were rare in all treatment groups.
Significant clinical improvement and a favorable benefit-risk profile can be achieved with dupilumab treatment in patients of White,
Asian, and Black/African American racial subgroups with moderate-to-severe AD inadequately controlled with topical medications.

ClinicalTrials.gov identifiers: NCT02277743, NCT02277769, NCT02260986

J Drugs Dermatol. 2019;18(8):804-813.

INTRODUCTION

A
topic dermatitis (AD) is a clinically defined, chronic skin
condition characterized by intense itch, disruption of
the skin barrier, and upregulation of type 2 immune
responses.1-3 The disease has an adverse impact on quality
of life (QoL) and is associated with sleep loss, anxiety, and
depression.4,5 Considerable heterogeneity in AD characteristics
and disease course has been noted between racial groups
and region.6,7 Genetic variations that influence AD incidence,

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Journal of Drugs in Dermatology
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presentation, and severity include differential expression
of specific polymorphisms in type 2 signaling pathway
genes, including those of interleukin (IL)-4 and IL-13 and their
receptors, and variations in skin barrier gene mutations.6
Disease presentation can also vary among racial subgroups,
with Asian patients presenting with better demarcated lesions
and increased scaling and lichenification compared with White
patients.6 Darker-skinned patients can have perifollicular
accentuation and scattered distinct papules on the extensors
and trunk, and erythema may be missed when assessing AD
lesions.6 AD prevalence also varies by racial subgroup, having
been reported more often in Asians and Blacks than in Whites.6,8
Therefore, diagnosis and severity assessment should consider
racial differences in genetics, presentation, and prevalence.
However, current guidelines do not propose any differences in
the diagnosis and treatment of AD by racial subgroup,9-11 and
no practical evidence exists to show that treatment should be
addressed differentially by racial subgroup.
Dupilumab, a fully human VelocImmune®-derived12,13
monoclonal antibody, blocks the shared receptor subunit for
IL-4 and IL-13, thus inhibiting signaling of both IL-4 and IL-13.
Dupilumab is approved for subcutaneous administration every
two weeks (q2w) for the treatment of patients aged 12 years and
older with moderate-to-severe AD inadequately controlled with
topical prescription therapies or when those therapies are not
advisable in the USA,14 for the treatment of adult AD patients
not adequately controlled with existing therapies in Japan,
and for use in adults with moderate-to-severe AD who are
Do Not Copy
approved by the US Food and Drug Administration14 as an add-
Penalties Apply
candidates for systemic therapy in the EU.15 Dupilumab is also
on maintenance treatment in patients with moderate-to-severe
asthma aged ≥12 years with an eosinophilic phenotype or with
oral corticosteroid-dependent asthma regardless of eosinophilic
phenotype.16-18 In clinical trials, dupilumab demonstrated
significant efficacy in improving signs and symptoms of AD,
and an acceptable safety profile.19-23 Efficacy and safety of
dupilumab have also been shown in clinical trials in other type
2 immune diseases, including chronic rhinosinusitis with nasal
polyposis, and eosinophilic esophagitis, thus demonstrating
the importance of IL-4 and IL-13 as drivers of multiple type 2
atopic/allergic diseases.24,25
LIBERTY AD SOLO 1 and SOLO 2 were two identically designed,
pivotal, 16-week, phase 3 trials that assessed efficacy and safety
of dupilumab monotherapy vs placebo,21 while the 52-week
CHRONOS trial assessed dupilumab with concomitant topical
corticosteroids (TCS) vs TCS alone22 in adults with moderate-
to-severe AD. Dupilumab significantly improved skin lesions,
symptoms (including pruritus and symptoms of anxiety and
depression), and QoL with an acceptable safety profile21,22 in
these randomized, placebo-controlled, double-blinded trials.
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A.F. Alexis, M. Rendon, J.I. Silverberg, et al
As the efficacy and safety of dupilumab among racial subgroups
have not been assessed previously, the objective of this report
is to present dupilumab efficacy, safety, and pharmacokinetics
(PK) among racial subgroups of adult patients with moderate-
to-severe AD in an analysis of the SOLO 1, SOLO 2, and
CHRONOS trials.
METHODS
Study Designs
Detailed descriptions of the study populations and method-
ologies of these trials have been published previously.21,22
All three studies were conducted following guidelines based
on the Declaration of Helsinki, International Conference on
Harmonisation-Good Clinical Practice, and local applicable
regulatory requirements. All patients provided written informed
consent prior to undertaking any study procedures.21,22
Briefly, in SOLO 1 (NCT02277743) and SOLO 2 (NCT02277769),
patients were randomized 1:1:1 to subcutaneous dupilumab 300
mg weekly (qw), q2w, or placebo for 16 weeks. A 35-day screening
and washout period preceded study drug administration. In
CHRONOS (NCT02260986), patients were randomized 3:1:3 to
subcutaneous dupilumab 300 mg qw, q2w, or placebo for 52
weeks with concomitant TCS; concomitant topical calcineurin
inhibitors could be used on body locations where TCS were
considered inadvisable. A 35-day screening period preceded the
study drug administration without a washout period for TCS. In
all three trials, a 600 mg loading dose was administered on day
1 to patients receiving dupilumab, while patients in the placebo
group received a double dose of placebo.
Patients self-reported their racial subgroup. Due to the very
low number or absence of patients of other racial subgroups
(American Indian, Alaska Native, Native Hawaiian or other
Pacific Islander, Others), this analysis only presented data from
White, Asian, and Black/African American patients.
Outcomes
Efficacy outcomes assessed in this analysis included: mean
and percent change from baseline to week 16 in Eczema Area
and Severity Index (EASI), Peak Pruritus Numerical Rating Scale
(NRS), Dermatology Life Quality Index (DLQI), and Patient-
Oriented Eczema Measure (POEM); proportion of patients
achieving Investigator’s Global Assessment (IGA) score 0 or
1 and a reduction of ≥2 points from baseline at week 16; and
proportion of patients with no pain or discomfort at week 16
using the European Quality of Life-5 Dimensions 3 level (EQ-5D-
3L) questionnaire among patients with at least moderate pain or
discomfort at baseline.
Safety outcomes included overall incidence of treatment-emergent
adverse events (TEAEs); treatment-emergent serious adverse
events (TE-SAEs); TEAEs leading to treatment discontinuation;
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Journal of Drugs in Dermatology
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deaths; and conjunctivitis from baseline to week 16. The generic
term “conjunctivitis” was used to summarize a cluster of Medical
Dictionary for Regulatory Activities Preferred Terms including
conjunctivitis, allergic conjunctivitis, viral conjunctivitis, bacterial
conjunctivitis, and atopic keratoconjunctivitis. Individual TEAEs
by racial subgroup were not analyzed due to low numbers of
patients in each subgroup.
The PK profile among different racial subgroups was assessed
as functional dupilumab levels in serum.26 The lower limit of
quantification of functional dupilumab concentration was 0.078
mg/L in undiluted human serum.
Statistical Analysis
Baseline, efficacy, and safety data for all three studies were
pooled. For CHRONOS, efficacy and safety data were used
through week 16, with week 52 data not reported due to
insufficient numbers of patients in some racial subgroups to
enable statistical analyses at that time point.
Efficacy analyses were performed on the full analysis set, which
included all randomized patients. Safety analyses by study drug
were performed using the safety analysis set, which included
all randomized patients who received at least one dose of any
study drug. PK analyses were performed on the PK analysis set,
which included all patients who had a PK measurement for a
particular time point.
All efficacy endpoints except IGA and EQ-5D-3L were analyzed
Do Not Copy
using an ANCOVA model with baseline measurement as
covariate, and treatment, region, and baseline IGA strata as
Penalties Apply
fixed factors for all studies, and study identifier. Values after first
rescue treatment were set to missing (censored) and imputed
using the multiple imputation method. P values (nominal) were
derived from an ANCOVA model using baseline as covariate, and
treatment, subgroup, treatment-by-subgroup interaction, region,
and baseline IGA strata as fixed factors. The ANCOVA model was
further adjusted with baseline weight (kg) as an additional factor
to generate weight-adjusted results for continuous endpoints.
IGA and EQ-5D-3L responder analyses were conducted using
a Cochran–Mantel–Haenszel (CMH) test stratified by region,
baseline disease severity (IGA=3 vs IGA=4), and study identifier.
CMH models are not amenable to adjustment with continuous
variables, therefore, body weight adjustment analyses were not
conducted for responder analyses.
Safety outcomes were summarized using descriptive statistics.
Statistical significance of differences in efficacy between the
dupilumab dose groups was not investigated.
All analyses were performed using SAS software, version 9.4
(SAS Institute Inc., Cary, NC, USA).
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A.F. Alexis, M. Rendon, J.I. Silverberg, et al
RESULTS
Patients
The pooled analysis population included 1,429 White patients,
501 Asian patients, and 128 Black/African American patients
(Table 1). Patient race was self-identified. White patients were
enrolled in the United States of America (USA, 29.2%), Poland
(16.9%), Germany (14.4%), Canada (12.0%), Spain (4.1%),
Estonia (3.8%), the United Kingdom (UK, 3.1%), Italy (2.5%), the
Netherlands (2.5%), Australia (2.4%), Hungary (1.9%), France
(1.5%), the Czech Republic (1.4%), Lithuania (1.2%), Bulgaria
(1.0%), Denmark (1.0%), Finland (0.6%), Romania (0.3%), and
New Zealand (0.2%). Asian patients were enrolled in Japan
(44.5%), Republic of Korea (21.2%), Canada (15.6%), the USA
(11.8%), Singapore (2.8%), Hong Kong (1.0%), the Netherlands
(1.0%), the UK (0.8%), Australia (0.6%), New Zealand (0.4%),
Germany (0.2%), and Spain (0.2%). Black/African American
patients were enrolled in the USA (92.2%) and Canada (7.8%).
Baseline demographics and disease characteristics were
generally balanced among treatment groups21,22 and among
racial subgroups in each of the studies (Table 1). Most patients
had a median AD duration of >20 years, mean baseline EASI
>30, and mean weekly Peak Pruritus NRS >7, showing a high
disease burden at baseline.
Efficacy
In the White and Asian subgroups, both dupilumab regimens
significantly improved AD signs (EASI, IGA), symptoms (POEM),
including itch (Peak Pruritus NRS) and pain/discomfort (EQ-
5D-3L), and QoL (DLQI) vs placebo at week 16 (Figure 1A-J,
P<0.0001). Weight-adjusted analyses support these findings
(Figure 2A-H).
In Black/African American patients, both dupilumab regimens
led to significant improvement vs placebo in the EASI endpoints
(Figure 1A-B) and mean change in Peak Pruritus NRS (Figure 1C)
and DLQI (Figure 1E), while only dupilumab 300 mg qw showed
significant improvement vs placebo in mean percent change in
Peak Pruritus NRS (Figure 1D), POEM endpoints (Figure 1G-H),
and proportions of patients achieving the IGA success endpoint
(Figure 1I) (P<0.05). Weight-adjusted analyses are consistent
with these findings (Figure 2).
Safety
Dupilumab was generally well tolerated, with an acceptable
safety profile in all three trials.21,22 TEAEs occurred at similar
rates across treatment groups. Conjunctivitis and injection-site
reactions were more frequent in the dupilumab-treated groups
in all studies, but were mild-to-moderate and rarely led to
treatment discontinuation. AD exacerbations and skin infections
occurred more frequently in the placebo groups.
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August 2019 • Volume 18 • Issue 8

TABLE 1.
Baseline Demographics and Clinical Characteristics by Treatment Group and Racial Subgroup
White Asian Black/African American

Dupilumab Dupilumab Dupilumab Dupilumab Dupilumab Dupilumab

Placebo Placebo Placebo
300 mg q2w 300 mg qw 300 mg q2w 300 mg qw 300 mg q2w 300 mg qw
(n=510) (n=189) (n=55)
(n=394) (n=525) (n=127) (n=185) (n=25) (n=48)

Age,
Median 38 38 39 33 33 31 41 35 31.5
(Q1, Q3), (26.0, 49.0) (28.0, 49.0) (26.0, 52.0) (24.0, 43.0) (25.0, 42.0) (25.0, 40.0) (27.0, 49.0) (28.0, 48.0) (24.0, 44.0)
Years
Male Sex,
282 (55.3) 230 (58.4) 313 (59.6) 128 (67.7) 83 (65.4) 127 (68.6) 23 (41.8) 9 (36.0) 20 (41.7)
n (%)
Weight,
76.4 77 77 65.55 64 65.3 82 84.2 81.9
Median
(65.00, 88.50) (65.70, 88.90) (64.80, 89.00) (55.40, 77.30) (56.40, 73.70) (59.30, 74.20) (68.10, 102.00) (72.50, 92.40) (67.00, 105.00)
(Q1, Q3), kg
BMI,
25.22 25.74 25.67 23.52 23.39 23.42 29.73 29.13 29.33
Median (Q1,
(22.50, 29.15) (23.05, 29.22) (22.24, 29.10) (21.08, 26.96) (20.98, 26.13) (21.25, 25.87) (24.84, 35.18) (27.05, 32.74) (21.31, 35.00)
Q3), kg/m2
Duration of
AD, Median 28 27.5 27 24 23.5 23.5 27 21 22
(Q1, Q3), (18.0, 40.0) (18.0, 42.0) (18.0, 42.0) (18.0, 35.0) (18.0, 32.0) (17.0, 32.0) (18.0, 40.0) (12.0, 28.0) (14.0, 31.0)
Years
EASI, Mean
32.9 (13.45) 32.3 (13.49) 32.1 (13.33) 35.8 (14.84) 34.0 (13.11) 34.3 (12.90) 30.8 (12.13) 30.9 (12.06) 28.3 (11.01)
(SD)
Patients With
IGA, n (%)
3 281 (55.1) 211 (53.6) 285 (54.3) 84 (44.4) 56 (44.1) 82 (44.3) 30 (54.5) 12 (48.0) 34 (70.8)
4 229 (44.9) 183 (46.4) 239 (45.5) 104 (55.0) 71 (55.9) 103 (55.7) 25 (45.5) 13 (52.0) 14 (29.2)
Missing
Weekly
0 0 0
Do Not Copy
1 (0.5) 0 0 0 0 0

Average
of Peak
Penalties Apply
7.4 (1.80) 7.4 (1.71) 7.3 (1.93) 7.4 (1.59) 7.3 (1.76) 7.2 (1.80) 6.9 (2.55) 8.3 (1.57) 6.9 (2.37)
Pruritus
NRS,
Mean (SD)
DLQI,
14 14 14 14 14 15 11 14 13
Median
(9.0, 21.0) (9.0, 20.0) (9.0, 20.0) (9.0, 21.0) (9.0, 21.0) (9.0, 21.0) (6.0, 18.0) (10.0, 20.0) (6.0, 18.0)
(Q1, Q3)
POEM,
21 21 21 21 21 21 19 22 19
Median
(16.0, 26.0) (17.0, 25.0) (17.0, 26.0) (16.0, 25.0) (16.0, 25.0) (15.0, 26.0) (13.0, 24.0) (19.0, 25.0) (13.5, 22.0)
(Q1, Q3)
EQ-5D-3L Pain/
Discomfort by
Category, n (%)
No Pain/
110 (21.6) 75 (19.0) 83 (15.8) 30 (15.9) 20 (15.7) 40 (21.6) 19 (34.5) 6 (24.0) 19 (39.6)
Discomfort
Moderate
Pain/ 301 (59.0) 252 (64.0) 345 (65.7) 105 (55.6) 83 (65.4) 101 (54.6) 27 (49.1) 12 (48.0) 22 (45.8)
Discomfort
Severe Pain/
99 (19.4) 67 (17.0) 96 (18.3) 53 (28.0) 24 (18.9) 44 (23.8) 9 (16.4) 7 (28.0) 7 (14.6)
Discomfort
Missing 0 0 1 (0.2) 1 (0.5) 0 0 0 0 0

AD, atopic dermatitis; BMI, body mass index; DLQI, Dermatology Life Quality Index; EASI, Eczema Area and Severity Index; EQ-5D-3L, European Quality of Life-5 Dimensions 3 level; IGA, Investigator’s
Global Assessment; NRS, Numerical Rating Scale; POEM, Patient-Oriented Eczema Measure; Q1, first quartile; Q3, third quartile; qw, weekly; q2w, every 2 weeks; SD, standard deviation.

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FIGURE 1. Forest plot of change from baseline to week 16: (A) LS mean change in EASI; (B) LS mean percent change in EASI; (C) LS mean change
in average of weekly Peak Pruritus NRS; (D) LS mean percent change in average of weekly Peak Pruritus NRS; (E) LS mean change in DLQI; (F) LS
mean percent change in DLQI; (G) LS mean change in POEM; (H) LS mean percent change in POEM; (I) Proportion of patients achieving IGA 0 or 1
and ≥2 point improvement; (J) Proportion of patients reporting no pain or discomfort at week 16 based on EQ-5D-3L. DLQI, Dermatology Life Quality Index; EASI,
Eczema Area and Severity Index; EQ-5D-3L, European Quality of Life-5 Dimensions 3 level; IGA, Investigator’s Global Assessment; LS, least squares; NRS, Numerical Rating Scale; POEM, Patient-Oriented
Eczema Measure; qw, weekly; q2w, every 2 weeks; SE, standard error. Solid squares represent difference vs placebo in dupilumab q2w and qw dose groups; error bars show 95% confidence interval;
P values are for difference vs placebo in dupilumab q2w and qw dose groups.

(A)
A A A
A (B)
B B B
B
Placebo Dupilumab
Placebo
Placebo Dupilumab
Dupilumab Placebo Dupilumab
Placebo
Placebo Dupilumab
Dupilumab
Subgroup
Subgroup
Subgroup Placebo Dupilumab P Value
P Value
P Value Subgroup
Subgroup
Subgroup Placebo Dupilumab P Value
P Value
P Value
Subgroup Change
Change (SE)(SE)
(SE) Change
Change (SE)(SE)
(SE) P Value Subgroup % Change (SE)% % Change
(SE)(SE)
P Value
Change
Change (SE) Change
Change (SE) %% Change
% Change
Change (SE)
(SE) %%
(SE) Change (SE)
Change
Change (SE)
Favors
Favors
Favors Dupilumab
Dupilumab
Dupilumab Favors
Favors
Favors Placebo
Placebo
Placebo Favors
Favors Dupilumab
Dupilumab
Favors Dupilumab Favors
Favors Placebo
Placebo
Favors Placebo
White White Favors Dupilumab Favors Placebo White White Favors Dupilumab Favors Placebo
WhiteWhite WhiteWhite
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo –14.91–14.91
(0.703)
–14.91 (0.703)–25.36
(0.703) –25.36
(0.693)
–25.36 (0.693) <0.0001
(0.693)<0.0001
<0.0001 Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –44.5 –44.5
(3.77)
–44.5 (3.77) –77.7
(3.77) –77.7
(3.83) <0.0001
(3.83) <0.0001
Dupilumab q2w vs Placebo –14.91 (0.703) –25.36 (0.693) <0.0001 Dupilumab q2w vs Placebo –44.5 (3.77) –77.7–77.7
(3.83)(3.83) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo –14.91 (0.703)–25.47
–25.47 <0.0001
(0.651)<0.0001 Dupilumab qw vs Placebo –44.5 (3.77) –78.0 –78.0 <0.0001
(4.22) <0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –14.91
–14.91 (0.703)
–14.91 (0.703)
(0.703) –25.47 (0.651)
–25.47 (0.651)
(0.651) <0.0001
<0.0001 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –44.5
–44.5 (3.77)
–44.5
(3.77)(3.77) (4.22)
–78.0–78.0
(4.22)(4.22) <0.0001
<0.0001
Asian Asian
Asian Asian Asian
Asian
Asian Asian
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo –10.97–10.97
(1.664)
–10.97 (1.664)–24.23
(1.664) –24.23
(1.615)
–24.23 (1.615)<0.0001
(1.615) <0.0001
<0.0001 Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –32.5 –32.5
(5.15)
–32.5 (5.15) –73.8
(5.15) –73.8
(4.89) (4.89) <0.0001
<0.0001
Dupilumab q2w vs Placebo –10.97 (1.664) –24.23 (1.615) <0.0001 Dupilumab q2w vs Placebo –32.5 (5.15) –73.8–73.8
(4.89)(4.89) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo –10.97 (1.664)–25.46
–25.46 (1.455)<0.0001
<0.0001 Dupilumab qw vs Placebo –32.5 (5.15) –75.6 –75.6 (4.47) <0.0001
<0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –10.97
–10.97 (1.664)
–10.97 (1.664)
(1.664) –25.46 (1.455)
–25.46 (1.455)
(1.455) <0.0001
<0.0001 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –32.5
–32.5 (5.15)
–32.5
(5.15)(5.15) (4.47)
–75.6–75.6
(4.47)(4.47) <0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African American
American
Black/African American
Black/African American Black/African American
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo –11.88–11.88
(1.947)
–11.88 (1.947)–20.02
(1.947) –20.02
(2.722)
–20.02 (2.722) 0.0161
(2.722) 0.0161
0.0161 Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –39.1 –39.1
(7.62)
–39.1 (7.62) –70.8
(7.62) –70.8
(9.09) (9.09) 0.00790.0079
Dupilumab q2w vs Placebo –11.88 (1.947) –20.02 (2.722) 0.0161 Dupilumab q2w vs Placebo –39.1 (7.62) –70.8–70.8
(9.09)(9.09) 0.0079
0.0079
Dupilumab
Dupilumab qw vs Placebo –11.88 (1.947)–19.98
–19.98 (1.925) 0.00280.0028 Dupilumab qw vs Placebo –39.1 (7.62) –69.5 –69.5 (6.70) 0.00300.0030
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –11.88
–11.88 (1.947)
–11.88 (1.947)
(1.947) –19.98 (1.925)
–19.98 (1.925)
(1.925) 0.00280.0028 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –39.1
–39.1 (7.62)
–39.1
(7.62)(7.62) (6.70)
–69.5–69.5
(6.70)(6.70) 0.0030
0.0030
–30 –20 –10 0 10 20 –100 –60
–80 –40
–60 –20
–40 –20 0 20 20
–30–30–30
–20–20–20
–10–10–100 0 010 10 10
20 20 20 –100
–100 –80–80–80
–100 –60 –60
–40 –40
–20 –200 0 20
0 20
LS Mean Difference LS Mean % Difference
LSLS Mean
LS
Mean MeanDifference
Difference
Difference LSLS Mean
LS
Mean %%
Mean Difference
% Difference
Difference

(C)
C C C
C (D)
D D D
D
Placebo Dupilumab
Placebo
Placebo Dupilumab
Dupilumab Placebo Dupilumab
Placebo
Placebo Dupilumab
Dupilumab
Subgroup
Subgroup
Subgroup Placebo Dupilumab P Value
P Value
P Value Subgroup
Subgroup
Subgroup Placebo Dupilumab P Value
P Value
P Value
Subgroup Change
Change (SE)(SE)
(SE) Change
Change (SE)(SE)
(SE) P Value Subgroup % Change (SE)% % Change(SE)(SE)
P Value
Change
Change (SE) Change
Change (SE) %% Change
% Change
Change (SE)
(SE) %%
(SE) Change (SE)
Change
Change (SE)
Favors
Favors
Favors Dupilumab
Dupilumab
Dupilumab Favors
Favors
Favors Placebo
Placebo
Placebo Favors
Favors Dupilumab
Dupilumab
Favors Dupilumab Favors
Favors Placebo
Placebo
Favors Placebo
White White Favors Dupilumab Favors Placebo White White Favors Dupilumab Favors Placebo
WhiteWhite WhiteWhite
Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –2.29 –2.29
(0.168)
–2.29 (0.168) –4.12
(0.168) –4.12
(0.158) <0.0001
(0.158) <0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –28.9 –28.9
(2.48) (2.48) –54.9 –54.9
(2.46) <0.0001
(2.46) <0.0001
Dupilumab q2w vs Placebo –2.29 (0.168) –4.12–4.12 (0.158)
(0.158) <0.0001
<0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –28.9–28.9
(2.48)(2.48) –54.9–54.9
(2.46)(2.46) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo –2.29 (0.168) –4.24 –4.24 <0.0001
(0.139) <0.0001 Dupilumab qw vs Placebo –28.9 (2.48) –55.2 –55.2 <0.0001
(2.15) <0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –2.29
–2.29 (0.168)
–2.29 (0.168)
(0.168) –4.24–4.24(0.139)
(0.139)
(0.139) <0.0001
<0.0001 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –28.9
–28.9 (2.48)
–28.9
(2.48)(2.48) (2.15)
–55.2–55.2
(2.15)(2.15) <0.0001
<0.0001
Asian Asian
Asian Asian Asian
Asian
Asian Asian
Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –1.41 –1.41
(0.298)
–1.41 (0.298) –3.59
(0.298) –3.59
(0.285)(0.285) <0.0001
<0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –18.1 –18.1
(4.17) (4.17) –49.4 –49.4
(4.06) (4.06) <0.0001
<0.0001
Dupilumab q2w vs Placebo –1.41 (0.298) –3.59–3.59 (0.285)
(0.285) <0.0001
<0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –18.1–18.1
(4.17)(4.17) –49.4–49.4
(4.06)(4.06) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo –1.41 (0.298) –3.68 –3.68 (0.261) <0.0001
<0.0001 Dupilumab qw vs Placebo –18.1 (4.17) –51.1 –51.1 (3.65) <0.0001
<0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –1.41
–1.41 (0.298)
–1.41 (0.298)
(0.298) –3.68–3.68(0.261)
(0.261)
(0.261) <0.0001
<0.0001 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –18.1
–18.1 (4.17)
–18.1
(4.17)(4.17) (3.65)
–51.1–51.1
(3.65)(3.65) <0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African American
American
Black/African American
Black/African American Black/African American
Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –2.18 –2.18
(0.364)
–2.18 (0.364) –3.82
(0.364) –3.82
(0.531)(0.531) 0.01180.0118 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –30.5 –30.5
(6.79) (6.79) –50.3 –50.3
(9.55) (9.55) 0.07750.0775
Dupilumab q2w vs Placebo –2.18 (0.364) –3.82–3.82 (0.531)
(0.531) 0.01180.0118 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –30.5–30.5
(6.79)(6.79) –50.3–50.3
(9.55)(9.55) 0.0775
0.0775
Dupilumab
Dupilumab qw vs Placebo –2.18 (0.364) –3.95 –3.95 (0.389) 0.00070.0007 Dupilumab qw vs Placebo –30.5 (6.79) –50.1 –50.1 (6.71) 0.04040.0404
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –2.18
–2.18 (0.364)
–2.18 (0.364)
(0.364) –3.95–3.95(0.389)
(0.389)
(0.389) 0.00070.0007 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –30.5
–30.5 (6.79)
–30.5
(6.79)(6.79) (6.71)
–50.1–50.1
(6.71)(6.71) 0.0404
0.0404
–5 0 5 –60 –50 –40 –30 –20 –10 0102010
20 20
–5 –5 –5 0 0 0 5 5 5 –60–60 –50
–60
–50 –40
–50
–40 –30
–40
–30 –20
–30
–20 –10
–20
–10 0 01001020
–10
LS Mean Difference LS Mean % Difference
LSLS Mean
LS
MeanMeanDifference
Difference
Difference LSLS Mean
LS
Mean %%
Mean Difference
% Difference
Difference

E E E(E)
E (F)
F F F
F
Placebo Dupilumab
Placebo
Placebo Dupilumab
Dupilumab Placebo Dupilumab
Placebo
Placebo Dupilumab
Dupilumab
Subgroup
Subgroup
Subgroup Placebo Dupilumab P Value
P Value
P Value Subgroup
Subgroup
Subgroup Placebo Dupilumab P Value
P Value
P Value
Subgroup Change
Change (SE)(SE)
(SE) Change
Change (SE)(SE)
(SE) P Value Subgroup % Change (SE)% % Change(SE)(SE)
P Value
%% Change (SE) %% Change (SE)

Do Not Copy
Change
Change (SE) Change
Change (SE) % Change
Change (SE) (SE) Change
Change (SE)
Favors
Favors
Favors Dupilumab
Dupilumab
Dupilumab Favors
Favors
Favors Placebo
Placebo
Placebo Favors
Favors Dupilumab
Dupilumab
Favors Dupilumab Favors
Favors Placebo
Placebo
Favors Placebo
White White Favors Dupilumab Favors Placebo White White Favors Dupilumab Favors Placebo
WhiteWhite WhiteWhite
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo –5.42 –5.42
(0.382)
–5.42 (0.382)–10.41
(0.382) –10.41
(0.365)
–10.41 (0.365) <0.0001
(0.365)<0.0001
<0.0001 Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –28.1 –28.1
(3.62)
–28.1 (3.62) –68.0
(3.62) –68.0
(3.73) <0.0001
(3.73) <0.0001
Dupilumab q2w vs Placebo –5.42 (0.382) –10.41 (0.365) <0.0001 Dupilumab q2w vs Placebo –28.1 (3.62) –68.0–68.0
(3.73)(3.73) <0.0001
<0.0001

Penalties Apply
Dupilumab
Dupilumab qw vs Placebo –5.42 (0.382)–10.56
–10.56 <0.0001
(0.335)<0.0001 Dupilumab qw vs Placebo –28.1 (3.62) –67.9 –67.9 <0.0001
(3.21) <0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –5.42
–5.42 (0.382)
–5.42 (0.382)
(0.382) –10.56 (0.335)
–10.56 (0.335)
(0.335) <0.0001
<0.0001 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –28.1
–28.1 (3.62)
–28.1
(3.62)(3.62) (3.21)
–67.9–67.9
(3.21)(3.21) <0.0001
<0.0001
Asian Asian
Asian Asian Asian
Asian
Asian Asian
Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –3.58 –3.58
(0.734)
–3.58 (0.734) –8.08
(0.734) –8.08
(0.732)(0.732) <0.0001
<0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –22.4 –22.4
(7.44) (7.44) –55.6 –55.6
(6.34) (6.34) <0.0001
<0.0001
Dupilumab q2w vs Placebo –3.58 (0.734) –8.08–8.08 (0.732)
(0.732) <0.0001
<0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –22.4–22.4
(7.44)(7.44) –55.6–55.6
(6.34)(6.34) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo –3.58 (0.734) –8.24 –8.24 (0.661) <0.0001
<0.0001 Dupilumab qw vs Placebo –22.4 (7.44) –59.5 –59.5 (5.89) <0.0001
<0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –3.58
–3.58 (0.734)
–3.58 (0.734)
(0.734) –8.24–8.24(0.661)
(0.661)
(0.661) <0.0001
<0.0001 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –22.4
–22.4 (7.44)
–22.4
(7.44)(7.44) (5.89)
–59.5–59.5
(5.89)(5.89) <0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African American
American
Black/African American
Black/African American Black/African American
Dupilumab
Dupilumab
Dupilumabq2w q2w
vs
q2w vs Placebo
Placebo
vs Placebo –6.09 –6.09
(0.742)
–6.09 (0.742) –9.34
(0.742) –9.34
(1.070)(1.070) 0.01200.0120 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –43.2 –43.2 (10.94) –68.8
(10.94) –68.8
(13.39)(13.39) 0.14300.1430
Dupilumab q2w vs Placebo –6.09 (0.742) –9.34–9.34 (1.070)
(1.070) 0.01200.0120 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –43.2–43.2 (10.94)
(10.94) –68.8–68.8 (13.39)
(13.39) 0.1430
0.1430
Dupilumab
Dupilumab qw vs Placebo –6.09 (0.742) –8.63 –8.63 (0.739) 0.01480.0148 Dupilumab qw vs Placebo –43.2 (10.94) –69.3 –69.3 (8.89) 0.08210.0821
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –6.09
–6.09 (0.742)
–6.09 (0.742)
(0.742) –8.63–8.63(0.739)
(0.739)
(0.739) 0.01480.0148 Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –43.2
–43.2 (10.94)
–43.2 (10.94)
(10.94) (8.89)
–69.3–69.3
(8.89)(8.89) 0.0821
0.0821
–20 –10 0 10 20 –100 –80 –60 –40 –200 2002040
20 40
–20–20–20–10–10–10 0 0 0 10 10 10 20 20 20 –100
–100 –80–80
–100 –60
–80
–60 –40
–60
–40 –20
–40
–20 0 0 20
–20 40 40
LS Mean Difference LS Mean % Difference
LSLS Mean
LS
Mean Mean Difference
Difference
Difference LSLS Mean
LS
Mean %%
Mean %Difference
Difference
Difference

G GG (G)
G
Placebo Dupilumab Dupilumab
(H)
H H H
H
Placebo Dupilumab
Dupilumab
Subgroup Placebo
Placebo
Placebo Dupilumab
Dupilumab P Value Subgroup Placebo
Placebo
Placebo Dupilumab
Dupilumab P Value
Subgroup
Subgroup Change P Value
P Value Subgroup
Subgroup P Value
P Value
Subgroup Change
Change
Change (SE) (SE)(SE)
(SE) Change
Change
Change
Change (SE) (SE)(SE)
(SE) P Value Subgroup
%% % % Change
Change
Change
Change (SE)
(SE)
(SE)%
%%
(SE) % Change
Change (SE)(SE)
(SE)
Change
Change (SE)
P Value
Favors
Favors
Favors Dupilumab
Dupilumab
Dupilumab Favors
Favors
Favors Placebo
Placebo
Placebo Favors
Favors Dupilumab
Dupilumab
Favors Dupilumab Favors
Favors Placebo
Placebo
Favors Placebo
White White Favors Dupilumab Favors Placebo White Favors Dupilumab Favors Placebo
WhiteWhite White
WhiteWhite
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo –5.75 –5.75
(0.466)
–5.75 (0.466)–12.70
(0.466) –12.70
(0.444)
–12.70 (0.444) <0.0001
(0.444)<0.0001
<0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –24.2 –24.2
(2.81) (2.81) –60.5 –60.5
(2.85) <0.0001
(2.85) <0.0001
Dupilumab q2w vs Placebo –5.75 (0.466) –12.70 (0.444) <0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –24.2 –24.2
(2.81)(2.81) –60.5–60.5
(2.85)(2.85) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo –5.75 (0.466)–12.88
–12.88 <0.0001
(0.427)<0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –5.75
–5.75 (0.466)
–5.75 (0.466)
(0.466) –12.88 (0.427)
–12.88 (0.427)
(0.427) <0.0001
<0.0001 Dupilumab
Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw
qw vs Placebo
Placebo
vs Placebo
Placebo –24.2
–24.2
–24.2
(2.81)
–24.2
(2.81)
(2.81) –61.1
(2.81) –61.1
(2.68)
–61.1–61.1
(2.68)(2.68) <0.0001
(2.68) <0.0001
<0.0001
<0.0001
Asian Asian
Asian Asian Asian
Asian AsianAsian
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo –1.66 –1.66
(0.927)
–1.66 (0.927) –9.97
(0.927) –9.97
(0.856)(0.856) <0.0001
<0.0001 Dupilumab q2w vs Placebo –6.0 (5.58) –50.7 –50.7 (5.58) <0.0001
<0.0001
Dupilumab q2w vs Placebo –1.66 (0.927) –9.97–9.97 (0.856)
(0.856) <0.0001
<0.0001 Dupilumab
Dupilumab
Dupilumab q2wq2w
vs vs
q2w Placebo
vs Placebo
Placebo –6.0
–6.0 (5.58)
–6.0
(5.58)(5.58) (5.58)
–50.7–50.7
(5.58)(5.58) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo –1.66 (0.927)–10.01–10.01 (0.764)<0.0001
<0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –1.66
–1.66 (0.927)
–1.66 (0.927)
(0.927) –10.01 (0.764)
–10.01 (0.764)
(0.764) <0.0001
<0.0001 Dupilumab
Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw
qw vs Placebo
Placebo
vs Placebo
Placebo –6.0
–6.0
–6.0
(5.58)
–6.0
(5.58)
(5.58) –51.6
(5.58) –51.6
(4.65)
–51.6–51.6
(4.65)(4.65) <0.0001
(4.65) <0.0001
<0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African American
American
Black/African American Black/African
Black/African American
American
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo –6.37 –6.37
(1.162)
–6.37 (1.162)–10.12
(1.162) –10.12
(1.571)
–10.12 (1.571) 0.0575
(1.571) 0.0575
0.0575 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –32.1 –32.1
(6.42) (6.42) –48.6 –48.6
(8.90) (8.90) 0.1346 0.1346
Dupilumab q2w vs Placebo –6.37 (1.162) –10.12 (1.571) 0.0575 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo –32.1 –32.1
(6.42)(6.42) –48.6–48.6
(8.90)(8.90) 0.1346
0.1346
Dupilumab
Dupilumab qw vs Placebo –6.37 (1.162)–12.85
–12.85 (1.139)<0.0001<0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo –6.37
–6.37 (1.162)
–6.37 (1.162)
(1.162) –12.85 (1.139)
–12.85 (1.139)
(1.139) <0.0001
<0.0001 Dupilumab
Dupilumabqwqw
Dupilumab
Dupilumab vs
vsqw
qw vs Placebo
Placebo
vs Placebo
Placebo –32.1
–32.1
–32.1
(6.42)
–32.1
(6.42)
(6.42) –65.8
(6.42) –65.8
(6.57)
–65.8–65.8
(6.57)
(6.57) 0.0002
(6.57) 0.0002
0.0002
0.0002
–20 –10 0 10 20 –60 –50 –40 –30 –20 –10 0204020
40 40
–20–20–20–10–10–10 0 0 0 10 10 10 20 20 20 –60–60
–50–50
–60 –40
–50
–40 –30
–40
–30 –20
–30
–20 –10
–20
–10 0 02002040
–10
LS Mean Difference LS Mean % Difference
LSLS Mean
LS
Mean Mean Difference
Difference
Difference LSLS Mean
LS
Mean %%
Mean Difference
% Difference
Difference

I I I(I) I Placebo Rate Dupilumab Rate

(J)
J J J
J
Placebo Rate Dupilumab Rate
Subgroup Placebo
Placebo
Placebo Rate
Rate Rate Dupilumab
Dupilumab
Dupilumab Rate
Rate Rate P Value Subgroup Placebo
Placebo Rate
Placebo
Rate Rate Dupilumab
Dupilumab
Dupilumab Rate
Rate Rate P Value
Subgroup
Subgroup n/N P Value
P Value Subgroup
Subgroup P Value
P Value
Subgroup n/N
n/N n/N
(%) (%)(%) n/N
(%) n/Nn/N
(%)
n/N
(%)(%) P Value
(%) Subgroup n/N1
n/N1
n/N1 (%)
(%)(%)(%)
n/N1 n/N1
n/N1
n/N1 (%)P Value
(%)(%)(%)
n/N1
Favors
Favors
Favors Placebo
Placebo
Placebo Favors
Favors
Favors Dupilumab
Dupilumab
Dupilumab Favors
Favors Placebo
Placebo
Favors Placebo FavorsFavors Dupilumab
Dupilumab
Favors Dupilumab
White White Favors Placebo Favors Dupilumab White Favors Placebo Favors Dupilumab
WhiteWhite White
WhiteWhite
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo 67/510 67/510
67/510 (13.1) (13.1)160/394
(13.1) 160/394
160/394 (40.6)
(40.6) <0.0001
(40.6)<0.0001
<0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo 70/40070/400
(17.5) (17.5)149/319
149/319
(46.7) (46.7)<0.0001
<0.0001
Dupilumab q2w vs Placebo 67/510 (13.1) 160/394 (40.6) <0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo 70/400
70/400 (17.5)(17.5) 149/319
149/319 (46.7)(46.7) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo 67/510 (13.1)209/525 209/525 <0.0001
(39.8)<0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo 67/510
67/510
67/510 (13.1)
(13.1) (13.1) 209/525
209/525 (39.8)
(39.8) (39.8) <0.0001
<0.0001 Dupilumab
Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw
qw vs Placebo
Placebo
vs Placebo
Placebo 70/400
70/400
70/400
(17.5)
70/400
(17.5)
(17.5)203/441
(17.5)203/441
203/441
(46.0)
203/441
(46.0)
(46.0)<0.0001
(46.0) <0.0001
<0.0001
<0.0001
Asian Asian
Asian Asian Asian
Asian AsianAsian
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo 5/189
5/1895/189(2.6)(2.6)
(2.6) 36/127 36/127
36/127 (28.3) (28.3) <0.0001
(28.3) <0.0001
<0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo 30/15830/158
(19.0) (19.0)50/107
50/107
(46.7) (46.7) <0.0001
<0.0001
Dupilumab q2w vs Placebo 5/189 (2.6) 36/127 (28.3) <0.0001 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo 30/158
30/158 (19.0)(19.0) 50/107
50/107 (46.7)(46.7) <0.0001
<0.0001
Dupilumab
Dupilumab qw vs Placebo 5/189(2.6)(2.6) 57/185 (30.8) <0.0001
<0.0001
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo 5/189
5/1895/189 (2.6)
(2.6) 57/185
57/18557/185 (30.8)
(30.8) (30.8) <0.0001
<0.0001 Dupilumab
Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw
qw vs Placebo
Placebo
vs Placebo
Placebo 30/158
30/158
30/158
(19.0)
30/158
(19.0)
(19.0)78/145
(19.0) 78/145
78/145
(53.8)
78/145
(53.8)
(53.8) <0.0001
(53.8) <0.0001
<0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African American
American
Black/African American Black/African
Black/African American
American
Dupilumab
Dupilumab
Dupilumabq2wq2wq2w
vs vs vs Placebo
Placebo
Placebo 8/55
8/55 8/55
(14.5) (14.5) 7/25
(14.5) 7/25 7/25
(28.0) (28.0) 0.0524
(28.0) 0.0524
0.0524 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo 11/36 11/36
(30.6) (30.6) 9/19 9/19
(47.4) (47.4) 0.1671 0.1671
Dupilumab q2w vs Placebo 8/55 (14.5) 7/25 (28.0) 0.0524 Dupilumab
Dupilumab q2w q2w
vs vs Placebo
Placebo 11/3611/36
(30.6)(30.6) 9/19
9/19 (47.4)(47.4) 0.16710.1671
Dupilumab
Dupilumab qw vs Placebo 8/55 (14.5) 21/48 21/48 (43.8) 0.0026 0.0026
Dupilumab qwqw
Dupilumab vs
vsqw Placebo
vs Placebo
Placebo 8/55
8/55 8/55(14.5)
(14.5) (14.5) 21/4821/48 (43.8)
(43.8) (43.8) 0.00260.0026 Dupilumab
Dupilumab
qwqw
Dupilumab
Dupilumab vs
vsqw
qw vs Placebo
Placebo
vs Placebo
Placebo 11/36
11/36
11/36
(30.6)
11/36
(30.6)
(30.6) 14/29
(30.6) 14/29
14/2914/29(48.3)
(48.3)
(48.3) 0.1734
(48.3) 0.1734
0.1734
0.1734
–50 –25 0 25 50
25 705070100
70100100 –50 –25 0 25 50
25 755075100
75100100
–50–50–50
–25–25–25
0 0 250 25 50 50 70 100 –50–50–50
–25–25–25
0 0 250 25 50 50 75 100
Difference
Difference vs Placebo (%) Difference vs Placebo (%)
Difference vs vs
Difference Placebo
vs (%)(%)(%)
Placebo
Placebo Difference
vs vs
Difference
Difference Placebo
vs (%)(%)(%)
Placebo
Placebo
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809
Journal of Drugs in Dermatology A.F. Alexis, M. Rendon, J.I. Silverberg, et al
August 2019 • Volume 18 • Issue 8

FIGURE 2. Forest plot of change from baseline to week 16 (weight-adjusted): (A) LS mean change in EASI; (B) LS mean percent change in EASI; (C)
LS mean change in average of weekly Peak Pruritus NRS; (D) LS mean percent change in average of weekly Peak Pruritus NRS; (E) LS mean change
in DLQI; (F) LS mean percent change in DLQI; (G) LS mean change in POEM; (H) LS mean percent change in POEM. DLQI, Dermatology Life Quality Index; EASI,
Eczema Area and Severity Index; LS, least squares; NRS, Numerical Rating Scale; POEM, Patient-Oriented Eczema Measure; qw, weekly; q2w, every 2 weeks; SE, standard error. Solid squares represent
difference vs placebo in dupilumab q2w and qw dose groups; error bars show 95% confidence interval; P values are for difference vs placebo in dupilumab q2w and qw dose groups.

(A)
A AA (B)
B BB
Placebo
Placebo
Placebo Dupilumab
Dupilumab
Dupilumab Placebo
Placebo
Placebo Dupilumab
Dupilumab
Dupilumab
Subgroup
Subgroup
Subgroup PPValue
Value
P Value Subgroup
Subgroup
Subgroup PPValue
Value
P Value
Change
Change
Change(SE)(SE) Change
(SE) Change
Change
(SE) (SE)
(SE) %%%Change
Change
Change (SE)(SE)% %
(SE) %Change
Change
Change (SE)(SE)
(SE)
Favors
Favors
Favors DupilumabFavors
Dupilumab
Dupilumab Favors
Favors Placebo
Placebo
Placebo Favors
Favors DupilumabFavors
Dupilumab
Favors Dupilumab Favors Placebo
Placebo
Favors Placebo
White
White
White White
White
White
Dupilumab
Dupilumab
Dupilumab
q2wq2w
q2w vsPlacebo
vs vs Placebo
Placebo –14.90
–14.90
–14.90 (0.738) –25.39
(0.738)
(0.738) –25.39
–25.39 (0.709) <0.0001
(0.709)
(0.709) <0.0001
<0.0001 Dupilumab
Dupilumab q2w
Dupilumab q2w vsPlacebo
vs vs
q2w Placebo
Placebo –44.0
–44.0 (3.77)
(3.77)
–44.0 (3.77) –77.7
–77.7 (3.73)
(3.73)
–77.7 (3.73) <0.0001
<0.0001
<0.0001
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –14.90
–14.90
–14.90 (0.738) –25.48
(0.738)
(0.738) –25.48
–25.48 (0.648) <0.0001
(0.648)
(0.648) <0.0001
<0.0001 Dupilumab
Dupilumab qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –44.0
–44.0 (3.77)
(3.77)
–44.0 (3.77) –78.7
–78.7 (4.09)
(4.09)
–78.7 (4.09) <0.0001
<0.0001
<0.0001
Asian
Asian
Asian Asian
Asian
Asian
Dupilumab
Dupilumab
Dupilumab
q2wq2w
q2w vsPlacebo
vs vs Placebo
Placebo –11.04
–11.04
–11.04 (1.757) –24.47
(1.757)
(1.757) –24.47
–24.47 (1.681) <0.0001
(1.681)
(1.681) <0.0001
<0.0001 Dupilumab
Dupilumab q2w
Dupilumab q2w vsPlacebo
vs vs
q2w Placebo
Placebo –33.0
–33.0 (5.28)
(5.28)
–33.0 (5.28) –74.6
–74.6 (5.21)
(5.21)
–74.6 (5.21) <0.0001
<0.0001
<0.0001
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –11.04
–11.04
–11.04 (1.757) –25.57
(1.757)
(1.757) –25.57
–25.57 (1.487) <0.0001
(1.487)
(1.487) <0.0001
<0.0001 Dupilumab
Dupilumab qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –33.0
–33.0 (5.28)
(5.28)
–33.0 (5.28) –76.0
–76.0 (4.64)
(4.64)
–76.0 (4.64) <0.0001
<0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African American
American
Black/African American
Dupilumab
Dupilumab
Dupilumab
q2wq2w
q2w vsPlacebo
vs vs Placebo
Placebo –11.89
–11.89
–11.89 (1.904) –20.31
(1.904)
(1.904) –20.31
–20.31 (2.633) 0.0118
(2.633)
(2.633) 0.0118
0.0118 Dupilumab
Dupilumab q2w
Dupilumab q2w vsPlacebo
vs vs
q2w Placebo
Placebo –38.6
–38.6 (7.17)
(7.17)
–38.6 (7.17) –71.9
–71.9 (8.82)
(8.82)
–71.9 (8.82) 0.0047
0.0047
0.0047
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –11.89
–11.89
–11.89 (1.904) –20.15
(1.904)
(1.904) –20.15
–20.15 (1.884) 0.0011
(1.884)
(1.884) 0.0011
0.0011 Dupilumab
Dupilumab qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –38.6
–38.6 (7.17)
(7.17)
–38.6 (7.17) –70.3
–70.3 (6.47)
(6.47)
–70.3 (6.47) 0.0006
0.0006
0.0006

–30
–30–30 –20
–20–20 –100 0 0 10 101020 2020
–10–10 –100
–100 –80
–80–80
–100 –60
–60–60 –40
–40–40 –20
–20–20 0 0 020 2020
LSLSLSMean
MeanMean Difference
Difference
Difference LSLSLSMean
MeanMean
%% %Difference
Difference
Difference

(C)
C CC (D)
D DD
Placebo
Placebo
Placebo Dupilumab
Dupilumab
Dupilumab Placebo
Placebo
Placebo Dupilumab
Dupilumab
Dupilumab
Subgroup
Subgroup
Subgroup PPValue
Value
P Value Subgroup
Subgroup
Subgroup PPValue
Value
P Value
Change
Change
Change (SE) Change
(SE)
(SE) Change
Change (SE)
(SE)
(SE) %%%Change
Change
Change (SE)(SE)% %
(SE) %Change
Change
Change (SE)(SE)
(SE)
Favors
Favors
Favors DupilumabFavors
Dupilumab
Dupilumab Favors
Favors Placebo
Placebo
Placebo Favors
Favors
Favors DupilumabFavors
Dupilumab
Dupilumab Favors
Favors Placebo
Placebo
Placebo
White
White
White White
White
White
Dupilumab
Dupilumab
Dupilumab q2w
q2w
q2w vsPlacebo
vs vs Placebo
Placebo –2.28
–2.28
–2.28 (0.150) –4.13
(0.150)
(0.150) –4.13
–4.13 (0.149)
(0.149) <0.0001
(0.149) <0.0001
<0.0001 Dupilumab
Dupilumab
Dupilumab
q2wq2w
q2w vsPlacebo
vs vs Placebo
Placebo –28.7
–28.7
–28.7 (2.35)
(2.35)
(2.35) –55.1
–55.1
–55.1 (2.32)
(2.32)
(2.32) <0.0001
<0.0001
<0.0001
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –2.28
–2.28
–2.28 (0.150) –4.23
(0.150)
(0.150) –4.23
–4.23 (0.137)
(0.137) <0.0001
(0.137) <0.0001
<0.0001 Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –28.7
–28.7
–28.7 (2.35)
(2.35)
(2.35) –55.0
–55.0
–55.0 (2.16)
(2.16)
(2.16) <0.0001
<0.0001
<0.0001
Asian
Asian
Asian Asian
Asian
Asian
Dupilumab
Dupilumab
Dupilumab q2w
q2w
q2w vsPlacebo
vs vs Placebo
Placebo –1.43
–1.43
–1.43 (0.280) –3.57
(0.280)
(0.280) –3.57
–3.57 (0.281) <0.0001
(0.281)
(0.281) <0.0001
<0.0001 Dupilumab
Dupilumab
Dupilumab
q2wq2w
q2w vsPlacebo
vs vs Placebo
Placebo –18.7
–18.7
–18.7 (3.98)
(3.98)
(3.98) –49.3
–49.3
–49.3 (4.00)
(4.00)
(4.00) <0.0001
<0.0001
<0.0001
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –1.43
–1.43
–1.43 (0.280) –3.66
(0.280)
(0.280) –3.66
–3.66 (0.247) <0.0001
(0.247)
(0.247) <0.0001
<0.0001 Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –18.7
–18.7
–18.7 (3.98)
(3.98)
(3.98) –50.9
–50.9
–50.9 (3.50)
(3.50)
(3.50) <0.0001
<0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African
Black/African American
American
American
Dupilumab
Dupilumab
Dupilumab q2w
q2w
q2w vsPlacebo
vs vs Placebo
Placebo –2.20
–2.20
–2.20 (0.375) –3.74
(0.375)
(0.375) –3.74
–3.74 (0.538)
(0.538)
(0.538) 0.0224
0.0224
0.0224 Dupilumab
Dupilumab
Dupilumab
q2wq2w
q2w vsPlacebo
vs vs Placebo
Placebo –31.0
–31.0
–31.0 (7.55)
(7.55)
(7.55) –49.5
–49.5
–49.5 (9.72)
(9.72)
(9.72) 0.1135
0.1135
0.1135
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –2.20
–2.20
–2.20 (0.375) –3.95
(0.375)
(0.375) –3.95
–3.95 (0.402)
(0.402)
(0.402) 0.0013
0.0013
0.0013 Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –31.0
–31.0
–31.0 (7.55)
(7.55)
(7.55) –50.0
–50.0
–50.0 (6.86)
(6.86)
(6.86) 0.0695
0.0695
0.0695

–5 –5–5 0 00 5 55 –60–50
–60–60
–50 –50–40
–40 –40–30
–30 –30–20
–20 –20–10
–10 –10 0 1020
0 010 10 2020
LSMean
LSLS Mean
Mean Difference
Difference
Difference LSLSLSMean
Mean Mean
%% %Difference
Difference
Difference

(E)
E EE (F)
F FF
Placebo
Placebo
Placebo Dupilumab
Dupilumab
Dupilumab Placebo
Placebo
Placebo Dupilumab
Dupilumab
Dupilumab
Subgroup
Subgroup
Subgroup PPValue
Value
P Value Subgroup
Subgroup
Subgroup PPValue
Value
P Value
Change
Change
Change (SE) Change
(SE)
(SE) Change
Change (SE)
(SE)
(SE) %%%Change
Change
Change (SE)(SE)% %
(SE) %Change
Change
Change (SE)(SE)
(SE)
Favors
Favors
Favors DupilumabFavors
Dupilumab
Dupilumab Favors
Favors Placebo
Placebo
Placebo Favors
Favors
Favors DupilumabFavors
Dupilumab
Dupilumab Favors
Favors Placebo
Placebo
Placebo
White
White
White White
White
White
Dupilumab
Dupilumab
Dupilumab q2w
q2w
q2w vsPlacebo
vs vs Placebo
Placebo –5.33
–5.33
–5.33 (0.362) –10.36
(0.362)
(0.362) –10.36
–10.36 (0.361)
(0.361) <0.0001
(0.361) <0.0001
<0.0001 Dupilumab
Dupilumab q2w
Dupilumab q2w vsPlacebo
vs vs
q2w Placebo
Placebo –27.4
–27.4 (3.68)
(3.68)
–27.4 (3.68) –67.1
–67.1 (3.64)
(3.64)
–67.1 (3.64) <0.0001
<0.0001
<0.0001
Dupilumab
Dupilumab
Dupilumab
Asian
Asian
Asian
qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –5.33
–5.33
–5.33 (0.362) –10.54
(0.362)
(0.362) –10.54
–10.54 (0.348)
(0.348) <0.0001
(0.348) <0.0001
<0.0001
Do Not Copy Dupilumab
Dupilumab
Asian
Asian
Asian
qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –27.4
–27.4 (3.68)
(3.68)
–27.4 (3.68) –67.6
–67.6 (3.42)
(3.42)
–67.6 (3.42) <0.0001
<0.0001
<0.0001

Penalties Apply
Dupilumab
Dupilumab
Dupilumab q2w
q2w
q2w vsPlacebo
vs vs Placebo
Placebo –3.59
–3.59
–3.59 (0.765) –8.22
(0.765)
(0.765) –8.22
–8.22 (0.748) <0.0001
(0.748)
(0.748) <0.0001
<0.0001 Dupilumab
Dupilumab q2w
Dupilumab q2w vsPlacebo
vs vs
q2w Placebo
Placebo –21.8
–21.8 (6.63)
(6.63)
–21.8 (6.63) –56.8
–56.8 (6.17)
(6.17)
–56.8 (6.17) <0.0001
<0.0001
<0.0001
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –3.59
–3.59
–3.59 (0.765) –8.33
(0.765)
(0.765) –8.33
–8.33 (0.662) <0.0001
(0.662)
(0.662) <0.0001
<0.0001 Dupilumab
Dupilumab qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –21.8
–21.8 (6.63)
(6.63)
–21.8 (6.63) –59.9
–59.9 (5.39)
(5.39)
–59.9 (5.39) <0.0001
<0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African American
American
Black/African American
Dupilumab
Dupilumab
Dupilumab q2w
q2w
q2w vsPlacebo
vs vs Placebo
Placebo –5.97
–5.97
–5.97 (0.793) –9.36
(0.793)
(0.793) –9.36
–9.36 (1.086)
(1.086)
(1.086) 0.0127
0.0127
0.0127 Dupilumab
Dupilumab q2w
Dupilumab q2w vsPlacebo
vs vs
q2w Placebo
Placebo –40.5
–40.5 (10.69) –68.9
(10.69)
–40.5 (10.69) –68.9 (12.46)
(12.46)
–68.9 (12.46) 0.0967
0.0967
0.0967
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –5.97
–5.97
–5.97 (0.793) –8.70
(0.793)
(0.793) –8.70
–8.70 (0.759)
(0.759)
(0.759) 0.0117
0.0117
0.0117 Dupilumab
Dupilumab qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –40.5
–40.5 (10.69)
(10.69)
–40.5 (10.69) –71.5
–71.5 (8.44)
(8.44)
–71.5 (8.44) 0.0248
0.0248
0.0248

–20 –10–10
–20–20 –10 0 0 0 10 1010 20 2020 –100
–100
–100 –80
–80–80 –60
–60–60 –40
–40–40 –20
–20–20 0 2020
0 0 20 40 4040
LSLS LSMean
MeanMean Difference
Difference
Difference LSLS LSMean
Mean Mean
%% %Difference
Difference
Difference

(G)
G GG
Placebo
Placebo
Placebo Dupilumab
Dupilumab
Dupilumab
(H)
H HH
Placebo
Placebo
Placebo Dupilumab
Dupilumab
Dupilumab
Subgroup
Subgroup
Subgroup PPValue
Value
P Value Subgroup
Subgroup
Subgroup PPValue
Value
P Value
Change
Change
Change (SE) Change
(SE)
(SE) Change
Change (SE)
(SE)
(SE) %%%Change
Change
Change (SE)(SE)% %
(SE) %Change
Change
Change (SE)(SE)
(SE)
Favors
Favors
Favors DupilumabFavors
Dupilumab
Dupilumab Favors
Favors Placebo
Placebo
Placebo Favors
Favors
Favors DupilumabFavors
Dupilumab
Dupilumab Favors
Favors Placebo
Placebo
Placebo
White
White
White White
White
White
Dupilumab
Dupilumab
Dupilumab q2w
q2wq2w vsPlacebo
vs vs Placebo
Placebo –5.79
–5.79
–5.79 (0.484) –12.70
(0.484)
(0.484) –12.70
–12.70 (0.458)
(0.458) <0.0001
(0.458) <0.0001
<0.0001 Dupilumab
Dupilumab q2w
Dupilumab q2w
vs vs
q2w vsPlacebo
Placebo
Placebo –24.2
–24.2 (2.90)
(2.90)
–24.2 (2.90) –60.4
–60.4 (2.91)
(2.91)
–60.4 (2.91) <0.0001
<0.0001
<0.0001
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –5.79
–5.79
–5.79 (0.484) –12.85
(0.484)
(0.484) –12.85
–12.85 (0.415)
(0.415) <0.0001
(0.415) <0.0001
<0.0001 Dupilumab
Dupilumab qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –24.2
–24.2 (2.90)
(2.90)
–24.2 (2.90) –60.9
–60.9 (2.63)
(2.63)
–60.9 (2.63) <0.0001
<0.0001
<0.0001
Asian
Asian
Asian Asian
Asian
Asian
Dupilumab
Dupilumab
Dupilumab q2w
q2wq2w vsPlacebo
vs vs Placebo
Placebo –1.68
–1.68
–1.68 (0.872) –9.79
(0.872)
(0.872) –9.79
–9.79 (0.861) <0.0001
(0.861)
(0.861) <0.0001
<0.0001 Dupilumab
Dupilumab q2w
Dupilumab q2w
vs vs
q2w vsPlacebo
Placebo
Placebo –6.1–6.1 (5.46)
(5.46)
–6.1 (5.46) –49.9
–49.9 (6.04)
(6.04)
–49.9 (6.04) <0.0001
<0.0001
<0.0001
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –1.68
–1.68
–1.68 (0.872) –9.89
(0.872)
(0.872) –9.89
–9.89 (0.773) <0.0001
(0.773)
(0.773) <0.0001
<0.0001 Dupilumab
Dupilumab qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –6.1–6.1 (5.46)
(5.46)
–6.1 (5.46) –50.9
–50.9 (4.75)
(4.75)
–50.9 (4.75) <0.0001
<0.0001
<0.0001
Black/African
Black/African
Black/African American
American
American Black/African
Black/African American
American
Black/African American
Dupilumab
Dupilumab
Dupilumab q2w
q2wq2w vsPlacebo
vs vs Placebo
Placebo –6.23
–6.23
–6.23 (1.149) –10.09
(1.149)
(1.149) –10.09
–10.09 (1.589) 0.0467
(1.589)
(1.589) 0.0467
0.0467 Dupilumab
Dupilumab q2w
Dupilumab q2w
vs vs
q2w vsPlacebo
Placebo
Placebo –31.7
–31.7 (6.37)
(6.37)
–31.7 (6.37) –48.7
–48.7 (8.99)
(8.99)
–48.7 (8.99) 0.1190
0.1190
0.1190
Dupilumab
Dupilumab
Dupilumab qwvs
qwqw
vs vsPlacebo
Placebo
Placebo –6.23
–6.23
–6.23 (1.149) –12.77
(1.149)
(1.149) –12.77
–12.77 (1.172) <0.0001
(1.172)
(1.172) <0.0001
<0.0001 Dupilumab
Dupilumab qwvs
qwqw
Dupilumab vs vsPlacebo
Placebo
Placebo –31.7
–31.7 (6.37)
(6.37)
–31.7 (6.37) –65.5
–65.5 (6.87)
(6.87)
–65.5 (6.87) 0.0003
0.0003
0.0003
–20 –10–10
–20–20 –10 0 0 0 10 1010 20 2020 –60–50
–60–60
–50 –50–40
–40 –40–30
–30 –30–20
–20 –20–10
–10 –10 0 2040
0 020 20 4040
LSLS LSMean
MeanMean Difference
Difference
Difference LSLSLSMean
Mean Mean
%% %Difference
Difference
Difference

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810
Journal of Drugs in Dermatology A.F. Alexis, M. Rendon, J.I. Silverberg, et al
August 2019 • Volume 18 • Issue 8

TABLE 2.
Adverse Events Reported Between Baseline and Week 16
White Asian Black/African American

Dupilumab Dupilumab Dupilumab Dupilumab Dupilumab Dupilumab

Placebo Placebo Placebo
Patients with 300 mg q2w 300 mg qw 300 mg q2w 300 mg qw 300 mg q2w 300 mg qw
(n=509) (n=188) (n=53)
(n=402) (n=517) (n=128) (n=184) (n=27) (n=47)

≥1 TEAE,a
362 (71.1) 292 (72.6) 372 (72.0) 128 (68.1) 83 (64.8) 121 (65.8) 24 (45.3) 12 (44.4) 26 (55.3)
n (%)
≥1 TE-SAE,a n (%) 22 (4.3) 11 (2.7) 13 (2.5) 7 (3.7) 1 (0.8) 1 (0.5) 0 1 (3.7) 0
≥1 TEAE
Causing
Discontinuation 12 (2.4) 6 (1.5) 12 (2.3) 7 (3.7) 0 3 (1.6) 1 (1.9) 0 0
of Study Drug
Permanently, n (%)
Death, n (%)b 0 0 1 (0.2) 0 0 0 0 0 0
Conjunctivitisc 29 (5.7) 45 (11.2) 80 (15.5) 6 (3.2) 13 (10.2) 15 (8.2) 1 (1.9) 1 (3.7) 3 (6.4)

a
Adverse events reported at the level of MedDRA PT. bDetailed description of the event is given previously.19 cThe generic term of conjunctivitis was used to summarize a cluster of MedDRA PTs that in-
clude: conjunctivitis (of undetermined etiology), allergic conjunctivitis, viral conjunctivitis, bacterial conjunctivitis, and atopic keratoconjunctivitis. MedDRA, Medical Dictionary for Regulatory Activities;
PT, Preferred Term; qw, weekly; q2w, every two weeks; TEAE, treatment-emergent adverse event; TE-SAE, treatment-emergent serious adverse event.

FIGURE 3. Mean (±SD) functional dupilumab concentration vs time
by racial subgroup: (A) Dupilumab 300 mg qw; (B) Dupilumab 300 mg
q2w; qw, weekly; q2w, every 2 weeks; SD, standard deviation.
(A) (B)
A B
300
DISCUSSION
Dupilumab with or without concomitant TCS significantly
improved AD signs, symptoms, and QoL across all racial
subgroups studied in this analysis, with efficacy generally
consistent with the data reported for the overall populations in
SOLO 1 and 221 and CHRONOS.22
300

Do Not Although
Copy the original trial publications also presented
250 250

categorical efficacy endpoints, this analysis focuses on21,22

Concentration (mg/L)

Concentration (mg/L)

200 200

150

100
150

100
Penaltiescontinuous
Applyoutcomes, which are the most sensitive and best
suited for subset analyses, particularly with relatively small
50 50
patient subsets. The reported endpoints in the present analysis
provide a comprehensive racial subgroup analysis by assessing
0 0
all major domains that define AD severity and response to
0 4 8
Week
12 16 0 4 8
Week
12 16
treatment, including objective signs, subjective symptoms, and
Dupilumab 300 mg qw / White (n=507) Dupilumab 300 mg q2w / White (n=393) QoL.
Dupilumab 300 mg qw / Asian (n=184) Dupilumab 300 mg q2w / Asian (n=128)
Dupilumab 300 mg qw / Black / African American (n=45) Dupilumab 300 mg q2w / Black / African American (n=26)

Efficacy outcomes in White and Asian patients were similar to

In all treatment groups within each racial subset, 44-73% of those in the overall populations of the trial.21,22 While numeric
patients reported ≥1TEAE (Table 2).TE-SAEs and discontinuation trends always favored dupilumab vs placebo in the Black/African
of study drug generally occurred more often in patients receiving American subset, statistical significance in efficacy outcomes
placebo (Table 2). One death was reported in a 31-year-old White was not achieved consistently in either dupilumab group due
male receiving dupilumab 300 mg qw in SOLO 2, but was not primarily to the low numbers of Black/African American patients.
considered to be treatment related.21 Conjunctivitis was the only Various other factors, including biologic, may have played a role
common TEAE of clinical concern attributable to dupilumab in the observed inconsistencies between Black/African American
(Table 2). patients and White and Asian patients.

Pharmacokinetics Slightly lower mean trough concentrations were noted in Black/

In all three trials and among all racial and treatment groups, African American patients compared with White and Asian
dupilumab PK steady state was achieved by week 16 (Figure patients, which could be due, at least in part, to the higher average
3). The mean trough concentrations were comparable between body weight of Black/African American patients in this analysis.
White and Asian patients, with slightly lower levels noted in Body weight was assessed as a potential confounding factor
Black/African American patients. of this analysis, but weight-adjusted and weight-unadjusted

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Journal of Drugs in Dermatology
August 2019 • Volume 18 • Issue 8
analyses were generally consistent. For example, significant
clinical improvements were reported more consistently with
the 300 mg qw regimen than q2w in both weight-adjusted and
unadjusted analyses. Of note, a separate population PK analysis
based on a larger dataset (Kovalenko P et al., manuscript in
preparation) found no meaningful effect of racial subgroup on
dupilumab PK after correction for body weight.
Differential mutations in skin barrier and innate/adaptive
immunity genes may impact the nature of AD in racial subgroups.
Filaggrin loss-of-function mutations, which lead to deficiency of
the structural protein filaggrin and resulting skin barrier defects,
have been identified as a major predisposing factor for the
development of AD in Europeans and Asians.6 In contrast, in
individuals of African descent, the association between filaggrin
mutations and AD is less clear; overall, evidence suggests these
mutations occur less frequently in African Americans compared
with European Americans. Loss-of-function mutations in the
closely related filaggrin-2 protein were associated with African,
but not European, American patients with AD. However,
filaggrin as well as lipid alterations may also be influenced by
cytokines, rather than by genetics.27,28 Other potential genetic
factors include variants of the tight junction gene claudin and
the immune-related genes TLSP and IRF2, which have been
noted in patients of African descent with AD.6 Race-specific
alterations in epidermal structure may contribute to molecular
and histologic differences observed between White, Asian,
and Black/African American individuals and may account
for some differences in transepidermal water loss observed
Do Not Copy
between European and African Americans.6 Racial and ethnic
Penalties Apply
variations in epidermal and dermal structure and function29 may
explain why the presentation of AD in individuals of African
descent often differs from that in other racial subgroups, with
notable extensor involvement and more frequent perifollicular
accentuation and scattered distinct papules on the extensors
and trunk, xerosis, Dennie–Morgan lines, hyperlinearity of the
palms, periorbital dark circles, lichenification, prurigo nodularis,
and post-inflammatory dyspigmentation.6 Similar differences
in AD characteristics have also been observed in patients
participating in studies conducted in Africa compared with
other regions.7 Collectively, these differences may impact the
course of AD in Black/African American patients. However, the
limited current data on AD in Black/African American patients
have restricted understanding of the disease and outcomes in
this patient subset. For example, a recent systematic review and
meta-analysis of studies evaluating the clinical features of AD in
various populations found that only 4% reported the inclusion
of Black/African American patients;7 while another review of US
studies of systemic AD therapy found that none presented a
stratification of results by racial subgroup.30
The safety data among racial subgroups were consistent with
those reported in the overall populations.21,22
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A.F. Alexis, M. Rendon, J.I. Silverberg, et al
Although data on racial differences are not available for other
systemic therapies, the efficacy and safety observations here
are generally consistent with studies of topical therapies such
as pimecrolimus (Whites, Asians, Blacks, and Hispanics)31
and tacrolimus (Asians vs Caucasians),32 which showed no
differences in treatment outcomes among racial subgroups.
The analysis had several limitations. First, only data from a
short 16-week treatment duration were presented, as the small
number of patients in some racial subgroups of the CHRONOS
trial at week 52 prevented robust statistical analyses. Second,
the analysis did not directly compare dupilumab dose regimens.
Finally, only a small number of Black/African American patients
were available for analysis; therefore, differences between
dupilumab and placebo did not always reach the level of
nominal statistical significance (P<0.05), particularly for the q2w
dose regimen.
CONCLUSIONS
Irrespective of racial subgroup, dupilumab results in significant
clinical improvement and a favorable benefit-risk profile in
patients with moderate-to-severe AD inadequately controlled
with topical medications. Trends in this analysis suggest that
dupilumab 300 mg qw may provide incremental benefits over
the q2w regimen in Black/African American patients; however,
interpretation is limited by the small sample size of the Black/
African American cohort and variations in mean body weight
between racial subgroups. Overall, these results support the
relevance of moderating type 2 inflammation by blocking IL-4 and
IL-13 signaling for treatment of AD among all racial subgroups.
ACKNOWLEDGMENTS
The authors thank Thomas Hultsch for his contributions.
FUNDING STATEMENT
Research sponsored by Sanofi and Regeneron Pharmaceuticals,
Inc. ClinicalTrials.gov Identifiers: NCT02277743; NCT02277769,
NCT02260986. Medical writing/editorial assistance provided by
Carolyn Ellenberger, PhD, of Excerpta Medica, funded by Sanofi
Genzyme and Regeneron Pharmaceuticals, Inc.
DISCLOSURES
Andrew F. Alexis is an advisory board member/consultant for
Almirall, Beiersdorf, BioPharmX, Celgene, Cipla, Dermavant,
Dermira, Galderma, LEO Pharma, Menlo Therapeutics,
Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi,
Trevi Therapeutics, Unilever, Valeant; investigator for Almirall,
Bristol-Myers Squibb, Celgene, Galderma, LEO Pharma, Menlo
Therapeutics, Novartis, RxL. Marta Rendon is an investigator for
Regeneron Pharmaceuticals, Inc. Jonathan I. Silverberg is an
investigator for AbbVie, Celgene, Eli Lilly & Co., GlaxoSmithKline,
Incyte, LEO Pharma, Realm, Regeneron Pharmaceuticals, Inc.,
Roche; consultant for AbbVie, Anacor Pharmaceuticals, Eli Lilly &
JO0819
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812
Journal of Drugs in Dermatology
August 2019 • Volume 18 • Issue 8
Co., Galderma, GSK, Incyte, Kiniksa, LEO Pharma, MedImmune
(AstraZeneca), Menlo Therapeutics, Pfizer, Procter & Gamble,
Realm, Regeneron Pharmaceuticals, Inc.; speaker for Regeneron
Pharmaceuticals, Inc. David M. Pariser is a consultant, received
honoraria from Bickel Biotechnology, Biofrontera, Celgene,
Dermira, DUSA Pharmaceuticals, LEO Pharma, Novartis,
Promius Pharma, Regeneron Pharmaceuticals, Inc., Sanofi,
TheraVida, Inc., Valeant; principal investigator, received
grants, research funding from Abbott Laboratories, Amgen,
Asana BioSciences, Bickel Biotechnology, Celgene, Dermavant
Sciences, Eli Lilly & Co., LEO Pharma, Merck & Co., Novartis,
Novo Nordisk, Ortho Dermatologics, Peplin, Pfizer, Photocure
ASA, Promius Pharma, Regeneron Pharmaceuticals, Inc., Stiefel/
GSK, Valeant; advisory board member, received honoraria from
Pfizer; principal investigator, received honoraria from LEO
Pharma, Pfizer; investigator, received grants, research funding
from Promius Pharma. Benjamin Lockshin received honoraria
and/or research grants from AbbVie, Celgene, Dermira, Eli Lilly
& Co., Franklin Bioscience, Galderma, Janssen, LEO Pharma,
Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Sanofi, Sun
Pharmaceutical Industries. Christopher E.M. Griffiths received
honoraria and/or research grants from AbbVie, Almirall, Eli
Lilly & Co., Janssen, LEO Pharma, Merck & Co., Novartis, Pfizer,
Regeneron Pharmaceuticals, Inc., Roche, Sandoz, Sanofi, Sun
Pharmaceutical Industries, Ltd., UCB Pharma. Jamie Weisman
received research grants from AbbVie, Allergan, Amgen,
Boehringer Ingelheim, Celgene, Dermira, Eli Lilly & Co.,
Galderma, GSK, Janssen, LEO Pharma, Merck & Co., Novartis,
Pfizer, Regeneron Pharmaceuticals, Inc., UCB; advisory board
Do Not Copy
member or speakers’ bureau for AbbVie, Eli Lilly & Co., Janssen,
Regeneron Pharmaceuticals, Inc., UCB. Andreas Wollenberg
Penalties Apply
is an advisor, speaker, or investigator for ALK Abelló, Almirall,
Anacor, Astellas, Beiersdorf AG, Bencard, Bioderma, Chugai,
Eli Lilly & Co., Galderma, GSK, Hans Karrer, LEO Pharma,
L’Oreal, Maruho, MedImmune, Novartis, Pfizer, Pierre Fabre,
Sanofi, Regeneron Pharmaceuticals, Inc. Zhen Chen, John D.
Davis, Abhijit Gadkari, Brad Shumel, Neil M.H. Graham, Marius
Ardeleanu are employees and shareholders of Regeneron
Pharmaceuticals, Inc. Meng Li, Laurent Eckert, Ana B. Rossi are
employees of Sanofi, and may hold stock and/or stock options in
the company. Ana B. Rossi ORCID: 0000-0001-5345-678X
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AUTHOR CORRESPONDENCE

Andrew F. Alexis MD
E-mail:................……...................... andrew.alexis@mountsinai.org

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