 Dupilumab Monotherapy
in Adults with Moderate-to-Severe Atopic
Dermatitis: A 12-Week,
Randomized, Double-Blind,
Placebo-Controlled Study
Thomas
Bieber,
Diamant
Thaçi,
Neil
Graham,
Gianluca
Pirozzi,
4
Ariel
Teper,
4
Haobo
Ren,
Neil
Stahl,
George
Yancopoulos,
Allen
Radin
1
Department
of
Dermatology
and
Allergy,
Friedrich-Wilhelms
University
of
Bonn,
Bonn,
Germany;
2
Comprehensive
Center
Inflammation
Medicine,
University
of
Lübeck,
Lübeck,
Germany;
3
Regeneron
Pharmaceuticals,
Inc.,
Tarrytown,
United
States;
4
Sanofi,
Bridgewater,
United
States
Exhibit 99.1
3
3
3
3
1
2
3 |
 Disclosures
•
D Thaçi is a consultant for Astellas, Novartis,
Regeneron, Celgene, Abbott, Pfizer, Janssen-Cilag,
MSD, Leo-Pharma
•
T Bieber is a consultant for Regeneron, Basilea, L’Oréal,
Oxagen, Bioalliance, Stern Biologics and a speaker for
Astellas
•
N Graham, H Ren, N Stahl, G Yancopoulos, and A
Radin are employees and shareholders of Regeneron
•
G Pirozzi and A Teper are employees and shareholders
of Sanofi
•
Study (NCT01548404) funded by Regeneron
Pharmaceuticals, Inc. and Sanofi
2 |
 Introduction
•
Moderate-to-severe atopic dermatitis (AD) is
characterized by eczematous dermatitis with
intractable pruritus associated with sleep
disturbance and lower quality-of-life
•
For many patients, current therapies are
inadequate and can be associated with
unwanted side effects
•
IL-4 and IL-13 are thought to be central to T-
helper 2 (Th2) inflammation, which mediates
many features of AD
3 |
 Introduction
4
•
Dupilumab is a fully human monoclonal antibody
targeting the IL-4 receptor alpha subunit (IL-4R
),
thus blocking the intracellular signaling of both IL-4
and IL-13
•
Earlier clinical trials indicated that dupilumab
monotherapy had an acceptable safety profile and
was efficacious in patients with moderate-to-
severe AD who cannot be adequately controlled
with topical medications
•
We assessed the clinical efficacy of repeated
subcutaneous doses of dupilumab monotherapy
for 12 weeks in adult patients with moderate-to-
severe AD poorly controlled by topical agents |
 Dupilumab (anti-IL-4R ) blocks the
IL-4/IL-13 receptor/ligand system
Type I Receptor
B cells, T cells, Monocytes,
Eosinophils, Fibroblasts
Type II Receptor
Epithelial cells, Smooth muscle
cells, Fibroblasts, Monocytes,
Activated B cells
IL-4
IL-13
IL-4R
IL-13R 1
c
IL-4R
5 |
 Study treatment
(weekly SC injection for 12 wks)
Screening
(adult patients
with moderate-to-
severe AD)
Safety follow-up
(16 wks)
Dupilumab Monotherapy in Adults with Moderate-to-Severe Atopic
Dermatitis: A European 12-Week, Randomized, Double-Blind,
Placebo-Controlled Phase 2a Study (NCT01548404)
Dupilumab 300 mg (n=55)
n=109
Placebo (n=54)
Primary
endpoint:
Percent
change
in
EASI
from
baseline
to
week
12
Secondary
endpoints:
Changes
from
baseline
to
week
12
in
EASI,
SCORAD,
%BSA,
pruritus
NRS,
5-D
pruritus
scale,
proportion
of
patients
achieving
EASI-50/75,
IGA
0-1;
and
safety
EASI=Eczema Area Severity Index; SCORAD=scoring of atopic dermatitis; BSA =
baseline body surface area; NRS=numeric
rating
scale;
EASI-50
50%
reduction
in
EASI
score;
EASI-75
75%
reduction
in
EASI
score
IGA 0-1=Investigator’s Global Assessment score of 0 (“clear”) or
1 (“almost clear”) 6 |
 Key
inclusion/exclusion criteria Inclusion
•
Male or female
18 yrs
•
Chronic AD 3 yrs
•
EASI 16
•
IGA 3
•
10% BSA of AD
involvement
•
History of inadequate response
to a stable ( 1 month) regimen
of topical corticosteroids or
calcineurin inhibitors within 3
months prior to screening visit
Exclusion
•
Prior treatment with dupilumab
•
Acute or chronic infections
•
Recent treatment with topical
corticosteroids, calcineurin
inhibitors, immunosuppressive/
immunomodulating drugs
•
Significant co-morbidities or lab
abnormalities
7 |
 Baseline demographics and disease
characteristics*
Placebo
(n=54)
Dupilumab
300 mg
(n=55)
Age, yrs
39.4 (12.3)
33.7 (10.4)
Caucasian, n (%)
54 (100)
55 (100)
Men, n (%)
27 (50.0)
31 (56.4)
BMI,
kg/m
24.51 (4.64)
25.89 (4.84)
AD diagnosis age, yrs
14.4 (18.35)
6.6 (10.52)
EASI score (0-72)
30.8 (13.63)
28.4 (13.57)
IGA score (0-5)
4.0 (0.69)
3.9 (0.67)
SCORAD score (0-103)
69.1 (13.38)
66.7 (13.82)
%BSA of AD
50.8 (24.14)
46.8 (24.55)
Pruritus (NRS) score (0-10)
5.00 (1.40)
6.43 (2.00)
5-D Pruritus Scale (5-25)
18.7 (3.50)
18.4 (3.04)
EASI=Eczema Area Severity Index (range 0-72);
IGA=Investigator’s Global Assessment (range 0-5); SCORAD=scoring of atopic
dermatitis (range 0-103); BSA = baseline body surface area; NRS=numeric
rating scale (range 0-10); 5-D Pruritus Scale (range 5-25)
8
*Values shown are mean (SD) or n (%).
2 |
 9
-80
-70
-60
-50
-40
-30
-20
-10
10
Study Day
Placebo
300 mg dupilumab
Study drug
administration
Study Day
300 mg dupilumab
10
20
30
40
50
60
70
80
90
-80
-70
-60
-50
-40
-30
-20
-10
0
10
0
10
20
30
40
50
60
70
80
90
Study drug
administration
†
p<0.002, **P<0.0001
*p<0.001, **P<0.0001
-23.3%
-74.0%
-53.6%
*, †**(LOCF)
Percent change in EASI and
SCORAD scores over 12 weeks
Placebo
-14.3% |
 Proportion of patients who achieve
EASI-50 and EASI-75 over 12 weeks
10
Placebo
300 mg dupilumab
0
80
60
40
30
20
10
100
70
50
90
Study Day
0
10
20
30
40
50
60
70
80
90
0
80
60
40
30
20
10
100
70
50
90
Study Day
0
10
20
30
40
50
60
70
80
90
Placebo
300 mg dupilumab
†
p<0.01, *p<0.001, **P<0.0001
Study drug
administration
Study drug
administration
†
p<0.01, *p<0.001, **P<0.0001
EASI-50
50%
reduction
in
EASI
score;
EASI-75
75%
reduction
in
EASI
score
35.2%
85.5%
61.8%
14.8%
*, †**(LOCF)
**
**
**
**
**
**
**
*
**
**
**
**
**
**
**
**
**
* |
 Percent patients achieving IGA 0-1
and mean BSA(%) at day 85
11
**
**
p<0.0001; LOCF
**
7.4
40.0
41.8
19.4
50.8
46.8
Placebo
300 mg
dupilumab
Placebo
300 mg
dupilumab
Baseline
Day 85 |
 10
20
30
40
50
60
70
80
90
0
Percent change in NRS and 5-D
pruritus scores over 12 weeks
12
Study drug
administration
Study drug
administration
Placebo
300 mg dupilumab
-10
-30
-40
-50
-60
-70
10
-20
0
Study Day
10
20
30
40
50
60
70
80
90
Placebo
300 mg dupilumab
-10
-20
-30
-40
-45
-50
0
-15
-5
Study Day
-25
-35
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**
**P<0.0001
**P<0.0001
NRS=numeric rating scale
-15.1%
-55.7%
-9.9%
-39.7%
**(LOCF) |
 Treatment emergent adverse
events over 28 weeks
Placebo
(n = 54)
Dupilumab 300 mg
(n = 55)
Total number of AEs
159
163
Total number of AEs related to study drug
45
49
Total number of serious AEs
11
1
Deaths
0
0
Number (%) of patients discontinued from study
Due to AE
3 (5.6)
1 (1.8)
Due to Lack of Efficacy
23 (42.6)
7 (12.7)
Infections and infestations*
31 (57.4)
31 (56.4)
Most common AEs (
10%)
Nasopharyngitis
10 (18.5)
22 (40.0)
Headache
7 (13.0)
9 (16.4)
Conjunctivitis
2 (3.7)
7 (12.7)
13
* System Organ Class |
 Skin
infections were less frequent with dupilumab treatment compared to placebo
14
*based
on
Standardized
MedDRA
Query;
**one
occurrence
considered
both
severe
and
serious
Placebo
(n = 54)
Dupilumab 300 mg
(n = 55)
Total number of patients (%)
with skin infections
13 (24.1%)
3 (5.5%)
Total number of skin infections*
14
3
Impetigo
3
1
Skin bacterial infection
3**
0
Eczema herpeticum
2**
0
Skin infection
2
0
Anorectal cellulitis
1
0
Cellulitis
1**
0
Infected dermatitis
1
0
Folliculitis
1
0
Infected blister
0
1
Pustular rash
0
1 |
 Serious Adverse Events
Placebo
(n = 54)
Dupilumab 300 mg
(n = 55)
Number of SAEs
11
1
Patients with SAE*, n (%)
7 (13.0%)
1 (1.8%)
Facial bones fracture [traumatic]
0
1 (1.8%)
Angina pectoris
1 (1.9%)
0
Cellulitis
1 (1.9%)
0
Eczema herpeticum
1 (1.9%)
0
Skin bacterial infection
1 (1.9%)
0
Renal failure
1 (1.9%)
0
Asthmatic crisis
1 (1.9%)
0
Lung disorder [pneumopathy]
1 (1.9%)
0
Dermatitis Atopic
4 (7.4%)
0
15
*
MedDRA
Preferred
Term;
all
SAEs
were
classified
as
such
due
to
hospitalization |
 Summary
•
In this Phase 2a study of 109 European adults with moderate-to-
severe AD, dupilumab (anti-IL-4R ) 300 mg SC weekly was
associated with rapid and marked sustained improvement in EASI,
SCORAD, IGA, and BSA%, and pruritus
•
At 12 weeks, the dupilumab group achieved statistically superior
clinical outcomes compared to the placebo group in all measures of
disease activity and pruritus
•
There were notably fewer patients with skin infections associated
with dupilumab (5.5%) treatment compared with placebo (24.1%)
•
There were no infection related SAEs or eczema herpeticum in the
dupilumab group
•
In the placebo group, 3 patients with skin infections and 4 patients
with AD exacerbations required hospitalization
•
The most common TEAEs were nasopharyngitis, headache, and
conjunctivitis
16 |
 Acknowledgements
Marius Ardeleanu
Elisa Babilonia
Warren Brooks
Josh Cantor
Usman Chaudhry
Olga Filipovska
Romana Machackova
Petr Trestik
Catherine Goujon
Jean-Paul Ortonne
Carle Paul
Alain Taieb
Jennifer Cairns
Jeffrey Ming
Susan Slaytylak-Cheeks
All participating patients
Investigators
Jens Ulrich
Thomas Werfel
Margitta Worm
Klara Bajor
Noemi Bakos
Zita Battyani
Sanofi
Judy Cusick
Kristen Dougherty
Chad Fish
Melissa Hager
Jennifer Hamilton
Richard Kao
Jacquie Kuritzky
Linda Williams
Regeneron
Lajos Kemeny
Marcin Ambroziak
Dorota Bystrzanowska
Maris Czubek
Maria
Juszkiewicz-Borowiec
Andrzej Kaszuba
Thomas Bieber
Regina Foelster-Holst
Martin Kaatz
Knut Schaekel
Margrit Simon
Diamant Thaçi
Athanasios Tsianakas
17 |
 BACK-UP
18 |
 The
5-D itch scale: a new measure of pruritus
•
5-D Pruritus Scale: Duration, Degree, Direction,
Disability, Distribution
–
Single-item domain scores (duration, degree and
direction) are equal to the value of the response choice
–
The disability domain includes four items that assess the
impact
of
itching
on
daily
activities:
sleep,
leisure
social
activities,
housework
errands
and
work
school
–
For the distribution domain, the number of affected body
parts is tallied
•
5-D scores can potentially range between 5 (no
pruritus) and 25 (most severe pruritus)
19
Elman S et al. Brit J Dermat 2010;162:587-93.
|