GBR 830 INDUCES PROGRESSIVE AND SUSTAINED 
IMPROVEMENTS IN ATOPIC DERMATITIS  

SKIN BIOMARKERS AND CLINICAL PARAMETERS
EMMA GUTTMAN -YASSK Y1; ANA B. PAVEL1; YERIEL ESTR ADA1; LISA ZHOU1; YACINE SALHI2;  

GIRISH GUDI2; VINU CA3; JULIE MACOIN4; JONATHAN BACK4; GERHARD WOLFF2
1ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, NEW YORK, NY, USA; 2GLENMARK PHARMACEUTICALS INC ., USA; 

3GLENMARK PHARMACEUTICALS LTD., INDIA; 4GLENMARK PHARMACEUTICALS SA , SWITZERL AND

SYNOPSIS/OBJECTIVE
◾◾ GBR 830 is an investigational, first-in-class, humanized, monoclonal 

IgG1 antibody specific for inhibiting OX40, a costimulatory receptor 
on activated T cells1

◾◾ By blocking binding of OX40 to its ligand OX40L, GBR 830 reduces 
longevity and efficacy of effector and memory T cells1 

◾◾ OX40 inhibition is suggested to have a potential therapeutic role 
in T  cell-mediated diseases, including atopic dermatitis (AD), one 
of the most common inflammatory skin disorders that affects up to 
10% of adults2

◾◾ This phase 2a proof-of-concept study in patients with moderate-to-
severe AD (NCT02683928) was conducted to investigate the safety 
of GBR 830, evaluate its effects on AD biomarkers, and generate the 
first clinical evidence of its biological activity

METHODS
Study Design
◾◾ Randomized, double-blind, placebo-controlled, repeated-dose study 

conducted in 17 North American centers 

◾◾ Three phases: screening (up to 30 days), treatment (Day 1 [baseline] 
and 29), follow-up (through Day 85) (Figure 1)

◾◾ Treatment: randomization 3:1 to GBR 830 or placebo; 2 repeated 
doses (each 10 mg/kg, administered intravenously) on Days 1 and 29

◾◾ Skin punch biopsies: obtained from lesional skin on Days 1, 29, and 71

Figure 1.  Study Design

-30 -1 4 8Day

Dosing

Skin Biopsy

15 22 29 32 4336 5750 71 85

S
cr

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e

n
in

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Treatment (Double-Blind) Follow-Up

1

GBR 830 (10 mg/kg)

Placebo

Subjects
◾◾ Key inclusion criteria:

•◾ Adult subjects (≥18 years) with moderate-to-severe AD for >1 year

•◾ Affected body surface area (BSA) ≥10%

•◾ Eczema Area and Severity Index (EASI) score ≥12

•◾ Scoring of Atopic Dermatitis (SCORAD) ≥20

•◾ Investigator’s global assessment (IGA) score ≥3 (5-point scale)

•◾ History of inadequate response to topical therapies

◾◾ Key exclusion criteria:

•◾ Live vaccination within 12 weeks before randomization

•◾ History of serious infection, including latent or active tuberculosis 

•◾ Prior treatment with systemic corticosteroids, topical steroids, 
phototherapy, and/or biologics

Study Endpoints
◾◾ Co-primary: treatment-emergent adverse events (TEAEs; frequency, 

severity); change from baseline in epidermal hyperplasia and active 
AD mRNA expression biomarker signatures measured from lesional 
skin biopsies

◾◾ Key secondary: EASI 50 response (≥50% improvement from baseline) 
on Day 29 and Day 71

Statistical Analyses
◾◾ Intent-to-treat (ITT) population: all subjects who were randomized and 

received ≥1 partial or full dose of study drug

◾◾ Safety population: all subjects who took ≥1 partial or full dose of study 
drug

◾◾ Biological Activity Set (BAS): all ITT subjects who had ≥1 post-baseline 
skin biopsy and received both doses of study drug

◾◾ EASI 50 response was analyzed descriptively at Day 29 and Day 71

◾◾ Immunohistochemistry and RT-PCR data was log2-transformed prior 
to analysis using a linear mixed effect model with Time, Tissue, and 
Treatment as fixed factors and a random intercept for each subject

RESULTS
Subjects
◾◾ ITT/safety population included 62 subjects: GBR 830, n=46; placebo, 

n=16 (Figure 2)

◾◾ BAS population included 40 subjects: GBR 830, n=29; placebo, n=11 

Figure 2. Subject Disposition

Screened (N=100)

Randomized (n=64)

Screen failures (n=36)

Placebo (n=16)GBR 830 (n=46)

Completed (n=8)Completed (n=26)

ITT/Safety (n=16)
Biological Activity Set

(n=11)b

ITT/Safety (n=46)a

Biological Activity Set
(n=29)b

Did not receive
study drug (n=2)

Discontinued
Withdrawal of consent
Adverse event
Protocol violation
Required rescue medication
Lost to follow-up
Other

22*
11 
2
1 
4
1 
3

Discontinued
Withdrawal of consent
Adverse event
Protocol violation
Required rescue medication
Lost to follow-up
Other

8
2
1 
0
4
0
1 

*Includes subjects who did not receive GBR 830 (n=2).
aExcludes subjects from the randomized population (GBR 830, n=2) who did not receive ≥1 partial or full dose of study 
drug.
bExcludes subjects from the ITT population (GBR 830, n=17; placebo, n=5) who did not receive both doses of study 
drug and have ≥1 post-baseline skin biopsy (Day 29 or Day 71). 
ITT, intent-to-treat.

◾◾ Demographic and baseline characteristics were generally similar 
between treatment groups in the ITT/safety and BAS populations (Table 1)

Table 1. Baseline Characteristics

ITT BAS

GBR 830
(n = 46)

Placebo
(n = 16)

GBR 830
(n = 29)

Placebo
(n = 11)

Demographics

Age, years

Mean ± SD 36.2 ± 13.4 40.4 ± 15.1 34.1 ± 12.2 40.7 ± 14.7

Median (min, max) 34 (18, 66) 41 (19, 59) 33 (18, 61) 42 (19, 59)

Sex, n (%)

Male 21 (45.7) 11 (68.8) 16 (55.2) 8 (72.7)

Female 25 (54.3)   5 (31.2) 13 (44.8) 3 (27.3)

Race, n (%)

Asian   5 (10.9)   2 (12.5)   4 (13.8) 2 (18.2)

Black or African 
American   9 (19.6)   3 (18.7)   5 (17.2) 1 (9.1)

White 31 (67.4) 11 (68.8) 19 (65.5) 8 (72.7)

Other   1 (2.2) 0 1 (3.4)  0

Body mass index, 
mean ± SD, kg/m2 26.1 ± 4.1 26.2 ± 3.7 25.7 ± 3.7 26.1 ± 3.9

Baseline Disease Characteristics

BSA affected,  
mean ± SD, % 38.6 ± 23.4 39.3 ± 21.5 38.6 ± 24.0 38.4 ± 21.6

EASI

Mean ± SD 25.1 ± 12.3 23.3 ± 9.4 25.4 ± 13.7 22.2 ± 9.6

Median (min, max) 21.0  (12.4, 65.0)
19.9  

(14.1, 47.5)
20.1  

(12.7, 65.0)
18.9  

(14.1, 47.5)

Epidermal thickness (lesional), μm

Mean ± SD NA NA 140.6 ± 57.6 125.0 ± 47.0

Median (min, max) NA NA 130.2  (58.4, 287.4)
136.9  

(60.8, 187.1)

Epidermal thickness (non-lesional), μm 

Mean ± SD NA NA 63.3 ± 25.2 59.0 ± 21.5

Median (min, max) NA NA 56.8 (29.5, 155.6)
54.2 

(33.1, 96.0)

BAS, Biological Activity Set; BSA, body surface area; EASI, Eczema Area and Severity Index; ITT, intent-to-treat; NA, not applicable; SD, standard deviation.

Adverse Events (Safety Population)
◾◾ TEAEs occurred with similar incidence between treatment groups 

(Table 2); most were mild or moderate in intensity

Table 2.  Treatment-Emergent Adverse Events 
(Safety Population)

Adverse Events, n (%)
GBR 830
(n = 46)

Placebo
(n = 16)

Deaths 0 0

Any TEAE 29 (63.0) 10 (63.0)

Any serious AE 1 (2.2)a 0

Discontinuation due to AEs 2 (4.3) 1 (6.3)

Common TEAEsb

   Headache 6 (13.0) 4 (25.0)

   Dermatitis atopic 6 (13.0) 2 (12.5)

   Nasopharyngitis 4 (8.7) 2 (12.5)

   Upper respiratory tract infection 4 (8.7) 2 (12.5)

   Post-procedural infection 4 (8.7) 0

   Myalgia 3 (6.5) 0

aSubject had coronary artery occlusion (not related to study treatment).
bReported in ≥5% of subjects in the GBR 830 group.
AE, adverse event; TEAE, treatment-emergent adverse event.

Biomarker Signatures (BAS Population)
◾◾ Significant decreases from baseline in OX40+ T-cell and OX40L+ DC 

cellular staining in lesional skin were found with GBR 830 treatment 
at Day 29 (p<0.05) and Day 71 (p<0.001) (Figure 3) 

•◾ Drug versus placebo trended on significance at Day 71 for both 
markers 

Figure 3.  OX40 Target Expression From 
Representative GBR 830- and  
Placebo-Treated Subjects

Figure 4

Immunohistochemistry staining of OX40 (A) and OX40L (B) at baseline and after treatment (Day 29 and Day 71); protein expression is shown in red staining 
and the images in each line were taken from the same subject. Mean fold change (FCH) from baseline in OX40 expression (C) and OX40L expression (D).
+P<0.1, *P<0.05, **P<0.01, ***P<0.001.

◾◾ GBR 830-treated subjects had significant reductions from baseline 
in epidermal thickness (Figure  4A, 4D), K16 mRNA expression   
(Figure 4B, 4E), and Ki67+ cells at Days 29 and 71 (Figure 4C, 4F)

•◾ Changes from baseline with placebo were not signif icant  
(thickness, K16) or less pronounced (Ki67+)

Figure 4.  Epidermal Proliferation at Baseline and 
After Treatment

Figure 5

Panels show (A) H&E staining, (B) K16 staining, and (C) Ki67 staining showing epidermal hyperplasia at baseline lesions; the images for both drug and 
placebo panels were taken from a representative subject for each. Mean fold change (FCH) from baseline is shown for (D) epidermal thickness, (E) K16 mRNA 
expression measured by RT-PCR, and (F) Ki67 protein expression measured by immunohistochemistry.
+P<0.1, *P<0.05, **P<0.01, ***P<0.001.
H&E, hematoxylin and eosin; K16, Keratin16; RT-PCR, real-time polymerase chain reaction.

◾◾ GBR 830-treated subjects had significant reductions in most mRNA 
biomarkers of disease activity compared with baseline and placebo 
(Figure 5)

Figure 5.  Changes in Quantitative RT-PCR mRNA 
Expression Following Treatment

Day 29 Day 71 Day 29 Day 71

Day 29 Day 71 Day 29 Day 71 Day 29 Day 71Day 29 Day 71

Day 29 Day 71 Day 29 Day 71 Day 29 Day 71 Day 29 Day 71

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GBR 830
Placebo

Th1

Th2

Th17/Th22

mRNA expression of representative inflammatory markers of Th1 (A-B), Th2 (C-F), and Th17/Th22 (G-J) pathways in subjects treated with GBR 830 compared 
with baseline and placebo.
+P<0.1, *P<0.05, **P<0.01, ***P<0.001.
mRNA, messenger ribonucleic acid; RT-PCR, real-time polymerase chain reaction.

Clinical Efficacy (ITT Population)
◾◾ A greater proportion of GBR 830-treated subjects achieved EASI 

50 versus placebo at Day 29 (43.6% vs 20.0%; p=0.2) and Day 71  
(76.9% vs 37.5%; p=0.02)

◾◾ GBR 830-treated subjects demonstrated greater percentage change in 
EASI from baseline through Day 85 compared with placebo (Figure 6)

◾◾ A positive association was seen between improvements in clinical 
assessments and changes in tissue AD biomarkers

Figure 6.  Percentage Change in EASI from Baseline 
Through Day 85 (ITT Population)

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Baseline Day 4 Day 8 Day 15 Day 22 Day 29 Day 32 Day 36 Day 50Day 43 Day 57 Day 71 Day 85

GBR 830
Placebo

Stars indicate intravenous dose administration.
+P<0.1, *P<0.05.
EASI, Eczema Area and Severity Index; ITT, intent-to-treat.

CONCLUSIONS
 ◾ GBR 830 was safe and well tolerated, with a similar TEAE 
profile to placebo 

 ◾ GBR 830 inhibits the OX40/OX40L pathway, as shown 
through reduced expression of OX40/OX40L in lesional skin

 ◾ Treatment with GBR 830 resulted in reductions in epidermal 
hyperplasia, proliferation, and mRNA biomarkers for disease 
activity, indicating an effect on both the acute and chronic 
stages of AD

 ◾ Although the study was not powered for statistical testing, 
subjects treated with GBR 830 had improvements in AD 
scores that were consistent with biomarker results

 ◾ Results of this proof-of-concept study indicate that GBR 830 
may be an effective treatment for AD

R E F E R E N C E S
1. Webb GJ, Hirschfield GM, Lane PJ. Clin Rev Allergy Immunol. 2016;50:312-32.
2. Hanifin JM, Reed ML. Dermatitis. 2007;18:82-91.
3. Suarez-Farinas M, Ungar B, Correa da Rosa J, et al. J Allergy Clin Immunol. 2015;135:1218-27.
4. Esaki H, Ewald DA, Ungar B, et al. J Allergy Clin Immunol. 2015;135:153-63.
5. Ewald DA, Malajian D, Krueger JG, et al. BMC Med Genomics. 2015;8:60.

D I SC LOSU R E S
This study was funded by Glenmark Pharmaceuticals, SA. Medical writing and editorial assistance were provided by 
Prescott Medical Communications Group, Chicago, IL.

P R E S E NTE D AT TH E FA LL C LI N I C A L D E R M ATO LO GY 

CO N F E R E N C E 

O C TO B E R 18-21, 2018 | L A S V E G A S , N V