Download Filgotinib, Jak1-selective inhibitor, represses similarly Jak1/Stat3

THE FIRST JAK1-SELECTIVE INHIBITOR, FILGOTINIB, DISPLAYS SIMILAR MOLECULAR
ACTIVITY IN THE GUT OF MICE WITH DSS-INDUCED COLITIS AND IN CULTURES OF
COLON BIOPSIES FROM INFLAMMATORY BOWEL DISEASE PATIENTS
P1586
Carole Delachaume1, Veerle De Vriendt2, Debby Laukens3, Béatrice Vayssière1, Didier Merciris1,Steve De Vos2,
Marie-Christine Ceccotti1, Christelle David1, Laetitia Perret1, Martine De Vos3, Reginald Brys2 and René Galien1
SASU, Romainville, France; 2Galapagos NV, Mechelen, Belgium; 3Ghent University Hospital, Ghent, Belgium
Filgotinib prevents mouse colitis
Introduction
control
DSS/30 mg/kg filgotinib
5
4
3
2
1
Control
control
27
DSS/vehicle
23
DSS/filgotinib
DSS/vehicle
19
vehicle
**
0
1
2
3
4
5
6
7
8
15
9 10 11 12 13 14 15 16
time (days)
Fig. 1. Efficacy of filgotinib on disease activity index and colon stretching
DSS/filgotinib
Chronic mouse colitis model
control
DSS/vehicle
DSS/filgotinib
0.1mm
0.1mm
0.015
0.010
0.005
Fig. 6. Efficacy of 5µM filgotinib on STAT3 phosphorylation
Fig. 4. Efficacy of filgotinib on STAT3 phosphorylation
4
JAK1-dependent
Mx1
SOCS3
2
inflammation
TNFa
IL6
JAK1-dependent
inflammation
MX1
IL6
**
0
0.1mm
filgotinib
0.000
6
colon lesion score
 Chronic colitis induction in Balb/c mice: 4% dextran sodium sulphate (DSS) in
drinking water for 5/7 days in 3 successive periods.
 Treatments: 30 mg/kg Filgotinib QD orally for 16 days
 Disease Activity Index score (DAI): composite score based on daily
assessment of weight loss, rectal bleeding and stool consistency.
 Histology: scoring of severity and extent of inflammation and epithelial
damage, cell infiltration by immunohistochemistry (IHC)
 JAK/STAT target engagement in colon tissue was evaluated by measuring
STAT3 phosphorylation using IHC and gene expression by qPCR
Filgotinib blocks JAK/STAT
signaling in IBD patient colon
biopsies
0.020
0
Methods
DSS/vehicle
colon/intestine
length (%)
disease activity index
Filgotinib (known as GLPG0634) is a JAK inhibitor selective for JAK1 over the 3
other family members (JAK2, JAK3 and TYK2) in biochemical and human whole
blood assays. It is efficacious in arthritis and colitis mouse models. Filgotinib is
currently being assessed as a treatment for Crohn’s disease (CD) in a Phase 2
study. The objective of this study was to compare signalling mechanisms, in
particular JAK1 inhibition-related effects, regulated by filgotinib in mouse IBD
model and in ex vivo human colon biopsies.
Filgotinib blocks JAK/STAT
signaling in mouse colitis
pSTAT3 staining
index
1Galapagos
**
***
***
***
**
**
SOCS3
**
*
TNFa
*
***
Fig. 2. Efficacy of filgotinib on colon lesion histological score
15
10
**
0
T cell
8
20
5
Macrophage
***
6
***
4
2
0
Fig. 5. Efficacy of filgotinib on JAK1-dependent and
inflammation genes
4
***
T cell surface (%)
25
Neutrophil
cell surface (%)
 Inflamed
biopsies fromresults
8 IBDafter
patients
were(left)
treated
withoral
filgotinib
5µM
Figurecolon
1. Pharmacokinetic
s.c. dosing
and after
dosing (right)
and JAK/STAT target engagement was evaluated by measuring STAT3
phosphorylation after 24h using immunoassay and gene expression after 18h
by qPCR
cell density (cells/mm2)
IBD patient colon biopsy culture
Fig. 7. Efficacy of filgotinib 5µM on JAK1-dependent and
inflammation genes
3
***
2
***
1
0
Fig. 3. Efficacy of filgotinib on inflammation-driven immune cell infiltration
Disclosures: AbbVie has provided funding to Galapagos for the development of GLPG0634
C. Delachaume, V. De Vriendt, B. Vayssière, D. Merciris, S. De Vos, M.C. Ceccotti, C. David, L. Perret, R. Brys and R. Galien are employees of Galapagos
This work was supported by a grant from IWT, N°120550
Conclusions
These data highlight the importance of JAK1/STAT3 pathway observed in both pre-clinical mouse
colitis model & human colon biopsy culture, further pointing out the role of JAK1 in the etiology of
IBD.
These data suggest that filgotinib, a JAK1-selective inhibitor, may be beneficial in treating CD patients
and support its evaluation in a clinical study.
Poster available online at: www.glpg.com
© Copyright 2015 Galapagos NV