Filgotinib, a selective JAK1
inhibitor, induces clinical remission
in moderate-to-severe Crohn’s
disease patients
Week 10 results FITZROY Phase II study
Séverine Vermeire, MD, PhD
S. Vermeire, S. Schreiber, R. Petryka, T. Kuehbacher, X. Hebuterne, X. Roblin,
M. Klopocka, A. Goldis, M. Wisniewska-Jarosinska, A. Baranovsky, R. Sike,
C. Tasset, A. Van der Aa, P. Harrison
Amsterdam, 18 March 2016
Disclosures Séverine Vermeire, MD, PhD
• Grant support: Abbvie, MSD, Takeda
• Lectures: Abbvie, MSD, Takeda, Ferring, Falk Pharma,
Hospira, Tillotts
• Consultancy: Abbvie, MSD, Takeda, Ferring,
Genentech/Roche, Shire, Pfizer, Galapagos,
Mundipharma, Hospira, Celgene, Second Genome, J&J
Investigators and Participating Countries
Belgium: Dr.Vijverman, Dr.Muls, Dr.De Vos, Dr.Vermeire, Dr.Dewit,
Dr.Pontus
Czech Republic: Dr.Vanasek, Dr.Drastich, Dr.Tichy, Dr.Kozeluhova,
Dr.Konecny, Dr.Knoflicek
Germany: Dr.Kuehbacher, Dr.Stallmach, Dr.Malfertheiner, Dr.Schreiber,
Dr.Bokemeyer, Dr.Helwig, Dr.Stein, Dr.Sturn
France: Dr.Hebuterne, Dr.Bouhnik, Dr.Michiels, Dr.Bommelaer,
Dr.Desreumaux, Dr.Grimaud, Dr.Roblin,
Hungary: Dr.Gurzo, Dr.Lakatos, Dr.Sike, Dr.Salamon, Dr.Csiki, Dr.Peterfai,
Dr.Heringh
Poland: Dr.Klopocka, Dr.Wisniewska-Jarosinska, Dr.Petryka, Dr.Romanczyk,
Dr.Wasko-Czopnik, Dr.Kierkus
Romania: Dr.Mateescu, Dr.Goldis, Dr.Gheorghe, Dr.Tantau
Russia: Dr.Osipenko, Dr.Yurkov, Dr.Abdulkhakov, Dr.Tkachenko,
Dr.Belousova, Dr.Alekseeva, Dr.Pershko, Dr.Pesegova, Dr.Baranovsky,
Dr.Ovchinnikova, Dr.Popova, Dr.Parfenov, Dr.Khalif
UK: Dr.Levison, Dr.Goh, Dr.Penez, Dr.McLaughlin
Kamran Ghoreschi, Arian Laurence & John J O'Shea
Nature Immunology 10, 356 - 360 (2009) Published online: 19 March 2009
Janus family tyrosine kinases (JAKs)
• JAK1 inhibition suppresses signaling for (pro)inflammatory cytokines
• JAK2 inhibition also suppresses GM-CSF, EPO, TPO, GH, PRL signaling
• JAK3 inhibition has an effect on γ-chain IL-s, critical for lymphocyte
function
Filgotinib (GLPG0634, GS-6034)
• Oral, potent, highly selective inhibitor of Janus kinase 1 (JAK1)
• t½ = 5-11 hours, with active metabolite t½ = 21-27 hours
• Dose selection for clinical studies based on PK/PD modeling
200 mg QD
300 mg QD
pSTAT1 Inhibition (%)
100 mg QD
Time after dosing (hr)
Black/gray lines: Predicted 634/445 PK (arb. units)
Colored thick (thin) lines: Median (95% CI) pSTAT1 inhibition in a typical patient
• Shown safe and effective in Phase 2 program in RA patients (N=877)
FITZROY: study design
Non-responders
200 mg
200 mg
200 mg
Responders
Rerandomized
100 mg
3:1 Randomization
Placebo
Non-responders
100 mg
Responders
Placebo
Placebo
Part 1: W0 – W10
Part 2: W10 – W20
FITZROY: Key eligibility criteria
• Inclusion:
• ileal, colonic, or ileocolonic Crohn’s Disease (on colonoscopy and
histology)
• Crohn’s Disease Activity Index (CDAI) 220 - 450
• endoscopic confirmation of active disease, ulceration (score of 2 or 3
in at least 5 of the ileocolonic segments - SES-CD, total score of at
least 7, central reading)
• Exclusion:
• indeterminate colitis, ulcerative colitis
• surgical bowel resection within past 6 months
• Concomitant medication:
• discontinuation: anti-TNFs, immuno-modulators AZA, MTX and 6-MP
• allowed: stable doses of oral steroids (≤ 30mg prednisolone eq/day),
mesalazine, CD-related antibiotics, and probiotics
FITZROY: Patient disposition
Screened
N = 322
Randomized & treated
N = 174
Placebo
N = 44
Not eligible / not treated
N = 148
200 mg
N = 130
Discontinued:
- Safety: 3 (7%)
- Efficacy: 3 (7%)
- Other: 1 (2%)
Total: 7 (16%)
W10 completed
N = 37 (84%)
Discontinued:
- Safety: 4 (3%)
- Efficacy: 9 (7%)
- Other: 6 (5%)
Total: 19 (15%)
W10 completed
N =111 (85%)
FITZROY: Baseline characteristics
Placebo 200 mg p-value
(N=44)
(N=130)
Age, mean, years
35.1
37.4
0.2472
Female
59%
55%
0.6054
Duration of CD, mean, years
6.8
8.8
0.1349
CDAI, mean
299
291
0.4417
SES-CD, mean
15.9
14.2
0.1504
CRP, mean, mg/L
19.8
14.2
0.1125
CRP > 10mg/L
41%
42%
0.9418
Concomitant oral corticosteroids
mean daily dose, mg
Anti-TNF naive
52%
23.6
36%
48%
23.1
44%
0.6621
0.8679
NA
Anti-TNF experienced non-responders
64%
56%
NA
FITZROY: CDAI clinical remission/response
ITT-NRI, Week 10
Primary endpoint
80
% responders
70
60
50
P<0.01
48%
40
(61/128)
30
20
10
0
60%
P<0.05
(77/128)
41%
(18/44)
23%
200 mg
(10/44)
Clinical remission
(CDAI<150 points)
Placebo
Clinical Response
(≥100-points decrease in CDAI)
FITZROY: Serum CRP normalization (<8mg/L)
ITT-LOCF, Week 10, subjects with high baseline CRP*
35
% subjects
30
30%
25
(20/66)
20
placebo
15
10
14%
(3/22)
5
0
* High baseline CRP ≥ 8mg/L
Serum CRP normalization (<8mg/L)
200 mg
FITZROY: Quality of life (IBDQ)
ITT-LOCF, Week 10
Placebo
200 mg
p-value
(N=44)
(N=130)
120.77
123.00
17.56
33.82
0.0045
Bowel symptoms
5.59
9.96
0.0042
Systemic symptoms
2.93
5.73
0.0043
Emotional status
6.10
12.07
0.0091
Social functioning
2.94
6.19
0.0188
IBDQ – mean at baseline
IBDQ – mean change from baseline
FITZROY: Safety summary
Placebo
200 mg
(N=44)
(N=130)
27 (61%)
86 (66%)
Infections and infestations
10 (23%)
34 (26%)
Gastrointestinal disorders
10 (23%)
31 (24%)
Nervous system disorders
8 (18%)
21 (16%)
Serious TE AE
3 (7%)
6 (5%)
Serious TE infections
0 (0%)
1 (1%)*
SAE leading to death
0 (0%)
0 (0%)
5 (11%)
15 (12%)
TE AE, n (%)
TE AE leading to discontinuation
* Community Acquired Pneumonia
FITZROY: Safety – labs
Mean change from baseline
Placebo
200 mg
(N=44)
(N=130)
Hemoglobin (g/L)
+2.2
+2.2
Neutrophils (Giga/L)
+0.1
-0.2
+0.09
-0.22
+4
+6
+0.6
+1.6
+0.01
+0.24
Lymphocytes (Giga/L)
Creatinine (μmol/L)
ALT (U/L)
HDL (mmol/L)
FITZROY Week 10 data: Conclusions
• First JAK1 selective inhibitor to show
• clinical efficacy in active Crohn’s disease
• improvement of patient’s quality of life (IBDQ) in a
population of TNF-naives and TNF-failures
• Safe and well-tolerated
• Safety profile consistent with previous studies in RA patients
• Results support further development in IBD