Download REACT/tailorix Vedo Stelara

Lentesymposium VVGE
inflammatoir darmlijden
Pieter Hindryckx, MD, PhD
Dienst gastro-enterologie, UZ Gent
Acknowledgement to Geert D’Haens
AMC Amsterdam, The Netherlands
Elewijt, 12 maart 2016
Inflammatory Bowel Diseases 2016
IBD innovations driving clinical decisions
• Amsterdam RAI
• EACCME applied
• Register online at www.ecco-ibd.eu
This year at ECCO: IBD drugs in the pipeline
Therapeutic
Target population
Company
Phase
Mesenchymal stem
cells
CD with complex
perianal fistula
TiGenix
Phase 3
Toll like receptor 9
agonist (Kappaproct)
Moderate to severe
UC
InDex
Pharmaceuticals
Phase 3
Ustekinumab
(Stelara)
moderate-severe CD, Johnson & Johnson
refractory to antiTNFα
Phase 3
anti-IL6
CD refractory to anti- Pfizer
TNF
Phase 2
Tofacitinib (Xeljanz)
Moderate to severe
UC
Pfizer
Phase 3
selective JAK1
inhibitor Filgotinib
Moderate to severe
Crohn’s Disease
Galapagos
Phase 2
Tofacitinib (Xeljanz)
Moderate to severe
Crohn’s Disease:
Pfizer
Phase 2
Oude farmaca in een nieuw jasje
Medicatie in de (directe) pipeline
ULCERATIVE COLITIS
51 placebo
111 steroiddependent UC
patients
Steroid-free remission at w16
60 MTX 25mg/w
SC or IM
FECAL MICROBIOTA TRANSPLANTATION FOR UC
N of patients
Moayyedi et al.1
Rossen et al.2
75
50
Way of administration Enema
Nasojejunal tube
Dose regimen
Weekly (6x)
Every 3 weeks (2x)
Placebo
Water enema
autologous FMT
Primary endpoint
Total Mayo <3 +
endoscopic Mayo=0
SCCAI<3 + at least a 1point decrease in
endoscopic Mayo
Study duration
7 weeks
12 weeks
Concomittant antiTNF allowed?
yes
no
Primary endpoint
reached
Yes
No
1Moayyedi
et al. Gastroenterology 2015, 2Rossen et al. Gastroenterology 2015
Moayyedi et al. Gastroenterology 2015
TURN
Rossen et al. Gastroenterology 2015
Friday, March 18
Gut, 2016
Development and validation of new UC histo-indices
Mosli et al. Gut in press
Marchal-Bressenot et al. Gut in press
Bryant et al. Gut, 2016
Drug development in IBD
2012 BMJ Publishing Group Ltd & British Society of Gastroenterology
Expected Selectivity of Hypothetical Single
JAK Specific Inhibitors
TYK2*
JAK3
JAK1
JAK1
TYK2
JAK1
JAK2*
JAK2
JAK1
TYK2
JAK2
JAK2
JAK2
JAK1 inhibitor
+
+
+
+
-
-
JAK2 inhibitor
-
-
+
+
+
+
JAK3 inhibitor
+
-
-
-
-
-
TYK2 inhibitor
-
+
+
-
+
-
TOFACITINIB (XeljanzR)
15
JAK inhibitors: Tofacitinib in UC
B. Clinical remission
Placebo
TOFA
0.5 mg
TOFA
3 mg
TOFA
10 mg
38/49
20/33
16/33
32
TOFA
15 mg
p=0.76
48
10
13
41
33
Placebo TOFA
0.5 mg
20/49
42
p=0.01
16/33
48
p<0.001
11/33
61
p=0.39
p<0.001
4/31
Patients (%)
78
p=0.55
100
90
80
70
60
50
40
30
20
10
0
5/48
p=0.10
10/31
90
80
70
60
50
40
30
20
10
0
p<0.001
20/48
Patients (%)
A. Clinical response
TOFA
3 mg
TOFA
10 mg
TOFA
15 mg
30
27
C. Endoscopic response
D. Endoscopic remission
TOFA
15 mg
p=0.14
2
10
Placebo TOFA
0.5 mg
18
13/49
TOFA
10 mg
38/49
22/33
19/33
TOFA
3 mg
p=0.01
10/33
TOFA
0.5 mg
p<0.001
6/33
Placebo
52
58
p<0.001
3/31
67
p=0.64
46
Patients (%)
78
p=0.30
100
90
80
70
60
50
40
30
20
10
0
1/48
p=0.07
16/31
90
80
70
60
50
40
30
20
10
0
22/48
Patients (%)
p=0.001
TOFA
3 mg
TOFA
10 mg
TOFA
15 mg
Sandborn WJ, et al. New Engl J Med 2012
Friday, March 18
Drug development in IBD
2012 BMJ Publishing Group Ltd & British Society of Gastroenterology
Lobaton T, APT 2014
Gut, in press
Enteric infections
Placebo
Vedolizumab
CMV
0/504
73/2830
Clostridium
0/504
15/2830
Streptococcus
1/2830
36/2830
Colombel et al. Gut in press
Efficacy of AJM300, an Oral Antagonist of α4 Integrin,
in induction therapy for patients with active ulcerative colitis.
Yoshimura et al. Gastroenterology 2015
S1P1R Modulation Results in Sequestration of
Select Lymphocyte subsets
• S1P1R modulators induce
S1P1R internalization so a
subset of auto-reactive
lymphocytes (central
memory T cells) are retained
in the lymph node.
• Protective immunity is
generally preserved by
effector memory T cells that
do not circulate trough the
lymph nodes.
• Ozanimod (RCP1063) is a
next generation oral S1P
receptor
OZANIMOD in UC Remission at week 8
Mayo ≤ 2 points + no subscore > 1 point
Δ = 10.8%
p = 0.0482
20%
Proportion of Patients in Remission
Δ = 7.8%
p = 0.1422
15%
16.400%
13.800%
10%
6.200%
5%
0%
Treatment Group
Placebo (N=65)
Ozanimod 0.5 mg (N=65)
Ozanimod 1 mg (N=67)
Sandborn et al. ECCO 2015
CONCLUSIONS: UC
2016/17
2018/20
Etrolizumab
Ozanimod
2012 BMJ Publishing Group Ltd & British Society of Gastroenterology
CROHN DISEASE
Khanna R et al. Lancet 2015
Vande Casteele N et al. Gastroenterology 2015
Vande Casteele N et al. Gastroenterology 2015
Drug development in IBD
2012 BMJ Publishing Group Ltd & British Society of Gastroenterology
Drug development in IBD
• IL12 → Th1 T cells → IFN γ
• IL-23 → TH17 T-cell → IL-17 →
chronic inflammatory and
autoimmune diseases
Neurath MF. Nat Med 2007; Sandborn WJ et al. Gastroenterology 2008
Anti-p40 and p19-antibodies
Ustekinumab
Medi 2070
L. Steinman. Nature Immunology 2010
Response to Ustekinumab in Psoriasis
At Least 75% Improvement in PASI
100
80
Patients (%)
Patients (%)
100
60
40
20
0
Physician’s Global Assessment of Clear or Excellent
0 2 5 8
12 16 20
Weeks
24
80
60
40
20
0
28 32
At Least 50% Improvement in PASI
100
80
60
40
20
0
0 2 5 8
12 16 20
Weeks
24
28 32
12 16 20
Weeks
24
28 32
At Least 90% Improvement in PASI
Patients (%)
Patients (%)
100
0 2 5 8
80
Placebo 4 x 45 mg
45 mg
4 x 90 mg
90 mg
60
40
20
0
0 2 5 8
12 16 20
Weeks
24
28 32
Krueger, G. et al. NEJM 2007
38
Overall UNITI Phase 3 Crohn’s Program
Two Induction Studies
One Maintenance Study
UNITI-1: αTNF Failure Population
IM-UNITI
Randomized Withdrawal
Maintenance Study
Placebo IV (N=225)*
R
Stelara 130 mg IV
(N=225)*
Stelara ~6 mg/kg IV
(N=225)*
Responders
90 mg SC q8 wks
UNITI-2: Failed Convent. Therapy
R
90 mg SC q12 wks
Placebo SC
Stelara 130 mg IV
(N=200)*
R
44 Week
maintenance
study:
Followed by
(up to) 4 yr LTE
Responders
Stelara ~6 mg/kg† IV
(N=200)*
Placebo IV (N=200)*
* Subjects randomized to placebo and subjects who are non-responders to Stelara are eligible for nonrandomized maintenance dosing after completion of the induction study.
Feagan B, et al. UEGW 2015.
UNITI-2
Primary Endpoint: Clinical Response at Week 6 (≥100
Point CDAI Reduction)
p=0.001
Proportion of Subjects (%)
100
80
60
40
20
p<0.001
p<0.001
p<0.001
∆ 23.0%
(13.83%, 32.11%)*
∆ 26.8%
(17.68%, 35.91%)*
∆ 24.9%
(17.10%, 32.66%)*
51.7
28.7
55.5
%
%
53.6
%
%
0
Placebo
(N=209)
130 mg
(N=209)
~6 mg/kg**
(N=209)
Ustekinumab
Combined
(N=418)
*95% CI
**Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 mg and ≤85 kg), 520 mg (weight >85 kg).
Subjects who had a prohibited Crohn's disease-related surgery or had prohibited concomitant medication changes prior to designated analysis
time point are considered not to be in clinical response, regardless of their CDAI score.
Subjects who had insufficient data to calculate the CDAI score at designated analysis endpoint are considered not to be in clinical response.
Feagan B, et al. UEGW 2015.
UNITI-2
Secondary Endpoint: CRP Concentration
Mean Change from Baseline in CRP
(mg/L)
Summary of Mean Change From Baseline in CRP Concentration (mg/L) at Weeks 3,
6, & 8a,b
4
All p-values <0.001
2
0
-2
-4
-6
-8
-10
0
1
Placebo
2
3
4
Weeks
130 mg Ustekinumab
5
6
7
8
~6 mg/kg Ustekinumab*
*Weight-range based UST doses approximating 6 mg/kg: 260 mg (weight ≤55 kg), 390 mg (weight >55 mg and ≤85 kg), 520 mg (weight >85 kg).
aSubjects who, prior to the designated analysis timepoint, had a prohibited Crohn’s disease-related surgery or had prohibited concomitant medication changes, had
their baseline value carried forward
bSubjects who had insufficient data at the designated analysis timepoint had their last value carried forward
Feagan B, et al. UEGW 2015.
UNITI-2
Summary of Key Safety Events Through Week 8
Ustekinumab
Placebo
130 mg
~6 mg/kg
Combined
Treated subjects
208
212
207
419
Avg. duration of follow-up (weeks)
7.88
7.89
7.90
7.90
0
0
0
0
AE
113 (54.3%)
106 (50.0%)
115 (55.6%)
221 (52.7%)
SAE
12 (5.8%)
10 (4.7%)
6 (2.9%)
16 (3.8%)
Infection
48 (23.1%)
31 (14.6%)
44 (21.3%)
75 (17.9%)
Serious infection
3 (1.4%)
3 (1.4%)
1 (0.5%)
4 (1.0%)
AEs during/<1hr post-Infusion
6 (2.9%)
0
5 (2.4%)
0
3 (1.4%)
0
8 (1.9%)
0
0
0
0
0
Subjects with ≥1, n (%)
Death
Malignancy
MACE*
* Major Adverse Cardiovascular Events
Feagan B, et al. UEGW 2015.
Response at week 6 (%)
UNITI-1
50
P=.002
40
P=.003
30
20
10
0
placebo (n=247)
130 mg (n=245) ~6mg/kg (n=249)
Remission at week 6 (%)
Ustekinumab
30
P=.001
25
P=.003
20
15
10
5
0
placebo (n=247)
130 mg (n=245) ~6mg/kg (n=249)
Ustekinumab
Sandborn W et al. Inflamm Bowel Dis. 2016 Mar;22 Suppl 1:S1 (2015 Advances in Inflammatory Bowel Disease; December 10- 12, 2015; Orlando, Florida. Abstract O-001
PSOLAR REGISTRY
Papp et al., J Drugs Dermatol 2015
MEDI2070 – ‘MedImmune’
Phase 2 Multicenter, Randomized, Double-Blind, Placebo Controlled Study
12 weeks
Placebo (N=60)
randomization
MEDI 2070 (N=59)
700 mg IV
At week 0 and week 4
100 week Open-Label Period
MEDI2070
210 mg SC q4wk
(26 doses)
• CRP ≥ 5 mg/L, FCP ≥ 250 µg/g and/or endoscopic evidence of inflammation
within 12 weeks of screening
• Primary endpoint: proportion of patients achieving CDAI clinical effect defined
as ≥100 point CDAI reduction from baseline or CDAI <150.
Sands et al., DDW 2015
MEDI2070 – ‘MedImmune’
Sands et al., DDW 2015
SMAD7 Signaling Blocks TGF-β signaling
Smad7, an intracellular protein that
inhibits TGF-β1-driven Smaddependent signalling.
In CD and UC, TGF-β1 is highly
produced but unable to signal through
Mongersen is an oral Smad7 antisense
oligonucleotide with negligible systemic
absorption
nucleus
Modified-release tablet → active
substance into lumen terminal ileum
and right colon.
Monteleone et al. N Engl J Med 2015
Study design
Phase 2 Multicenter, Randomized, Double-Blind, Placebo Controlled Study
2 weeks
D 14
baseline
placebo
10 mg Mongersen
40 mg Mongersen
D 28
D 84
Follow up
Maintenance of
remission after
cessation Mongersen
160 mg Mongersen
Monteleone et al. N Engl J Med 2015
Proportion of pts in remission at d15
Proportion of pts in clinical response
Clinical response = a decrease in CDAI score ≥ 100
CONCLUSIONS: CD
2016/17
Mongersen
2019/20
2012 BMJ Publishing Group Ltd & British Society of Gastroenterology
Take home summary
• Insights from previous FMT studies (optimal treatment regimen,
donor selection) may improve outcome in future trials
• Postoperative treatment in CD: according to risk stratification +
follow-up endoscopy
• Increasing role for therapeutic drug monitoring and dose
optimization
• Anti-integrins may become first choice biologic for moderate UC
• Ustekinumab will be the next big asset for CD
• Tofacitinib may come ahead of biologics in UC
• Mongersen for CD promising, but uncertain