new medications in ibd: what’s coming?
TRANSCRIPT
11/2/14
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New Medications In IBD: What’s Coming?
Barrett G. Levesque MD
Inflammatory Bowel Disease Center
University of California, San Diego
La Jolla, California
DISCLOSURES
BG Levesque has received consulting fees from Santarus Inc,
Prometheus Labs, Abbvie, Takeda, and Nestle Health Sciences
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What is our target What is our target What is our target What is our target
if we want to prevent disease progression ?if we want to prevent disease progression ?if we want to prevent disease progression ?if we want to prevent disease progression ?
4
SYMPTOMSSYMPTOMSSYMPTOMSSYMPTOMS
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SYMPTOMS
X-
SECTIONAL/TRANSMURAL
ACTIVITY
HISTOLOGICAL ACTIVITY
BIOLOGIC ACTIVITY
• CRP
• Fecal Calprotectin
ENDOSCOPIC ACTIVITY
What is our target if we want to prevent disease progression ?What is our target if we want to prevent disease progression ?What is our target if we want to prevent disease progression ?What is our target if we want to prevent disease progression ?
Mucosal Healing Relevance ?
6
Normal Mild
Moderate Severe
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Endoscopic healing Endoscopic healing ---- ACCENT IACCENT I
Week 0 Week 10 Week 54
Following induction
regimen (IFX 5 mg/kg)
at weeks 0, 2, and 6
Following infusions (IFX 5 mg/kg)
every 8 weeks after
induction regimen
Baseline
Efficacy
IN04616
Surgery Rates at 10 years by Mucosal Healing Status One Year After Diagnosis
Crohn’’’’s diseaseUlcerative colitis
Pro
po
rtio
n o
f C
D P
ati
en
tsR
esecte
d
Pro
po
rtio
n o
f U
C P
ati
en
ts
Co
lecto
mis
ed
HR 0.34 (0.14-0.86) p<0.02 HR 0.42 (0.20-0.89) p=0.027
Solberg IC, et al. Scand J Gastroenterol. 2009; 44:431-40
Solberg IC, et al. Clin Gastroenterol Hepatol. 2007; 5:1430-8
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PREDEFINED TIMEFRAME PREDEFINED TIMEFRAME
BASELINE ASSESSMENTBASELINE ASSESSMENT
CONTINUE THERAPY
TARGET SURVEILLANCE
TARGET
HIGH
RIS
K O
F
PR
OG
RE
SS
IO
N
LOW
TARGE
T
THERAPY ACCORDING
TO RISK AND TARGET
CONTROL OF
INTESTINAL
INFLAMMATI
ON
AV
OID
AN
CE
OF
LO
NG
-TE
RM
BO
WE
LD
AM
AG
E
AN
DS
UB
SE
QU
EN
TD
ISA
BIL
ITY
ASSESSMENTASSESSMENT ASSESSMENTASSESSMENT
Bouguen G, Levesque BG et al. Clin Gastroenterol Hepatol, 2013.
OPTIMIZEOPTIMIZEOPTIMIZEOPTIMIZE
10
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Time to Initiation of Treatments
perc
ent
perc
ent
perc
ent
perc
ent
P=0.78
ECI 21.0%
CM 21.2%
A Corticosteroids B Antimetabolitesa
ECI 26.7%P<0.001
CM 15.6%
C TNF-Antagonistsb
ECI 27.4%
CM 17.4%
P<0.001
D Combination Therapy with Antimetabolites and TNF-Antagonists
ECI 19.7%
CM 9.6%
P<0.001
HR = 0.97 (0.77, 1.21) HR = 1.84 (1.39, 2.44)
HR = 1.72 (1.34, 2.22)
HR = 2.29 (1.73, 3.04)
Early Combined
Immunosuppression
Conventional
Management
%
Khanna, Levesque, Feagan ECCO 2014
perc
ent
perc
ent
perc
ent
perc
ent
CM 9.5%
ECI 6.6%
P = 0.03
SurgeryA B Serious Complication
P<0.001
CM 30.9%
ECI 24.3%
C Hospitalization
CM 15.6%
ECI 12.9%
P = 0.16
D Hospitalization, Surgery or Serious Disease-Related Complication
CM 34.7%
ECI 27.4%P<0.001
HR = 0.69 (0.50, 0.97)
HR = 0.84 (0.65,1.08)
HR = 0.73 (0.61, 0.87)
HR = 0.73 (0.62, 0.86)
Conventional
Management
Early Combined
Immunosuppression
Proportion of Patients with Major Adverse Outcomes at 24 Months
%
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Early Combined
Immunosuppression
N (%)
Conventional
Management
N (%)
P Value
Worsening Crohn’s disease
Abscess 32 (3.0) 33 (3.7) 0.36
Fistula 29 (2.7) 39 (4.3) 0.03
Stricture/bowel obstruction 67 (6.2) 82 (9.1) 0.01
Serious worsening disease 98 (9.0) 96 (10.7) 0.65
Serious extra-intestinal
manifestations
47 (4.3) 50 (5.6) 0.37
Serious drug-related
complications
10 (0.9) 10 (1.1) 0.84
Deaths
Cardiovascular 2 (0.2) 5 (0.5)
Thromboembolic 1 (0.1) 1 (0.1)
Cancer 3 (0.3) 2 (0.2)
Infection 1 (0.1) 1 (0.1)
Other 0 (0.0) 1 (0.1)
Total Mortality 7 (0.7) 10 (1.1) 0.33b
Serious Disease and Drug-Related Complications and Mortality
Optimizing TNF Antagonist TherapyEmerging Concepts
• Objective evidence of the presence of inflammation should
drive clinical decision making not the presence of symptoms in
isolation
• Combining antimetabolite therapy and a TNF antagonist results
in optimal efficacy and protects the latter against sensitization
• The pharmacokinetics of TNF antagonists are complex and
therapy should be optimized for individual patients
• Therapeutic drug monitoring is a useful guide for clinical
decision making
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The ACT Studies: Proportions of Patients with Clinical Remission by Serum IFX Concentration
Quartiles
Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4
%
26.3
37.0
43.9
43.1
P=0.0504
P<0.0001
Reinisch W. et al DDW 2012
Colectomy Rate According to the Presence and Absence of a Detectable Trough Serum
Infliximab Concentration
% Colectomy
P<0.001
55
7
Seow CH. et al. Gut 2010;59:49-54
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37
5563
0
25
50
75
100
AZA (N=76) IFX (N=77) IFX/AZA (N=78)
Fra
cti
on
of
pts
(%
)
UC SUCCESS: Mucosal Healing Week 16
n=38 n=53 n=60
**
* p<0.05 vs. AZA alone
†Mayo endoscopy sub-score 0 or 1
Panaccione et al. ECCO 2011. Abstract OP13
ULTRA 1: Clinical Remission at Week 8
ITT-A3 analysis set (NRI)
Clinical remission: Mayo score ≤2 with no individual subscore >1
0
5
10
15
20
25
30
35
Ma
yo
sc
ore
re
mis
sio
n (
%)
Placebo
N=130
9.2%
ADA 80/40 mg
N=130
10.0%
ADA 160/80 mg
N=130
18.5%
N=390
*p=0.031, ADA 160/80 vs placebo
Reinisch W, et al. Gut, 2011; 60:780-787
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Cyclosporine vs Infliximab in UC
Laharie D. et al. Gastroenterology 2011;140(5;Suppl 1):S112
ULTRA 2: Remission- Weeks 8 and 52
0
5
10
15
20
Cli
nic
al re
mis
sio
n (
%)
Week 8
n=246
9.3%
25
n=248
16.5%
p=0.019
Week 52
n=246
8.5%
n=248
17.3%
p=0.004
Placebo
ADA 160/80/40 mg
ITT analysis set (NRI)
Clinical remission: Mayo score ≤2 with no individual subscore >1
Sandborn WJ, et al. Gastroenterology 10.1053/j.gastro.2011.10.032
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PURSUIT-SC Induction: Clinical Response† at Week 6
Pro
po
rtio
n o
f p
atie
nts
(%
)
Placebo(n=256)
200 mg → 100 mg(n=257)
400 mg → 200 mg(n=258)
**
* p<0.0001 vs. placebo
Randomized Patients in Phase 3 After the Dose Selection
Sandborn WJ et al. DDW 2012
PURSUIT-SC Induction: Secondary Endpoints at Week 6
Pro
po
rtio
n o
f p
atie
nts
(%
)
p<0.0001
‡†
→→
Randomized Patients in Phase 3 After the Dose Selection
Normal/Inactive Mucosal Disease
p<0.0001
p<0.0005
p<0.0001
*p=0.043 vs. placebo
**p<0.001 vs. placebo
* **
†
‡Sandborn WJ et al. DDW 2012
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Recruitment of Neutrophils Into Inflamed Tissue
Van Deventer. Gut. 2002
Endothelial and Leukocyte Adhesion: αααα4 Integrins
ββ11/β/β77α4α4• Leukocyte membrane
glycoproteins
• β1 and β7 subunits
• Interact with endothelial ligands VCAM-1, fibronectin, and MAdCAM-1
• Mediate leukocyte adhesion and trafficking
Springer TA. Cell. 1994;76:301–314. Butcher EC, et al. Science. 1996;272:60-66.
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Clinical Efficacy: 3 Point Improvement in UCSS Score
0
10
20
30
40
50
60
70
Week 6
Placebo 0.5 mg/kg 2.0 mg/kg
33%
57%66%
Overall p=.001
p=.001 p=.010
Feagan et al New Eng J Med 2005
Vedolizumab & Mucosal Healing Through 52 Weeks, ITT Population
%
∆26.1 ∆29.1 ∆32.8 ∆28.5 ∆32.0 ∆36.3 ∆11.8 ∆15.3 ∆17.6 ∆31.4
***
***
**
**
***
*** ***
***
*
***
*P<0.05. **P<0.01. ***P<0.0001
n: 72 70 73
Feagan BG et al New Engl J Med 2013
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Primary and Secondary Outcomes Through 52 Weeks
%
***
***
***
*** ***
***
***
****
*
∆26.1 ∆29.1 ∆32.8 ∆28.5 ∆32.0 ∆36.3 ∆11.8 ∆15.3 ∆17.6 ∆31.4
72 70 73n:
*P<0.05 **P<0.01 ***P<0.0001
Maintenance ITT Population
27 Feagan, NEJM 2013
22.324.8
22.7 24.2
39.2*
46.8†
39.2‡
47.8†
0
10
20
30
40
50
60
Week 6 Week 10 Week 6 Week 10
Vedolizumab Phase 3 Induction Trial in CD CDAI-100 Response
Pati
en
ts, %
*P=0.0011 vs placebo; †P<0.0001 vs placebo; ‡P=0.0002 vs placebo
PBO
VDZ
Overall Population(n=416)
ITT Population
Anti-TNFα Failure Population(n=315)
CDAI-100 Response
Sandborn, NEJM 2014
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Budesonide MMX for Active Ulcerative ColitisClinical and Endoscopic Remission at Week 8
Sandborn WJ, et al. Gastroenterology. 2012;143(5):1218-1226.
Travis S, et al. Gut. 2013;
*Statistically significant (P<0.025)
+Statistically significant (P<0.05)
Remission (%)* *
+
n=103n=109n=89n=124n=123n=121
Cytokine Signaling of Janus Kinase (JAK)
30
Tofacitinib blocks phosphorylation of STAT and downstream activationJAK
α
STA
T
STA
T
mRNA
JAKPP
STA
T
STA
T
P
P
P
β γCytokine
Abstract: 1029156
Cytokine Effects on the immune system
IL-2Stimulate the proliferation and differentiation of Th,
Tc, B, and natural killer (NK) cells
IL-4Induce the differentiation of Th0 to Th2
Induce immunoglobulin switching
IL-7Promote the development, proliferation and survival
of T, B, and NK cells
IL-9 Stimulate intrathymic T cell development
IL-15Promote the proliferation, cytotoxicity and cytokine
production of NK cells
IL-21 Enhance T and B cell function
Ig, immunoglobulin; IL, interleukin; JAK, Janus kinase; NK, natural killer; STAT, signal transducer and activator of transcription; Th, T helper; Tc, cytotoxic T cell
1ADIS. Drugs 2010; 10(4): 271-274; 2Coombs J et al. Ann Rheum Dis 2007; 66: 257; 3Li X et al. Presented at the 15th IIRA Conference, Chantilly, Virginia, September 21-24, 2008; 4Rochman Y et al. Nat Rev Immunol 2009; 9(7): 480-490
� Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor that is being investigated as a targeted immunomodulator for several inflammatory diseases including ulcerative colitis (UC) and Crohn’s disease1,2
� Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3 over JAK2.3 Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -214
Courtesy of Dr. William Sandborn
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Rates of Primary and Major Secondary Endpoints at 8 Weeks in the
Modified Intention-to-Treat Population According to Study Group
Sandborn WJ. et al. New Eng J Med. 2012 Aug. In Press
Ustekinumab (Anti-Interleukin 12/23 p40) for Active
Crohn’s Disease: Clinical Response at Week 6
Sandborn W. Gastroenterology 2011 Abstract
Number of Subjects in Clinical Remissiona,b at Week 22; Subjects Randomized as Responders to UST Induction
Pro
po
rtio
n o
f S
ub
jects
(%
)
Ustekinumab
p=0.021p=0.057
p=0.005p=0.005
N=132 N=131 N=131N=132 N=394
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Ustekinumab (Anti-Interleukin 12/23 p40) for Active
Crohn’s Disease: Clinical Remission at Week 22
p=0.029
20/73Pro
po
rtio
n o
f S
ub
jects
(%
)Number of Subjects in Clinical Remissiona,b at
Week 22; Subjects Randomized as Responders to UST
Induction
30/72
Sandborn W. Gastroenterology 2011 Abstract
Etrolizumab vs Placebo – Eucalyptus Phase II Randomized Induction Study in Active UC –
Clinical Remission at Wk 10
100 mg 300 mg + LD
PlaceboEtrolizumab
20.5%
10.3%
0%
%
P=0.004
P=0.049
• Humanized monoclonal
antibody to the B7 subunit
of the heterodimeric
integrins α4β7 and αEβ7
in patients with mod-sev
active UC
• N=124
• Randomized to 2 dose
groups vs placebo
Vermiere S. et al. Lancet 2014
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• S1P1R agonism induces receptor
internalization lymphocytes lose
response to S1P gradient
• Become trapped in lymph nodes
causing peripheral lymphopenia
• Upon drug withdrawal receptor
expression is restored and
lymphocytes leave nodes reversing
lymphopenia
Sphingosine 1‐‐‐‐Phosphate Receptor 1 Modulation:Mechanism of Action
Courtesy Dr. Alan Olsen
Anti Smad 7GED-0301
Marafini,
Monteleone,JCCI
2014
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On the Horizon?
• Bacterial Release Oral Anti-TNF Therapy?
• Cow’s Milk Clostrum Oral Anti-TNF therapy?
• Phosphatidyl Choline (oral Therapy) for UC?
• Andrographis Paniculata (oral therapy) For UC?
• Nutritional Therapies?
Conclusions