1. Positioning our recent and future advances in therapies for Crohn’s disease
William J. Sandborn, MD
Professor & Chief, Division of Gastroenterology
Director, UCSD IBD Center

2. Recent and future advances
Azathioprine – new data
Deep remission and treat to target
New agents
Mild to moderate disease
Rifaximin EIR
Moderate to severe disease
Vedolizumab (anti-alpha 4 beta 7)
Ustekinumab (anti-interleukin 12/23
Tocilizumab (anti-interleukin 6)
Tofacitinib (Janus Kinase [JAK] inhibitor)
Eldelumab (Anti-IP 10)

3. Top Down Therapy With Azathioprine + Prednisone Versus Step Up Therapy With Prednisone And Then Azathioprine In Adults With Newly Diagnosed Crohn’s Disease
Cosnes J. Gastroenterology 2013

4. Top Down Therapy With Azathioprine + Prednisone Versus Prednisone In Adults With Newly Diagnosed Crohn’s Disease
Sustained steroid free remission
Survival free of relapse
Panes J. Gastroenterology 2013

5. Treat-to-Target Algorithm)
CRP, C-reactive protein.
Bouguen G, et al. Clin Gastroenterol Hepatol Sep 10. [Epub Ahead of Print]

6. Rifaximin Extended Intestinal Release for Crohn’s Disease: Results at Week 12
Prantera C, et al. Gastroenterology 2012

7. Therapeutic Targets for Lymphocyte Trafficking
Leucocyte Adhesion
NATALIZUMAB
CD 11a/CD18
VEDOLIZUMAB
LEUCOCYTE
41 (VLA-4)
47
ISIS-2302
CCX282-B
CCR9
ETROLIZUMAB
MAdCAM mAb (PF )
ICAM-1
CCL-25
MAdCAM-1
VCAM-1
ACTIVATED INTESTINAL MICROVASCULAR ENDOTHELIAL CELLS
Adapted from Danese S Gut 2011;60:

8. Vedolizumab: A Humanized, Monoclonal Antibody (mAb) Against 47 Integrins
CH3
CH2
CH1 VH VL CL
CDR3
CDR2
CDR1
Targets only a4b7 integrin
Created by insertion of ACT-1 CDRs into human IgG1 framework
Two amino acid substitutions abrogate Fc-receptor binding and complement fixation (ADCC)
IV infusion over 30 – 60 minutes

9. Vedolizumab For Active Crohn’s Disease Response and Remission at Week 8
P=NS
185 patients with active Crohn’s disease receiving a stable dose of 5-ASA or antibiotics or no medical therapy
Randomized to receive IV doses of placebo, 0.5 mg/kg, or 2.0 mg/kg MLN-02 on days 1 and 29
The primary endpoint was % clinical response (decrease in CDAI of 70 points) at day 57
Secondary endpoint was % remission (CDAI < 150) at day 57
Saturation of 47 on peripheral blood lymphocytes was not consistently achieved
P=0.04
Remission (%)
Response or
Feagan Clinical Gastroenterology & Hepatology 2008

10. Vedolizumab For Active Crohn’s Disease Remission at Week 8
* p-value < 0.05
ITT population * * *
MLN0002 induced a significantly greater clinical remission rate in patients with Crohn’s disease compared to placebo (2 mg/kg group) at days 15, 29, and 57.
Feagan Clinical Gastroenterology & Hepatology 2008

11. Induction ITT Population
Vedolizumab (Anti-Alpha 4 Beta 7 Integrin) For Moderately-to-Severely Active Crohn’s Disease: Results at Week 6 in 368 Patients
Induction ITT Population
P=0.23
P=0.02
Patients, %
Sandborn W.
N Engl J Med 2013
95% CI:
Δ 7.8
1.2, 14.3
Δ 5.7
–3.6, 15.0

12. Maintenance ITT Population
Vedolizumab (Anti- 47 Integrin) For Maintenance of Response in Moderately-to-Severely Active Crohn’s Disease: Results at Week 52 in 461 Patients
Maintenance ITT Population ** * ** ** * *
Patients, %
Δ17.4 Δ14.7
Δ13.4 Δ15.3
Δ7.2 Δ2.0
Δ15.9 Δ12.9
*P< **P< †CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.
Sandborn W.
N Engl J Med 2013

13. Other Drugs in this Class
Anti-MAdCAM1 (PF-00547,659)
Etrolizumab (anti-7, rhumab beta 7)
Anti-7 (AMG181)

14. Biology of Interleukins 12 and 23
Anti-IL-12/23
IL-12
Anti-
IL-12/23
Ustekinumab and briakinumab are fully human IgG1 monoclonal antibodies
Bind the p40 subunit of human IL-12/23
Prevent IL-12 and IL-23 from binding IL-12Rb1
Normalize IL-12 and IL-23 mediated signaling, cellular activation, and cytokine production
In development in Crohn’s disease and psoriasis
Stimulus
TLR?
p35
p40
IL-12Rb1 X
IFNg
(Th1) b2 Ag
CD4+
Antigen
Presenting Cell
MHCII
IL-23
p40
p19
IL-17
(Th17)
IL-23R
IL-12Rb1
TCR

15. Ustekinumab (anti-IL 12/23p40) for Induction of Clinical Response in Moderate to Severe Crohn’s Disease
All Patients
Previously Treated with Infliximab
100
100
Placebo 80 80
Ustekinumab
P=.001
P=.004
P=.022
P=.02
P=.046 60
P=.019 60
P=.337
Infliximab-Experienced
Patients (%)
Patients (%)
P=.335 40 40 20 20 2 4 6 8 2 4 6 8
Weeks
Weeks
CRP in All Patients
1.2
1.0
Week 0
0.8
Week 8
Median CRP (mg/dL)
0.6
0.4
0.2
Subcutaneous
Intravenous
Subcutaneous
Intravenous
Placebo
Ustekinumab
Sandborn WJ. Gastroenterology 2008;135:

16. +p<0.05 vs. PBO by CMH test
Ustekinumab (Anti-IL-12/23p40) for Induction of Moderate to Severe Crohn’s Disease
Clinical Response
Clinical Remission + + + + + + + + + +
+p<0.05 vs. PBO by CMH test
Sandborn WJ. N Engl J Med 2012; 367:

17. Ustekinumab (Anti-IL-12/23p40) for Maintenance of Moderate to Severe Crohn’s Disease
Sandborn WJ. N Engl J Med 2012; 367:

18. Tofacitinib an Oral Janus Kinase (JK) Inhibitor
Cytokine
Effects on the immune system
IL-2
Stimulate the proliferation and differentiation of Th, Tc, B, and natural killer (NK) cells
IL-4
Induce the differentiation of Th0 to Th2
Induce immunoglobulin switching
IL-7
Promote the development, proliferation and survival of T, B, and NK cells
IL-9
Stimulate intrathymic T cell development
IL-15
Promote the proliferation, cytotoxicity and cytokine production of NK cells
IL-21
Enhance T and B cell function
Cytokine
Tofacitinib blocks phosphorylation of STAT and downstream activation α β γ
JAK
JAK P
STAT P P
STAT
mRNA
Tofacitinib (CP-690,550) is a novel, small-molecule, oral JAK inhibitor
Tofacitinib inhibits JAK1, JAK2, and JAK3 in vitro with functional cellular specificity for JAK1 and JAK3 over JAK2. Importantly, tofacitinib directly or indirectly modulates signaling for an important subset of pro-inflammatory cytokines including IL-2, -4, -7, -9, -15, and -21
Sandborn W. New England Journal of Medicine 2012

19. Tofacitinib for Induction in Moderate to Severe Crohn’s Disease: Clinical Response and Remission at Week 4
Clinical Response-70
Clinical Response-100
49.9%
Estimated clinical response rate (80% CIs)
48.0%
42.9%
44.8%
40.8%
38.8%
33.7%
28.1%
N=34
N=36
N=34
N=35
N=34
N=36
N=34
N=35
Tofacitinib
Tofacitinib
Sandborn W. Gastroenterology 2011 Abstract

20. Mean percentage change from baseline in log transformed CRP (mg/L) in those patients with baseline CRP ≥5 mg/L (B)
Sandborn W. Gastroenterology 2011 Abstract

21. P=0.019 P=NS Ito Gastroenterology 2004
Tocilizumab (Humanized Monoclonal Antibody Interleukin-6 Receptor – Previously Atlizumab or MRA) For Active Crohn’s Disease
36 patients with active Crohn’s disease (CDAI > 150, ↑ CRP)
Randomized to receive IV placebo, tocilizumab (previously atlizumab, MRA) 8 mg/kg every 2 weeks, or atlizumab 8 mg/kg every 4 weeks for 12 weeks
The endpoints were % response (decrease in CDAI  70) and remission (CDAI  150) at week 12
Frequency of adverse events similar in all groups
P=0.019
P=NS
Ito Gastroenterology 2004

22. Other Drugs in this Class
BMS (fully human antibody to interleukin-6)
PF (fully human IgG2 antibody to interleukin-6)

23. Interferon Gamma Inducible Protein 10 (IP-10 or CXCL-10)
Belongs to CXC family of chemokine ligands
Induced by IFN- and produced by various cell types including hematopoietic & stromal cells
Mechanism of action
CXCR3-mediated recruitment of T cells to inflamed tissues
CXCR3-independent (or dependent) modulation of functions of other cells including epithelial, endothelial and islet b cells
IP-10
CXCR3
Unidentified
receptor
Heparan
sulfate
TLR4 (?)
T cell
Epithelial
Islet b cell
Endothelial
↑ Trafficking
↓ Proliferation
& Migration1,2
↓ Proliferation3
↑ Apoptosis4
1 Suzuki et al. Pathology International 2007; 57(7): ; 2. Soejima et al, J Immun 2001; 167: ;
3. Luster et al. J Exp Med 1995; 182: ; 4. Schulthess et al. Cell Metabolism 2009;9(2):

24. Drug in this Class
Eldelumab (fully human antibody to IP-10)

25. Conclusions
Top down therapy with steroids and azathioprine is not effective in adults with newly diagnosed Crohn’s disease
Treatment goals in Crohn’s disease are evolving towards deep remission achieved via a treat to target strategy
Agents targeted against multiple targets including beta 7 integrin, MAdCAM-1, and the p40 subunit of interleukin 12/23, and possibly JAK, IP-10, and interleukin-6, hold great promise for the future