1. The Long and Winding Road to Gut Health- Current Therapeutic Trials for Inflammatory Bowel Disease
Dr. Denis M. Petrunia, B.Sc., M.Sc., MD, FRCP (C)
Consultant Gastroenterologist,
Victoria, BC
CSGNA Meeting, Sept 21, 2017
Slides Provided by Dr Remo Panaccioni, University of Calgary

2. 1

3. Objectives 1. Discuss treatment targets in IBD
Where we were
Where we are
Where we are going
2. Review the latest data that will impact IBD clinical practice in and beyond
3. Discuss potential new therapies in IBD 4

4. Pathogenesis of Inflammatory Bowel Disease
Figure 1. Pathogenesis of Inflammatory Bowel Disease.
Normal epithelium, with its highly evolved tight junctions and products of goblet-cell populations, most notably trefoil peptides and mucin glycoproteins, provides an effective barrier against luminal agents. The integrity of the barrier may be compromised by genetic variations in key molecular determinants, a diminished reparative response to injury, or exogenous agents, such as nonsteroidal antiinflammatory drugs. Chronic, recurrent intestinal inflammation appears to result from stimulation of the mucosal immune system by products of commensal bacteria in the lumen. Antigens from dietary sources may also contribute. Stimulation may occur as a result of the penetration of bacterial products through the mucosal barrier, leading to their direct interaction with immune cells, especially dendritic cells and lymphocyte populations, to promote a classic adaptive immune response. Alternatively, bacterial products may stimulate the surface epithelium, possibly through receptors that are components of the innate immune-response system; the epithelium can, in turn, produce cytokines and chemokines that recruit and activate mucosal immune cells. Activation of classic antigen-presenting cells, such as dendritic cells, or direct stimulation through pattern-recognition receptors promotes the differentiation of type 1 helper T cells (Th1) in patients with Crohn's disease (shown here) or, possibly, atypical type 2 helper T cells in patients with ulcerative colitis. The stereotypical products of Th1 promote a self-sustaining cycle of activation with macrophages. In addition to producing the key cytokines that stimulate Th1 (interleukin-12, interleukin-18, and macrophage migration inhibitor factor), macrophages produce a mix of inflammatory cytokines, including interleukin-1, interleukin-6, and most notably tumor necrosis factor, which target a broad variety of other types of cells. The latter include endothelial cells, which then facilitate the recruitment of leukocytes to the mucosa from the vascular space, as well as fibroblasts and epithelium, modulating their functional properties. Most important, these functions may be altered either by genetically determined variants, as exemplified by germ-line mutations in the gene encoding NOD2, the product of the IBD1 locus, in some patients with Crohn's disease, or by environmental factors.
Podolsky, D. K. N Engl J Med 2002;347:

5. Managing IBD in 2017: An evolution in IBD care
Crohn’s disease (CD)
5-ASA Steroids Azathioprine1
Anti-TNFs for CD
Initial report Anti-TNFs for CD
Vedolizumab for UC
Biosimilars
1995
5-ASA Steroids Azathioprine, Cyclosporin1,2
2000
2005
2010
Ustekinumab for CD Vedolizumab for CD5
Anti-TNFs for UC
Ulcerative Colitis (UC)
Surgery
Mulder DJ, et.al. A tale of two diseases: The history of inflammatory bowel disease. J Crohn Colitis 2013; 8:341–348
Botoman AV, et al. Management of Inflammatory Bowel Disease. Am Fam Physician 1998;57:57–68
National Institute for Health and Care Excellence technology appraisal guidance [TA40]: The clinical effectiveness and cost effectiveness of infliximab for Crohn's Disease
National Institute for Health and Care Excellence technology appraisal guidance [TA329]: Infliximab, adalimumab and golimumab for treating moderately to severely active ulcerativ after the failure of conventional therapy (including a review of TA140 and TA262):
National Institute for Health and Care Excellence technology appraisal guidance [TA342] - Vedolizumab for treating moderately to severely active ulcerative colitis. June accessed June 2015. 5
w.nice.org.uk/guidance/ta40. e colitis
/ Last

6. Introducing Biological Therapy: Where we were
The biologic revolution began over 15 years ago with the approval of infliximab for the treatment of moderate to severe CD1.
Despite the development and approval of “newer” anti TNFs, the overall induction of remission in RCTs was ~30-50%2-5 and maintenance of remission was ~20-40%.6-10
Therefore there is a need to develop new agents for the treatment of IBD. .
Schreiber S, et al. N Engl J Med 2007;357:239–50.
Hanauer SB, et al. Lancet 2002;359:1541–9.
Colombel JF, et al. Gastroenterology 2007;132:52–65.
Sandborn WJ, et al. N Engl J Med 2007;357:228–38.
Schreiber S, et al. Gastroenterology 2005;129:807–18.
Sandborn WJ, et al. N Engl J Med 2007;357:228–38.
Hanauer SB, et al. Gastroenterology 2006;130:323–33.
Targan SR, et al. N Engl J Med 1997;337:1029–35. 6

7. Where we are: Lessons learned during the anti-TNF era
Anti-TNFs are safe
Antibodies are bad; adequate drug levels are good
There is value in combination therapy
Treating early is better
We can treat beyond symptoms
We can decrease surgical /hospitalization rates
We do better in real life than in clinical trials 7

8. Starting Anti-TNF Therapy: The Importance of Timing
100
PRECiSE 2
80 SUTD1 <1 year8
SONIC2
CD patients in remission (%)
CHARM 6
GETAID3 60
<2 years
PRECiSE 2
≥5 years8
PRECiSE 27
CHARM5
CHARM
2–5 years6
ACCENT 14
CHARM 6 40
>5 years 20
Disease duration (years)
Colombel JF, et al. Gastroenterology 2007;132:52–65;
Schreiber S, et al. J Crohns Colitis 2012;7:213–21;
Schreiber S, et al. New Eng J Med 2007;357:239–50;
Schreiber S, et al. Am J Gastroenterol 2010;105:1574–82. 9 10
1. D’Haens G, et al. Lancet 2008;371:660–67;
Sandborn WJ, et al. Presented at ACG 2008;
Lemann M, et al. Gastroenterology 2006;130:1054–1061; 4. Hanauer S, et al. Lancet 2002;359:1541–49; 8 8

9. Phenotypic features of Crohn's disease associated with anti-TNF treatment failure
Retrospective study using the Alberta Inflammatory Bowel Disease Consortium registry. Probability of surgery over time after anti-TNF prescription depending on phenotype at prescription (B1=inflammatory, B2=stricturing, B2L1=ileal stricturing , B3=penetrating)
Cumulative probability of major abdominal surgery (%)
0.5
0.4
0.3
0.2
0.1
B2 B2L1 B3 B1
2 3
Follow-up in years 1 4 5 9
Moran, Panaccione et al. Clin Gastroenterol Hepatol 2014 Mar;12(3):434-42

10. UC SUCCESS study: Corticosteroid-free clinical remission and mucosal healing at Week 16
Clinical remission Mucosal healing
100 p= p= p= p= p=0.028
80 80
p=0.295 63
Patients (%) 55
60 60 40 37
40 40 24 22
20 20
18/76 17/77 31/78
28/76
42/77
49/78
0 0
AZA + PBO IFX + PBO IFX + AZA AZA + PBO IFX + PBO
IFX + AZA
AZA, 2.5 mg/kg, oral; IFX, 5 mg/kg, intravenous infusion; PBO, (oral capsule [+IFX] or intravenous infusion [+AZA] administered together with test drug)
p values were calculated with a two-sided Cochran-Mantel-Haenszel chi-square test Steroid-free clinical remission = total Mayo score ≤2
Mucosal healing = Mayo subscore of 0 or 1 10
Panaccione R, et al. Gastroenterology 2014;146:392–400. 1

11. Randomized Evaluation of an Algorithm
for Crohn’s Treatment (REACT 1)
60 patients per practice
20 practices 20 practices
Symptomatic remission (HBI≤4 and no corticosteroids)
Conventional management
Usual care Accelerated care treatment algorithm
Time to first hospitalisation, surgery or complication
HR (95% CI) = 0.73 (0.62, 0.86), p<0.001
CM ECI
100
Early combined immunosuppression
p=0.790 p=0.498 p=0.389 p=0.250 80
Hospitalisation, surgery or complications (%) 40
Patients (%)
34.7%
27.4% 60 30 40 20 20 10
Time (months)
Baseline Month 6 Month 12 Month 18 Month 24
REACT cluster randomisation:
898 CD in conventional management vs 1094 CD in early combined immunosuppression 11
Khanna R, et al. Lancet 2015

12. CALM: Conventional versus ‘tight control’ approach
Open-label, multicenter study in Europe and Canada Evaluating two treatment algorithms in CD
Conventional
CDAI, steroid use
Prednisone up to 9 weeks
Patients naïve to immunomodulators and biologic therapy (n = 240)
Primary endpoint: Mucosal healing 48 weeks after randomisation
Tight control
CDAI, steroid use, high-sensitivity CRP, faecal calprotectin
Treatment intensification in both arms:
1) No treatment, 2) Adalimumab every other week,
3) Adalimumab weekly, 4) Adalimumab weekly + azathioprine
12 Colombel JF, Panaccione R et al DDW 2017 1

13. CALM: Primary Endpoint at 48 Weeks After Randomization
CDEIS < 4 AND NO DEEP ULCERATIONS
1 0 0
8 0
P e r c e n t a g e o f p a t ie n t s
P =
6 0
4 5 .9
4 0
3 0 .3
2 0
3 7 / 122
5 6 / 122
C l i n i c a l M a n a g e m e n t
T r e a t t o T a r g e t
13 Colombel JF, Panaccione R et al DDW 2017

14. Temporal trend analysis of colectomy rates: stratified by emergent vs
Temporal trend analysis of colectomy rates: stratified by emergent vs. elective colectomy
Colectomy rates in adults hospitalised for a flare of UC 6
Incidence per 100,000 population
Total Elective Emergent 5 4 3 2 1
UC, ulcerative colitis.
Temporal changes were evaluated using linear regression models to estimate the average annual percent change (AAPC) in surgical rates. 14
Kaplan GG, et al. Am J Gastro 2012; 107:1879–87.

15. Real Life vs. Clinical Trials: The example of ADA and IFX in UC15
Sandborn et al. Curr Med Res Opin Mar 30:1-9

16. Many biologic agents have failed in IBD
Anti-IL-2 receptor
Basiliximab1
Daclizumab2
Anti-CTLA-4
Abatacept3
Anti-CD3 receptor
Visilizumab4
1. Sands BE, et al. Gastroenterology 2012 Aug;143:356– Van Assche G, et al. Gut 2006;55:1568–74.
3. Sandborn WJ, et al. Gastroenterology 2012;143:62– Sandborn WJ, et al. Gut 2010;59:1485–92. 16

17. The IBD therapeutic pipeline
TNFK-005 Neovacs
C326 QPharm
IL inhibitors
Phase I
Chemokine receptors
SCH Merck & Co
Ustekinumab Centocor
Vidofludimus 4SC
Pfizer
PF Pfizer
M mgen
SK GSK
IN 457 Novartis
ELND-004 Elan/Biogen Idec
Phase II C
GSK
CCX-025 G
Immunomodulators
RDP 58 G e
laquinimod Teva / Active Biotec
Phase III
Z 1848
and
Registration
576 N
Launched if Al
n EI
ess ann
Novo Nordisk zu
ogen Idec PF
Pfizer
CAM inhibitors N
Tofaciti er
Vedolizum
mumab
ille
/ Takeda
300 Ajinomoto
olizu
gol UC
JAK inhibitors
Remestem
I ab
ocor HM
Hutchinson
Osiris
alizumab Pfizer
PDA-001 Celgene
lular
ave TX
acs
Stem cell therapies
TNF-α inhibitors
Adapted from Danese S. Gut 2012;61:918–32. 17

18. Emerging therapies in IBD
Leukocyte Trafficking inhibitors
Vedolizumab
Etrolizumab
Anti-MAdCAM
Anti IL-12/23
Ustekinumab
Briakinumab
Rizankizumab
Jak inhibitors
Anti S1 P1
Ozanimod
Anti-SMAD 7
Mongersen 18

19. What does the patient want to know about a therapy?
IBD patient-reported attributes that make one therapy preferable over another
Clinical attributes
Efficacy / symptom relief1,4–6
Mixed data
on which attributes are considered most important
Sustained remission3
Good side-effect profile4
Rapid clinical response3,4
Nonclinical attributes
SC injection vs IV infusion1,2
Administration at home vs hospital2
Administration ease, frequency and duration1,3
Vavricka et al, Inflamm Bowel Dis 2012;18:1523–1530;
Borruel et al, IMPLICA study 2014;
Gray et al, Aliment Pharmacol Ther 2009;29:1114–1120;
Johnson et al., Gastroenterology 2007;133:769–779;
Johnson et al., Risk Anal. 2009;29:121–136;
Lichtenstein et al, Patient 2010;3(2): ;
Bewtra M et al, Inflamm Bowel Dis. 2014;20:103–114;
Johnson et al., J Manag Care Pharm 2010;6:616-28 19

20. Lymphocytes Preferentially Migrate to Particular Tissues Throughout the Body
As part of the body’s adaptive immune response, lymphocytes are imprinted for migration to areas of inflammation in certain tissues
Lymphocytes become imprinted
in certain lymphoid tissues in which they first encounter antigen
After this initial activating encounter, lymphocytes preferentially leave the blood in the same type of tissue in which they became activated
20 Panaccion r, Ghos S Nat Rev Immunol 2012; 144: ; Salmi M, Jalkanen S. Immunol Rev. 2005;206:

21. α4β7 Integrin–MAdCAM-1 is One of the Interactions That Contributes to Chronic Inflammation in UC and CD
MAdCAM-1
MAdCAM-1
Accumulation of excess infiltrating lymphocytes in the gastrointestinal tissue
Memory
T lymphocyte
α4β7 integrin
α4 subunit
β7 subunit
α4β7−MAdCAM-1 interaction has been implicated as an important contributor to the chronic inflammation that is a hallmark of UC and CD
MAdCAM-1=mucosal addressin cell adhesion molecule-1 21
Briskin M, et al. Am J Pathol. 1997;151:

22. Vedolizumab is a novel gut-selective anti-inflammatory biologic
Humanized mAb that binds exclusively to the α4β7 integrin heterodimer
Does not bind to α4β1 or αEβ7 integrin1
Selective antagonist of α4β7 integrin
Inhibits adhesion to MAdCAM-1 and fibronectin, but not VCAM
Contains a mutated Fc region, preventing elicitation of2
Complement-mediated cytotoxicity
Antibody-dependent cellular cytotoxicity
Cytokine release
Fc, fragment crystallisable; mAb, monoclonal antibody ; VCAM-1, vascular cell adhesion molecule
1. Soler D, et al. J Pharmacol Exp Ther 2009;330:864–75;. 22

23. GEMINI I: vedolizumab induction therapy for UC
Phase 3, multicentre, prospective, RCT (N=374)
Randomised 3:2, patients received VDZ 300mg (IV) or PBO on days 1 & 15
Mod-to-severe active UC (Mayo 8.6, mean), despite conventional therapy
UC diagnosis ~6.4 yrs, CS (~54%), IS (~31%) and anti-TNF failures (~39%)
Rates of AEs and serious AEs were similar between VDZ and PBO groups
Week 6 outcomes after 2-dose induction
All p< VDZ vs. PBO
Primary endpoint
100 80 60 40 20
VDZ 300 mg (n=225)
PBO (n=149) 47
Patients (%) 41 25 25 17 5
Response Remission
Mucosal healing
AE, adverse event; CS, corticosteroid; IS, immunosuppressant; RCT, randomised controlled trial 23
Feagan et al, N Engl J Med Aug 22;369(8):

24. GEMINI I: vedolizumab in UC maintenance
Primary and secondary efficacy endpoints
Placebo (n=126)
VDZ 300 mg every 8 weeks (n=122)
VDZ 300 mg every 4 weeks (n=125)
100 80
56.6
p<0.001
51p< 56 60 40 52
p<0.0001
44.8
Patients (%)
41.8
23.8
19.8
15.9 20
Clinical remission at 52 weeks
Durable clinical response
(at 6 and 52 weeks)
Mucosal healing at 52 weeks 24
Feagan BG et al, N Engl J Med Aug 22;369(8):

25. GEMINI I: vedolizumab in UC maintenance
Steroid-free clinical remission
Durable clinical remission
100 80
Percent of subjects *
45.2 60 *
31.4 40 **
20.5
***
24.0
13.9 20
8.7
Placebo N=72
VDZ
300 mg q8w N=70
VDZ
300 mg q4w N=73
Placebo N=126
VDZ
300 mg q8w N=122
VDZ
300 mg q4w N=125
p<0.0001, **p=0.0079, ***p= vs placebo. 25
Feagan BG et al, N Engl J Med Aug 22;369(8):

26. GEMINI II: vedolizumab in CD induction
Induction ITT population
Patients with prior anti-TNF failure (n=175)
Patients without prior anti-TNF failure 45 40 35 30 25 20 15 10 5
(n=193)
Placebo
38.3
VDZ
Patients (%)
28.2
23.8
22.9
18.3
10.5
9.0
4.3
Clinical remission
CDAI-100 response
-11.8, 13.7
Clinical remission
-0.2, 18.8
CDAI-100 response
-3.3, 23.4
6.2
1.0
9.3
10.1
95% CI: , 21.3
26 Sandborn W et al N Engl J Med Aug 22;369(8):711-21

27. GEMINI II: vedolizumab in CD maintenance
Maintenance ITT population 50 45 40 35 30 25 20 15 10 5 ** * **
Placebo **
VDZ Q8wk * *
VDZ Q4wk
Patients (%)
30.1
21.6
21.4
15.9
16.2
14.4
Clinical remission CDAI-100 response
CS-free remission†
Durable remission
*p<0.05,**p<0.01
†CS tapering began in responders at 6 weeks; for others, as soon as a clinical response was achieved.
27 Sandborn W et al N Engl J Med Aug 22;369(8):711-21

28. Is there a better way forward with vedolizumab?
Bridging: co-induction with steroids?
GEMINI II: Clinical Remission at Week 6
By Concomitant Medication Use at Week 0 30 25 20 15 10 5
PBO (n=148)
VDZ (n=220)
20.9
Patients, %
18.4
12.1
7.7
7.7
4.4
VDZ CS only and VDZ
IMM only and VDZ
CS and IMM and VDZ
CS, corticosteroid; IMM, immunomodulator; VDZ, vedolizumab. 28
Colombel JF, et al. J Crohns Colitis 2015;9;S344. Abstract P528.

29. Is there a better way forward with vedolizumab?
Define timeline for response?
Appropriate induction therapy / maintenance therapy for responders
Role of combination therapy is being defined
Allow weeks for maximal induction response
GEMINI II: CDAI-100 Response
Among Week 6 Non-responders*
PBO (n=69) VDZ (n=351)
13.2 30
25.4
23.1
23.9
21.7 20
Patients, %
11.6
11.6
8.7 10
7.2
7.2
Week 10 Week 14 Week 18 Week 22 Week 52
*In GEMINI II, 31.4% patients in the vedolizumab and 25.7% of patients in the placebo group had a CDAI-100 response at week 6. This is a post-hoc analysis; therefore P values are not reported. 29
Sandborn WJ, et al. J Crohns Colitis 2014;8;S Abstract P497.

30. Number of patients with event /100 PY (95% CI)
Integrated Phase 2 and 3 Safety Analysis – Treatment up to 5 years
Vedolizumab and Infections: Exposure-Adjusted Incidence Rates in CD
100 80 60 40 20
89.7
PBO (n=355)a
Number of patients with event /100 PY (95% CI)
VDZ (n=1723)b
68.6
37.2
29.5
6.1
5.3
4.6
3.8
1.5
3.6
Data shown for patients with any infection and common infections (defined as ≥0.5 patient events/100 PY in any patient group). aGEMINI 2 and 3 studies. bStudies C13004, GEMINI 2 and 3, and GEMINI LTS. cMedDRA PTs listed under ‘infections and infestations’ system organ class. dMedDRA high-level terms Candida infections, fungal infections NEC, tinea infections. eMedDRA PTs listed under ‘sepsis, bacteremia, viremia and fungemia NEC’ high-level term. CD, Crohn’s disease; GI, gastrointestinal; CI, confidence interval; LTS, long-term safety; MedDRA, Medical Dictionary for Regulatory Activities; NEC, not elsewhere classified; PBO, placebo; PT, preferred term; PY, person-year; VDZ, vedolizumab.  30
Colombel J-F, et al. Gut 2016;0:1–13. doi: /gutjnl

31. Integrated Phase 2 and 3 Safety Analysis – Treatment up to 5 years
Vedolizumab and Serious Infections: Exposure-Adjusted Incidence Rates in CD
Number of patients with event /100 PY (95% CI) 7 6 5 4 3 2 1
5.6
PBO (n=355)a VDZ (n=1723)b
3.0
2.4
0.8
0.8
0.5
0.3
0.3
0.1
0.1
<0.1
<0.1
<0.1
AGEMINI 2 and 3 studies. bStudies C13004, GEMINI 2 and 3, and GEMINI LTS. cMedDRA PTs listed under ‘infections and infestations’ system organ class. dMedDRA PTs anal abscess, perirectal abscess, rectal abscess, rectovaginal septum abscess, abdominal abscess, abscess intestinal, abscess, perineal abscess, pelvic abscess. eMedDRA high-level terms Candida infections, fungal infections NEC, tinea infections. fMedDRA PTs under ‘sepsis, bacteremia, viremia and fungemia NEC’ high-level term. CD, Crohn’s disease; CI, confidence interval; LTS, long-term safety; MedDRA, Medical Dictionary of Regulatory Activities; NEC, not elsewhere classified; PBO, placebo; PT, preferred term, PY, person-year; VDZ, vedolizumab.  31
Colombel J-F, et al. Gut 2016;0:1–13. doi: /gutjnl

32. Etrolizumab
Etrolizumab is a humanized mAB that targets the integrin receptors that regulate trafficking and retention of leukocyte/lymphocyte subsets in the intestinal mucosa signals
Etrolizumab differs from vedolizumab by blocking αEβ7 as well as α4β7
Etrolizumab is GI specific and targets β7 not α4β1, therefore risk PML thought to be low. 32

33. IBD=Inflammatory Bowel Disease; MAdCAM-1=Mucosal Vascular Addressin Cell Adhesion Molecule 1.
Etrolizumab Mechanism of Action: Available from: (accessed March 2017). 33 33

34. S1P Receptor Modulators and the S1P Signaling Pathway
S1P receptor modulators prevent migration of lymphocytes from lymph nodes to sites of inflammation where they contribute to immune-mediate pathology
S1P receptor modulation
Lymph
(high S1P concentration)
Endothelium
Lymphocyte egression
Lymphocyte egression blocked
Lymph node
(low S1P concentration)
Internalisation and degradation
Lymphocyte
S1P
S1P1
Internalised S1P
Degraded S1P
S1P modulators 37
Nielsen OH et al. Exp Opin Invest Drugs. 2016: doi.

35. Leukocyte trafficking Inhibitors in IBD analysis
PROS
Good efficacy in induction period
Stable efficacy in maintenance
Superior steroid sparing?
SAFETY
CONS
Slow onset of action (CD)
IV (vedolizumab)
?effects on systemic EIMs 40

36. Biology and site of action of interleukins 12 and 23
Ustekinumab and risankizumab are fully human monoclonal IgG1 antibodies
Ustekinumab bind the p40 subunit of IL-12/23
Risankizumab is a selective blocker of the IL23 p19 subunit
Ustekinumab is approved for the treatment of PsA and plaque psoriasis 41

37. Improvement in SES-CD From Induction Baseline (Week 0)
Ustekinumab Endoscopy Substudy
Outcomes in Pooled Weeks 8 & 16 Responders at Week 44 (52 Weeks of Treatment)
Improvement in SES-CD From Induction Baseline (Week 0)
Placebo UST Q12W UST Q8W
(n=51) (n=47) (n=74)
Placebo (n=51)
UST Q12W (n=47) UST Q8W (n=74)
∆21.1
p=0.017
0.0
-0.5
-1.0
-1.5
-2.0
-2.5
-3.0
-3.5
-4.0
48.6
∆ 20.1
p=0.012 50 40 30 20 10
Mean SES-CD Reduction
Proportion of Subjects (%)
∆ 11.8
p=0.082
33.8
29.8
27.5
-1.5
p=0.758
21.6
-2.0 7
12.8 9…
p=0.054
-3.8
SES-CD ≥3-pt
Reduction
Endoscopic Response
Mucosal Healing
4477
Rutgeerts P et al. UEGW Oral presentation 104

38. Phase 2 Psoriasis: Risankizumab vs. ustekinumab PASI Results
Papp K et al. NEJM 2017 April 20; 376 (16): 51

39. Anti-IL 12/23 inhibition in CD analysis
PROS
Rapid efficacy in induction period (ustekinumab IV)
Stable efficacy in maintenance with convenience of SC
Large therapeutic window (anti-IL 23)
Low immunogenicity
Safety
CONS
Lack of robust mucosal healing data
?effects on systemic EIMs
No data in UC 52

40. Binding of cytokine receptors by cytokines activates JAK pathways signaling
STAT PP
P P P
STAT
STAT
Gene transcription
JAK=Janus kinase; P=Phosphate; STAT=Signal Transducer and Activator of Transcription 53
Shuai K, Liu B. Nat Rev Immunol 2003;3:900−911. 53

41. JAK inhibitors VX-509 Upadacitinib Baricitinib Filgotinib
More potently inhibits JAK1 over JAK2 and JAK3
(ABT-494)
VX-509
More potently inhibits JAK3 over JAK 1 and JAK2
Baricitinib
More potently inhibits JAK1 and JAK 2 over JAK3
Tofacitinib
Non-selective (inhibits JAK1, JAK2 and JAK3)
Filgotinib
More potently inhibits JAK1 over JAK2 and JAK3
TYK2
JAK1
JAK2
TYK2
JAK1
JAK1
JAK2
JAK2
TYK2
JAK1
JAK3
JAK2
JAK2
Erythropoiesis
Myelopoiesis
Megakaryocyte/ platelet production
Growth
Mammary development
Growth/maturation lymphoid cells
Differentiation/ homeostasis
T cells, NK cells
B-cell class switching
Inflammation
Naive T-cell differentiation
T-cell homeostasis
Inflammation
Granulopoiesis
Innate immunity
Differentiation/ proliferation of Th17 cells
Inflammation
FUNCTION
Antiviral
Inflammation
Antitumor
Antiviral
Inflammation
54 JAK=Janus kinase; STAT=Signal Transducer and Activator of Transcription; TKY2=Tyrosine Kinase 2
Image courtesy of Stefan Schreiber 54

42. Tofacitinib is a JAK Inhibitor
Tofacitinib (CP-690,550) blocks phosphorylation
Cytokineof STAT and downstream activation
Cytokin e
Effects on the immune system
IL-2
Stimulate the proliferation and differentiation of Th, Tc, B, and NK cells
IL-4
Induce the differentiation of Th0 to Th2 Induce Ig 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   
JAK
JAK
STAT
STAT
mRNA
 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
 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
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): ; 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):
5555

43. Efficacy and Safety of Tofacitinib in Phase 3 Moderate to Severe UC
Tofacitinib 10 mg BID (n=476)
Placebo (n=122)
Tofacitinib 10 mg BID (n=429)
Placebo (n=112)
OCTAVE Induction 1
OCTAVE Induction 2
Remission
Mucosal Healing
Remission
Difference from placebo
***Δ13.0
Mucosal Healing
***Δ16.8 60 50 40 30 20 10 60 50 40 30 20 10
***Δ15.7
Patients (%)
Patients (%) **
Δ10.3
31.3
28.4
18.5
15.6
16.6
11.6
8.2
3.6
Overall
Overall
Δ13.3
Overall
Overall
Δ17.3
Patients (%)
39.6
Patients (%)
Δ9.4
36.4
Δ17.9
Δ13.5
Δ15.6
25.2
26.3
24.0
Δ11.1
Δ12.0
22.1
21.8
15.8
19.1
12.6
12.0
8.5
6.2
6.2
1.5
TNFi-
TNFi-
TNFi-
TNFi-
TNFi-
TNFi-
TNFi-
TNFi-
treated naive treated naive treated naive treated naive
Safety data showed no new or unexpected observations from results in tofacitinib studies in other populations
**P<0.01 vs placebo; ***P<0.001 vs placebo. BID=twice daily; TNFi=tumor necrosis factor inhibitor.
Sandborn WJ et al. ECCO Abstract A-1213. 56

44. JAK inhibition in IBD analysis
PROS
Rapid efficacy in induction period (UC and CD)
Stable efficacy in maintenance with convenience of oral
NO immunogenicity
Pre-biologic
CONS
Safety depending on selection
Adherence? 61

45. Inhibition of IL-6
IL-6's role as an anti- inflammatory cytokine is mediated through its inhibitory effects on TNF- alpha and IL-1, and activation of IL-1ra and IL
PF is a fully human antibody that binds to and neutralizes the IL-6 ligand. 62

46. SMAD7 Inhibition and the TGF- β/SMAD Pathway
Inhibition of SMAD7 restores SMAD2/3 activity and TGF-β-mediated signaling, thereby suppressing the production of proinflammatory cytokines1
Mongersen Phase 2 study in UC is ongoing2
TGF-βI P P
SMAD2
SMAD3
SMAD7
Mongersen
SMAD4
Cytoplasm
SMAD3 P
SMAD2
e.g. SMAD7
SMAD4 N
ucleus
Image adapted from Nielsen et al. Exp Opin Invest Drugs. 2016: doi /
63 1. Nielsen et al. Exp Opin Invest Drugs. 2016: doi / ClinicalTrials.gov NCT 63

47. Smad7 Antisense Oligonucleotide Proposed Mechanism of Action
In IBD, Smad7 appears over-expressed and this may result in decreased activity of TGF-β1 which is protective against an inflammatory state
GED-0301 (Mongersen) is an oral antisense DNA oligonucleotide targeting Smad7 mRNA
In mouse models, knockout of Smad7 restores TGF-β1 activity, with the downstream effect of inhibiting inflammatory cytokine production 64
Monteleone et al. (2012) Mol Ther 20:

48. Pathogenesis of Inflammatory Bowel Disease
Figure 1. Pathogenesis of Inflammatory Bowel Disease.
Normal epithelium, with its highly evolved tight junctions and products of goblet-cell populations, most notably trefoil peptides and mucin glycoproteins, provides an effective barrier against luminal agents. The integrity of the barrier may be compromised by genetic variations in key molecular determinants, a diminished reparative response to injury, or exogenous agents, such as nonsteroidal antiinflammatory drugs. Chronic, recurrent intestinal inflammation appears to result from stimulation of the mucosal immune system by products of commensal bacteria in the lumen. Antigens from dietary sources may also contribute. Stimulation may occur as a result of the penetration of bacterial products through the mucosal barrier, leading to their direct interaction with immune cells, especially dendritic cells and lymphocyte populations, to promote a classic adaptive immune response. Alternatively, bacterial products may stimulate the surface epithelium, possibly through receptors that are components of the innate immune-response system; the epithelium can, in turn, produce cytokines and chemokines that recruit and activate mucosal immune cells. Activation of classic antigen-presenting cells, such as dendritic cells, or direct stimulation through pattern-recognition receptors promotes the differentiation of type 1 helper T cells (Th1) in patients with Crohn's disease (shown here) or, possibly, atypical type 2 helper T cells in patients with ulcerative colitis. The stereotypical products of Th1 promote a self-sustaining cycle of activation with macrophages. In addition to producing the key cytokines that stimulate Th1 (interleukin-12, interleukin-18, and macrophage migration inhibitor factor), macrophages produce a mix of inflammatory cytokines, including interleukin-1, interleukin-6, and most notably tumor necrosis factor, which target a broad variety of other types of cells. The latter include endothelial cells, which then facilitate the recruitment of leukocytes to the mucosa from the vascular space, as well as fibroblasts and epithelium, modulating their functional properties. Most important, these functions may be altered either by genetically determined variants, as exemplified by germ-line mutations in the gene encoding NOD2, the product of the IBD1 locus, in some patients with Crohn's disease, or by environmental factors.
Podolsky, D. K. N Engl J Med 2002;347:

49. Volume 132, Issue 7, Pages 2313-2319 (June 2007)
Two-Year Combination Antibiotic Therapy With Clarithromycin, Rifabutin, and Clofazimine for Crohn’s Disease 
Warwick Selby, Paul Pavli, Brendan Crotty, Tim Florin, Graham Radford-Smith, Peter Gibson, Brent Mitchell, William Connell, Robert Read, Michael Merrett, Hooi Ee, David Hetzel 
Gastroenterology 
Volume 132, Issue 7, Pages (June 2007)
DOI: /j.gastro
Copyright © 2007 AGA Institute Terms and Conditions

50. Figure 1 Subject disposition.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2007 AGA Institute Terms and Conditions

51. Figure 2 Subjects remaining in remission at each time point.
Gastroenterology  , DOI: ( /j.gastro )
Copyright © 2007 AGA Institute Terms and Conditions

52. Summary
Emerging strategies are defining improved ways of managing patients with IBD
New therapies provide us with more choice and greater treatment flexibility
Our task is to use the right treatment in the right patient at the right time
Explore the evidence base
Understand best practice
Optimise your first biologic
Tailor treatment to patient needs
Invest in biomarker discovery 69