1. Future Clinical Trials: Unanswered Questions in the Care of IBD Patients
William J. Sandborn, MD
Chief, Division of Gastroenterology
Director, UCSD IBD Center

2. Unanswered Questions Step down Test Versus No Test Mucosal healing
Prevention of postoperative recurrence
Anti-TNF versus vedolizumab

3. Step Down

4. Curatio PowerPoint Template
4/22/ :24 AM
Withdrawal of AZA in 80 Patients With CD Treated With Scheduled IFX Maintenance: Clinical Outcomes
No need for early rescue IFX
No need to discontinue IFX
1.0
1.0
Continued
Discontinued
0.8
0.8
Log rank (Cox): P=0.374
0.6
0.6
Proportion of Patients
Proportion of Patients
0.4
Log rank (Cox): P=0.735
0.4
0.2
0.2
Dr Sandborn prefers to leave slide title “as is”
Curatio Fact Check
***PERMISSION NEEDED FOR HANDOUT***
This is Figure 2A+B, Page Van Assche G, et al. Gastroenterology 2008;134:1861.
Con=Continue
Dis=Discontinue
0.0
0.0 8 16 24 32 40 48 56 64 72 80 88 96 8 16 24 32 40 48 56 64 72 80 88 96
104
Weeks
Weeks
Reprinted from Gastroenterology 134(7), Van Assche G, et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial, Copyright 2008, with permission from the AGA Institute. 4

5. Curatio PowerPoint Template
4/22/ :24 AM
Withdrawal of AZA in CD Patients Treated With Scheduled IFX Maintenance: Serum CRP and IFX Concentrations Over Time 11
Discontinued * 10
Continued 20 * * * * 9 8 7 15
CRP (mg/L) 6 5
CRP (mg/L) 10 4
P<.005 3 2 5
2.8 1
1.6 8 16 24 32 40 48 56 64 72 80 88 96
104
Con
Dis
Weeks
Continued
P=.0046
Discontinued 7
P=.11
P=.028 6
P=.051
P=.043 10
P<.0001 5
P=.15
P=.048
P=.19
Trough IFX (μg/mL) 4
2.87
[IFX] μg/mL 3
Curatio Fact Check
***PERMISSION NEEDED FOR HANDOUT***
This is Figure 3A+B, Page Van Assche G, et al. Gastroenterology 2008;134:1861. 2 1
1.65 1
Con
Dis 8 16 24 32 40 48 56 64 72 80 88 96
104
Weeks
Con Dis N=
Reprinted from Gastroenterology 134(7), Van Assche G, et al. Withdrawal of immunosuppression in Crohn's disease treated with scheduled infliximab maintenance: a randomized trial, Copyright 2008, with permission from the AGA Institute.
CRP, C-reactive protein

6. STORI Trial
Patients with Crohn's disease who were treated for at least 1 year with scheduled infliximab and an antimetabolite and had been in corticosteroid-free remission for at least 6 months
Assessed the risk of relapse after discontinuation of infliximab in patients on combined maintenance therapy with immunosuppressors and to identify the risk factors for relapse
Results:
After 1 year of infliximab discontinuation, the relapse rate was 44%
Patients who relapsed were successfully retreated with infliximab
Of the 40 evaluable responses to retreatment at 4 weeks, 37 were in remission
Predictive Factor
Hazard Ratio
P Value
CDEIS >0
hsCRP ≥5 mg/L
Hemoglobin ≤14.5 g/dL
Infliximab trough levels ≥2 μg/mL
2.3
3.2
6.0
2.5
0.04
<0.001
0.02
Fact check:
Dash 1- taken from abstract 1-year relapse was 44%
Dash 2-3 taken from page 67, bottom paragraph
Table Taken from table 2 Louis 2012, pg 68
Reprinted from Gastroenterology 141(1), Louis E, et al. Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped, Copyright 2012, with permission from the AGA Institute.
CDEIS, Crohn’s Disease Endoscopic Index of Severity; usCRP, ultrasensitive C-reactive protein

7. Test Versus No Test

8. Factors Affecting the Pharmacokinetics of Monoclonal Antibodies
IMPACT on PK
Presence of ADAs
Decreases serum [mAbs]
Three fold-increased clearance
Worse clinical outcomes
Concomitant use of IS
Reduces formation
Increases serum [mAbs]
Decreases mAbs clearance
Better clinical outcomes
High Baseline [TNF-α]
May decrease [mAbs] by increasing clearance
Low Albumin
Increases clearance
High Baseline CRP
Body size
High BMI may increase clearance
Gender
Males have higher clearance
Ordas I, Feagan B, Mould D, Sandborn WJ. Clin Pharmacol Ther 2012

9. ACT 1+2: Proportions of Patients with Ulcerative Colitis Achieving Efficacy Endpoints by Serum Infliximab Concentrations
Proportion of patients (%)
≥21.3 – < 33.0
≥33.0 – < 47.9
≥0.11- <2.4
≥2.4- <6.8
<21.3
> 47.9
<0.11
> 6.8
Reinisch W, et al., Digestive Disease Week 2012; Abstract # 566

10. Elevating Infliximab Concentration from Sub-Therapeutic Levels is Effective in Regaining Response in HACA (-) Patients
Clinical Outcomes of Patients with Detectable Antibodies to Infliximab or Sub-therapeutic Infliximab Concentrations
Response to test
Complete/partial response (%)
P value
Detectable HACA
Increase infliximab
1/6 (17)
P<0.004
Change anti-TNF
11/12 (92)
Subtherapeutic concentration
25/29 (86)
P<0.016
2/6 (33)
In a retrospective medical record review of 155 patients tested for HACA and infliximab concentrations between Jan 2003 and August 2008, 35 patients had HACA positivity. [Afif/2010/p3/C1/para3/ll1-3]
Ninety-two percent (11/12) patients with HACA positivity who changed to another anti-TNF agent had a complete or partial response whereas only 17% (1/6) with HACA positivity who increaed infliximab levels had a complete or partial response (P<0.004) [Afif/2010/p4/C1/para3/ll1-6]
Of 63 patients with subtherapeutic concentrations of infliximab, increasing the dose achieved clinical/partial response in 86% of the patients (25/29), while changing to another anti-TNF agent resulted in a 33% response (2/6; P<0.016). [Afif/2010/p4/C2/para2/ll1-7]
The authors conclude that routine assessment of HACA levels and infliximab concentrations is clinically useful and may help to optimize patient treatment regimens. [Afif/2010/page 7/Study Highlights]
Reference
Afif W, et al. Am J Gastroenterol 2010;105:
Afif W, Sandborn WJ. Am J Gastroenterol 2010;105: 10

11. Curatio PowerPoint Template
Treatment Algorithm in IBD Patients With Clinical Symptoms (Infliximab and HACA Concentrations)
4/22/ :24 AM
Therapeutic IFX concentration
Subtherapeutic IFX concentration
Positive HACA
Increase infliximab dose or frequency
Change to different
anti-TNF agent
Active disease on endoscopy/radiology?
Change to another anti-TNF agent
yes no
persistent disease
Change to different
anti-TNF agent
Investigate alternate etiologies
Change to different
anti-TNF agent
Change to non-
anti-TNF agent
Change to non- anti-TNF agent
Afif W, et al. Am J Gastroenterol 2010;105:

12. Mucosal Healing

13. Mucosal Healing and Time to Colectomy in Infliximab-treated Patients
0 = NORMAL
1 = MILD
2 = MODERATE
3 = SEVERE
Colombel JF, et al. Gastroenterology

14. Association Between Week 8 Mayo Endoscopy Sub-score and and Corticosteroid-Free Symptomatic Remission at Week 30 During Anti-TNF Antibody Therapy
Week 8 Mayo endoscopy sub- score
Corticosteroid-free symptomatic remission, %
P value 46
< 0.001 1 34 2 11 3
6.5
Colombel JF, et al. Gastroenterology 2011

15. Working Definition of Deep Remission
Curatio PowerPoint Template
4/22/ :24 AM
Working Definition of Deep Remission
Overall, aiming for deep remission (DR) is managing disease beyond symptom control
In patients with no bowel damage or disability, DR is resolution of one or more objective measures of inflammation (endoscopy, markers, imaging) AND resolution of symptoms
To prevent damage and disability
In patients with existing bowel damage and disability, DR is resolution of one or more objective measures of inflammation (endoscopy, markers, imaging) AND improvement of symptoms if possible
To prevent further damage and disability, and reverse damage if possible
KEY SLIDE TO PRINT IN HANDOUT

16. Development of the Crohn’s Disease Digestive Damage Score, the Le´mann Score
Benjamin Pariente, Jacques Cosnes, Silvio Danese, William J Sandborn, Maı¨te´ Lewin, Joel G Fletcher, Yehuda Chowers, Geert D’Haens, Brian G Feagan, Toshifumi Hibi, Daniel W Hommes, E. Jan Irvine, Michael A. Kamm, Edward V Loftus, Edouard Louis, Pierre Michetti, Pia Munkholm, Tom Oresland, Julian Pane´s, Laurent Peyrin-Biroulet, Walter Reinisch, Bruce E Sands, Juergen Schoelmerich, Stefan Schreiber, Herbert Tilg, Simon Travis, Gert van Assche, Maurizio Vecchi, Jean-Yves Mary, Jean-Fre´de´ric Colombel, Marc Le´mann
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.

17. Peyrin-Biroulet L et al. GUT. 2011.

18. Inflammatory activity (CDAI, CDEIS, CRP)
Inflammatory Activity and Progression of Damage in a Theoretical Patient with CD
Stricture
Surgery
Digestive damage
Fistula/abscess
Inflammatory activity (CDAI, CDEIS, CRP)
Stricture
KEY SLIDE TO PRINT IN HANDOUT
Curatio Fact Check
**PERMISSION NEEDED FOR HANDOUT**-
This is an adaptation of Figure 1, page 1420 of Pariente 2011.
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415.
Disease onset
Diagnosis
Early disease
CDAI, Crohn’s Disease Activity Index; CDEIS, Crohn’s disease endoscopic index of severity
CRP; c-reactive protein
Pariente B et al. Inflamm Bowel Dis. 2011;17(6):1415. 18 18 18 18

19. EXTEND: patients with Crohn’s disease who achieved deep remission
EXTEND: patients with Crohn’s disease who achieved deep remission* with adalimumab at Week 12 and hospitalization rates
All-cause hospitalization through Week 52
CD-related hospitalization through Week 52 20 20 17 15 15
All hospitalization (%) 10
CD-related hospitalization (%) 10 9 5 5
0/11
9/53
0/11
5/53
Deep remission* (Week 12)
Non-deep remission* (Week 12)
Deep remission*
(Week 12)
Non-deep remission*
(Week 12)
None of the patients from EXTEND who achieved deep remission at Week 12 were hospitalised during the remainder of the trial.
In contrast, 17% and 9% of patients who did not achieve deep remission at Week 12 were hospitalised for all causes (graph on left) and Crohn’s disease-related causes (graph on right), respectively.
* Deep remission defined as clinical remission (CDAI <150) and complete mucosal healing in EXTEND CD: Crohn’s disease; CDAI: Crohn’s disease activity index
Colombel JF, Sandborn WJ, et al. Gut 2010;59(Suppl 3):A80: OP371 at UEGW 2010 19 19 19 19

20. Prevention Of Postoperative Recurrence

21. Crohn’s Disease: Recurrence After Surgery20 40 80
100 60 Yr
Patients (%) 1 2 3 4 5 6 7 8
Survival without surgery
Survival without laboratory recurrence
Survival without symptoms
Survival without endoscopic lesions
Rutgeerts P, et al. Gastroenterology. 1990;99(4):956

22. Infliximab for Prevention of Postoperative Recurrence in Crohn’s Disease
Crohn’s disease patients with surgical resection of the ileum with an ileocolonic anastomosis
P=.0006
Placebo
100 90
P=.0009
Infliximab 5 mg/kg 80
P=.67 80 67 60 54
P=.05
(%) 39 40 15 20 15 8
Endoscopic
remission
Absence of CD
on colonoscopy
Clinical
remission
Clinical
recurrence
N=23; within 4 wk of surgery, patients received study drug at 0, 2, 6 wk then Q 8 wk for 1 yr
Regueiro M, et al. Gastroenterology 2009 22 22

23. Anti-TNF Versus Vedolizumab

24. Infliximab Induction and Maintenance Therapy in Patients with Ulcerative Colitis: Clinical Response
ACT 1
ACT 2 ‡ ‡ ‡ ‡ ‡ ‡ † ‡ ‡ ‡
In ACT 1 and ACT 2, clinical response was seen at 1.7 to 2 times the placebo rate in both treatment groups at all timepoints. Statistical significance was reached at all timepoints in both treatment groups.
Concomitant medications did not change the outcomes of response or remission in the subgroup analysis. CRP levels also did not change outcomes.
Infliximab allowed reductions in the median daily steroid dose. In ACT 1, the median doses at baseline, 8, 30 and 54 weeks were: 20 mg, 20 mg, 5.6 mg and 5 mg in the 5 mg/kg group and 20 mg, 20 mg, 10 mg and 10 mg in the 10 mg/kg group.
In ACT 2, the median doses at baseline, 8 and 30 weeks were: 20 mg, 20 mg and 7.5 mg in the 5 mg/kg group and 20 mg, 20 mg and 5 mg in the 10 mg/kg group.
Safety:
In ACT 1 at week 54 (N=229), 6.1% had positive tests for antibodies, 15.7% had negative tests and 78.2% had inconclusive tests. In ACT 2 (N=188) 6.4% had positive tests for antibodies, 18.1% had negative tests and 75.5% had inconclusive tests.
Presence of antibodies did not appear to influence response rates.
Infusion reactions and delayed hypersensitivity reactions occurred at similar rates in the infliximab and placebo groups.
The rate of serious AE, including infections, was similar in infliximab groups and placebo groups.
3 neurological events occurred, all in infliximab groups: 2 optic neuritis and 1 multifocal motor neuropathy with conduction block syndrome
1 patient treated with infliximab developed a lupus-like syndrome
†P.002 vs placebo ‡P<.001 vs placebo
Rutgeerts P. N Engl J Med. 2005;353:2462.

25. Infliximab Induction and Maintenance Therapy in Patients with Ulcerative Colitis: Clinical Remission
ACT 1
ACT 2 ‡ ‡ ‡ ‡ ‡ ‡ ‡ † ‡ †
In both ACT 1 and ACT 2 at all timepoints and all doses, the treatment groups had a remission rate 2 to 2.5 that seen with placebo, which was significant.
†P.003 vs placebo ‡P<.001 vs placebo
Rutgeerts P. N Engl J Med. 2005;353:2462.

26. Mucosal healing = endoscopic subscore of 0 or 1
Infliximab Induction and Maintenance Therapy in Patients with Ulcerative Colitis: Mucosal Healing
ACT 1
ACT 2 ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ †
In both ACT 1 and ACT 2, the rate of mucosal healing was about doubled in the infliximab groups at almost every timepoint, which was significant.
Mucosal healing = endoscopic subscore of 0 or 1
†P.009 vs placebo ‡P<.001 vs placebo
Rutgeerts P. N Engl J Med. 2005;353:2462.

27. Vedolizumab (Anti-Alpha 4 Beta 7 Integrin) For Moderately-to-Severely Active Ulcerative Colitis: Results at Week 6 in 374 Patients
P<0.001
P=0.0012
P=0.0009
Feagan B. DDW 2012 Late Breaking Abstract

28. Vedolizumab (Anti- 47 Integrin) For Maintenace of Response in Moderately-to-Severely Active Ulcerative Colitis: Results at Week 52 in 373 Patients
Feagan B. ACG 2012 Abstract

29. Comparative Effectiveness Trials Already Completed But Results Not Fully Implemented By Clinicians
Mesalamine not effective for Crohn’s disease
SONIC and UC Success – azathioprine < infliximab < combination therapy
Early use of azathioprine + steroids not more effective than a tapering course of steroids

30. Conclusions
Comparative effectiveness studies are needed to better guide future clinical practice