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

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

Step Down

Curatio PowerPoint Template 4/22/2017 12:24 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 10-7-11 Dr Sandborn prefers to leave slide title “as is” Curatio Fact Check ***PERMISSION NEEDED FOR HANDOUT*** This is Figure 2A+B, Page 1864. 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, 1861-1868. Copyright 2008, with permission from the AGA Institute. 4

Curatio PowerPoint Template 4/22/2017 12:24 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 1865. 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 40 39 32 31 28 27 22 22 20 20 19 18 17 16 Dis 40 38 33 28 25 22 20 20 18 18 18 18 18 18 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, 1861-1868. Copyright 2008, with permission from the AGA Institute. CRP, C-reactive protein

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, 63-70. Copyright 2012, with permission from the AGA Institute. CDEIS, Crohn’s Disease Endoscopic Index of Severity; usCRP, ultrasensitive C-reactive protein

Test Versus No Test

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

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

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;105:1133-9. Afif W, Sandborn WJ. Am J Gastroenterol 2010;105:1133-9. 10

Curatio PowerPoint Template Treatment Algorithm in IBD Patients With Clinical Symptoms (Infliximab and HACA Concentrations) 4/22/2017 12:24 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;105:1133-9.

Mucosal Healing

Mucosal Healing and Time to Colectomy in Infliximab-treated Patients 0 = NORMAL 1 = MILD 2 = MODERATE 3 = SEVERE Colombel JF, et al. Gastroenterology. 2011.

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

Working Definition of Deep Remission Curatio PowerPoint Template 4/22/2017 12:24 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

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.

Peyrin-Biroulet L et al. GUT. 2011.

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

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

Prevention Of Postoperative Recurrence

Crohn’s Disease: Recurrence After Surgery 20 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

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

Anti-TNF Versus Vedolizumab

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.

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.

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.

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

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

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

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