1. Newer Therapies in IBD: When, What and How Stephen B. Hanauer, MD Clifford Joseph Barborka Professor of Medicine Northwestern University Feinberg School of Medicine

2. Treatment Goals c.2015 Induce and maintain remission  Mucosal healing Prevent complications  Disease Related  Therapy Related Improve quality of life Limit surgery?

3. Evolving Approach to Treating UC Near Future Approach Newer therapies with favorable safety and side effect profiles Individualized therapy based on genetics and physiology Treatment to hard endpoints such as mucosal healing or surrogates of it Disease monitoring to prevent relapse Current Approach Assessment of prognosis “Optimization” of azathioprine/6-MP (dose or metabolites) Adopt biologic therapy earlier in disease Appreciation for the implications of a healed mucosa

4. Predictors of Poor Response or Colectomy Low serum albumin ESR >30 mm/h Bandemia Prolonged flare Active infection Hospitalization setting Severe endoscopic lesions Disease duration Stool frequency Percentage of bloody stools Body temperature >37.5 Heart rate >90 bpm Increased CRP Toxic megacolon Low hemoglobin <10.5 g/dL CRP=C-reactive protein. Lindgren SC, et al. Eur J Gastroenterol Hepatol. 1998;10:831-835.; Gonzalez-Lama Y, et al. Hepatogastroenterology. 2008;55:1609-1614. Suzuki Y, et al. Dig Dis Sci. 2006;51:2031-2038.; Cacheux W, et al. Am J Gastroenterol. 2008;103:637-642. Ananthakrishnan AN, et al. Am J Gastroenterol. 2008;103:2789-2798.

5. High-Risk Patients Oxford Index identifies patients with a high risk for colectomy  Evaluate CRP concentration  Evaluate number of bloody bowel movements Biomarkers to identify high-risk patients  Serum albumin concentration  Fecal calprotectin concentration Endoscopic disease severity is predictive Residual histopathologic inflammation Oxford Index: >8 stools/day or 3-8/day and CRP >45mg.dL on third day of corticosteroid. Travis SP, et al. Gut. 1996;38:905-910; Ho GT, et al. Aliment Pharmacol Ther. 2004;19:1079-1087; Carbonnel F, et al. Dig Dis Sci. 1994;39:1550-1557; Sandborn W, et al. 2010;105(Suppl 1):S438.

6. Mucosal Healing as a Surrogate for Longer Term Outcomes Associated with: Better quality of life Fewer hospitalizations Fewer surgeries Longer time to clinical relapse Reduction in dysplasia/cancer Sands, B. ACG-FDA Workshop 2012

7. Therapy is stepped up according to severity at presentation or failure at prior step Aminosalicylate Oral/Topical/Combo Corticosteroid Anti-TNF +/IS Cyclosporine (UC) Disease Severity at Presentation Anti-Integrin Aminosalicylate/ Thiopurine Anti-TNF/ Thiopurine Induction Maintenance Severe Moderate Mild Aminosalicylate Oral/Topical/Combo Sequential Therapies for Ulcerative Colitis

8. Anti-TNF agents in Ulcerative colitis

9. Infliximab Adalimumab Golimumab IgG1 Fc Fab Etanercept IgG1 Fc Receptor Monoclonal antibody Human Human recombinant receptor/Fc fusion protein Chimeric Fab ′ Certolizumab pegol PEG PEGylated humanized Fab′ fragment 2 × 20 kDa PEG Anti-TNF Agents Evaluated in Ulcerative Colitis

10. Clinical Remission in UC: ACT (Infliximab), ULTRA-2 (Adalimumab) and PURSUIT (Golimumab) Patients failing 5-ASA/Steroids/IS ** * *P<0.05 versus placebo; **P<0.01 versus placebo Sandborn WJ, et al. Gastroenterology. 2014;146(1):96-109; Sandborn WJ, et al. Gastroenterology. 2014;146(1):85-95; Sandborn WJ, et al. Gastroenterology. 2012;142(2):257-265; Rutgeerts P, et al. N Engl J Med. 2005;353(23):2462-2476; Panaccione R, et al. Can J Gastroenterol. 2008;22(3):261-272.

11. Is Combination Therapy Superior?

12. P=0.017 P=0.813 P=0.032 Panaccione R, et al. Gastroenterology. 2014;146(2):392-400. UC SUCCESS: Corticosteroid-free Remission in Early UC

13. P=0.028 P=0.001 P=0.295 Panaccione R, et al. Gastroenterology. 2014;146(2):392-400. UC SUCCESS: Mucosal Healing in Early UC

14. Therapeutic Monitoring for Anti-TNF Congestive heart failure Autoimmunity, immunogenicity Demyelinating disease, PML* Infection Malignancy/ lymphoma Infusion reactions, injection-site reactions Hepatotoxicity Bone marrow suppression *Reported with natalizumab. Use combination therapy with thiopurines? Check anti-TNF levels? Check for antibodies? Use combination therapy with thiopurines? Check anti-TNF levels? Check for antibodies? Vaccinations: flu, pneumonia TB testing Hepatitis screening Vaccinations: flu, pneumonia TB testing Hepatitis screening Switch to another anti-TNF agent? Switch to agent with different mechanism of action? Switch to another anti-TNF agent? Switch to agent with different mechanism of action?

15. A New Mechanism of Action

16. α4β7 Integrin–MAdCAM-1 Is One of the Interactions that Contributes to Chronic Inflammation in UC and CD MAdCAM-1=mucosal addressin cell adhesion molecule-1 Briskin M, et al. Am J Pathol. 1997;151:97-110. 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 α4β7 integrin Memory T lymphocyte MAdCAM-1 β7 subunit β7 subunit α4 subunit α4 subunit Artist’s rendition

17. Vedolizumab Binds to α4β7 Integrin and Blocks Its Interaction With MAdCAM-1 Memory T lymphocyte Vedolizumab: A humanized monoclonal antibody (mAb) that binds to the α4β7 integrin Vedolizumab: A humanized monoclonal antibody (mAb) that binds to the α4β7 integrin Vedolizumab blocks the interaction of α4β7 integrin with MAdCAM- 1 Endothelial cell β7 subunit β7 subunit α4 subunit α4 subunit MAdCAM-1 β7 subunit β7 subunit α4 subunit α4 subunit vedolizumab Artist’s rendition

18. Vedolizumab Phase III Trial in UC: Clinical Response, Clinical Remission, and Mucosal Healing at 6 weeks †  21.7 11.6, 31.7  11.5 4.7, 18.3  16.1 6.4, 25.9 95% CI: *P = 0.001 **P<0.0001 † ITT population, 6 weeks Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.

19. 19 Please see Important Safety Information contained on slides 33-34. Corticosteroid-Free Clinical Remission at Week 52 in UC II P=0.012 Secondary endpoint CS-free clinical remission was assessed in the subgroup of patients who were receiving CS at baseline and who were in clinical response at Week 6. CS-free clinical remission was defined as the proportion of patients in this subgroup that discontinued CS by Week 52 and were in clinical remission at Week 52. Placebo (n=72) Entyvio 300 mg Q8 weeks (n=70) a a Patients must have achieved clinical response at Week 6 to continue into UC Trial II. This group includes patients that were not in clinical remission at Week 6. Feagan BG et al. New Engl J Med. 2013;369:699-710.

20. Vedolizumab Phase III Clinical Trial in UC: Clinical Remission and Durable Clinical Response at 52 Weeks 25.4 (5.1, 43.8) 29.7 (10.3, 47.7) 24.9 (7.1, 42.6) 27.0 (9.4, 44.6) 26.8 (12.4, 41.2) 29.0 (14.6, 43.3) 38.7 (24.0, 53.4) 29.6 (14.6, 44.6) Mean  % vs VDZ/PBO (95% CI) VDZ/VDZ Q8W: VDZ/VDZ Q4W: PBO = placebo; VDZ = vedolizumab Feagan BG, et al. New Engl J Med. 2013;369(8):699-710.

21. Positioning New Therapies

22. What Is the Optimal Positioning for Golimumab in UC? Therapy is stepped up according to severity at presentation or failure at prior step Corticosteroid Anti-TNF +/IS Cyclosporine (UC) Anti-Integrin Aminosalicylate/ Thiopurine Anti-TNF/ Thiopurine Induction Maintenance Severe Moderate Mild Golimumab Tested Possible Unlikely in Severe/Fulminant With/Without IS?

23. What Is the Optimal Positioning for Vedolizumab in UC? Corticosteroid Anti-TNF +/IS Cyclosporine (UC) Anti-Integrin Aminosalicylate/ Thiopurine Anti-TNF/ Thiopurine Induction Maintenance Severe Moderate Mild Vedolizumab Before Steroids? Before Anti-TNFs?

24. Vedolizumab in Crohn’s Disease

25. PBO=placebo; VDZ=vedolizumab Sandborn WJ et al. New Engl J Med. 2013;369:711-721. Clinical Remission and CDAI-100 Response at Week 6 P=.02 7.8 (1.2, 14.3)5.7 (–3.6, 15.0) Mean  % vs PBO (95% CI) P=.23

26. Primary and Secondary Outcomes at 52 Weeks † P<.01 vs placebo; ‡ P<.05 vs placebo CS=corticosteroid; VDZ=vedolizumab Sandborn WJ et al. New Engl J Med. 2013;369:711-721. Primary Outcome Secondary Outcomes 17.4 14.7 13.4 15.3 7.2 2.0 15.9 12.9 Mean  % vs VDZ/PBO

27. Patients With Prior Anti-TNFα Exposure (n=253) Patients Without Prior Anti-TNFα Exposure (n=208) Clinical Remission, CDAI-100 Response at 52 Weeks by Prior TNF Antagonist Exposure VDZ=vedolizumab Sandborn WJ et al. New Engl J Med. 2013;369:711-721. 12.5 (–0.1, 25.0) 10.6 (–2.0, 23.2) 7.5 (–5.8, 20.8) 15.4 (1.5, 29.3) 24.8 (8.9, 40.6) 19.7 (4.2, 35.2) 22.6 (6.3, 38.9) 15.5 (–0.7, 31.7) Mean  % vs VDZ/PBO (95% CI) VDZ/VDZ Q8W: VDZ/VDZ Q4W:

28. *P=.0011 vs placebo; † P<.0001 vs placebo; ‡ P=.0002 vs placebo PBO=placebo; VDZ=vedolizumab Sands B et al. Presented at ECCO 2013. Vedolizumab Phase 3 Induction Trial in CD CDAI-100 Response Anti-TNFα Failure Population (n=315) Overall Population (n=416)

29. Vedolizumab Trough Concentration (μg/mL): Vedolizumab Trough Levels Also Correlate with Response to Therapy: UC Week 6 n=54 n=53 FirstSecondThirdFourthQuartile: Vedolizumab Trough Concentration (μg/mL): 0 to <16.7 16.7 to <24.8 24.8 to <33.3 33.3 to 65.6 n=53n=54 Feagan B et al. N Engl J Med. 2013;369:699-710.

30. Vedolizumab Indications Adult Crohn’s Disease (CD) Adult patients with moderately to severely active CD who have had an inadequate response with, lost response to, or were intolerant to a TNF blocker or immunomodulator; or had an inadequate response with, were intolerant to, or demonstrated dependence on corticosteroids: achieving clinical response achieving clinical remission achieving corticosteroid-free remission Entyvio [package insert]. Deerfield, IL: Takeda Pharmaceuticals America, Inc; May 2014.

31. Positioning Vedolizumab in Crohn’s? Therapy is stepped up according to severity at presentation or failure at prior step Aminosalicylate Oral/Topical/Combo Corticosteroid Anti-TNF +/IS Disease Severity at Presentation Natalizumab (CD) Aminosalicylate/ Thiopurine Anti-TNF/ Thiopurine Induction Maintenance Severe Moderate Mild Aminosalicylate Oral/Topical/Combo Vedolizumab?

32. Positioning Vedolizuma for Crohn’s Disease Vedolizumab  Before (?)/After (?) anti-TNF  Maintenance benefits>Induction Earlier disease? Steroid induction?

33. IL-12 and IL-23 Cytokines and Receptors Are First Cousins IL-23R polymorphisms are found in Crohn’s disease and ulcerative colitis Targeting p19 (blocking IL-23 signaling) is therapeutic in mouse colitis models Now shown to be effective in Crohn’s disease Adapted from Trinchieri G. Nat Rev Immunol. 2003;3:133-145. IL-12R  1IL-12R  2 Anti-p40 Ab IL-12 p35 p40 IL-12R  1 IL-23R Anti-p40 Ab IL-23 p19 p40 Anti-p19 Ab Initial Evaluation of MEDI2070 (specific anti-IL-23 antibody) in patients with active Crohn’s disease who have failed anti-TNF antibody therapy: A randomized, double-blind placebo- controlled phase 2a induction study Bruce Sands et al. Abstract #830 Tuesday 8a Initial Evaluation of MEDI2070 (specific anti-IL-23 antibody) in patients with active Crohn’s disease who have failed anti-TNF antibody therapy: A randomized, double-blind placebo- controlled phase 2a induction study Bruce Sands et al. Abstract #830 Tuesday 8a

34. IL-23 Oppmann B et al. Immunity. 2000;13:715. IL-12 Presky DH et al. Proc Natl Acad Sci U S A. 1996;93:14002. p40 p19 p40 p35 Anti-p40 Mechanism of Action IL-12R  1 IL-23R IL-12R  1 IL-12R  2 NK or T cell membrane No Signal Ustekinumab Briakinumab Parham C et al. J Immunol. 2002;168:5699. Chua AO et al. J Immunol. 1995;155:4286.

35. Ustekinumab for Crohn’s disease: blocks IL-12/IL-23 Ustekinumab for Crohn’s disease: blocks IL-12/IL-23 *P<.05 23.5 36.6* 34.1 39.7* 36.8* 17.4 32.1* 31.8* 43.5* 35.8* 10.6 15.9 12.2 14.7 10.6 17.4 18.3 17.8 16 17.6 Clinical Response and Remission at Weeks 6 and 8 Sandborn W, et al. N Engl J Med. 2012 Oct 18;367(16):1519-28.

36. What and When?  Now Golimumab for UC Vedolizumab for UC and CD  12 Months Ustekinemab for CD How?  Earlier the better  Combine with Immunosuppressive? Safety vs Efficacy  Therapeutic Drug Monitoring Likely Summary: Newer Biologic Therapies in IBD