1. Future Therapies for the Inflammatory Bowel Diseases Ryan W. Stidham, MD Crohn’s and Colitis Program University of Michigan Health System Ann Arbor, Michigan

2. We’ve come a long way… Crohn’s and UC are described IBD is recognized Prednisone Mesalamine Remicade Azathioprine Methotrexate Humira Cimzia Tysabri 1700-1900 193019401950196019701980199020002010 2020

3. Goals of Therapy in the Inflammatory Bowel Diseases Symptom Improvement Improve the Future Reduce Hospitalization Reduce need for surgery Reduce social &occupational burden Mucosal Healing Targeted Therapy Against Inflammation in IBD Improve Safety and Tolerability of Medications

4. Future Therapies in IBD Lecture Outline IBD Immunology 101 Novel Targets for Therapy in IBD New Treatments in Development How to Get Involved in IBD Clinical Trials. There is a great need for new therapies in IBD

5. IBD Immunology 101

6. Mucosa Submucosa Blood Vessels IBD Immunology 101

7. Mucosa Submucosa Blood Vessels IBD Immunology 101

8. Mucosa Submucosa Blood Vessels

9. Anti-adhesion therapies – Chemokine Antagonists – Anti-Integrin blockade Interleukin and Cytokine Antagonists – IL-12/23 pathways Blockade of Intracellular Inflammation Control – JAK-STAT Kinase Pathways Targets for Therapy

10. CCL-25 Ligand CCR9 Receptor Blockade of Cell Adhesion and Homing Cytokines

11. Chemokine CCR-9 Chemokines are selectively released to activate elements of inflammatory response Chemokine CCR9 has many function in intestinal inflammation Attracts T and B-cells to the site of inflammation CCR9 Binds to intestinal endothelium to help pull T-cells into the intestine Also activates endothelial Integrins, permitting other inflammatory cells to enter the gut. Blockade of Cell Adhesion and Homing Cytokines

12. Compound CCX282-B Anti-chemokine CCR9 medication In Phase III Testing in Large Crohn’s Population Taken in pill form twice a day Developed by GlaxoSmithKline Pharmaceuticals For Study in Crohn’s Disease Blockade of Cell Adhesion and Homing Cytokines

13. Blockade of Cell-Homing Signals: Anti-CCR9 Compound CCX282-B Symptom Response Achieved at Week 12 PROTECT-1 STUDY

14. Blockade of Cell-Activating Signals: Anti-CCR9 Compound CCX282-B SHEILD Study Clinicaltrials.gov ID: NCT01316939 Enrolling Crohn’s Patients at UM To participate, you must: Have active Crohn’s symptoms Have failed at least one medication in the past Not have Cancer, Hepatitis B, or HIV Not have C. diff infection Be off anti-TNFs for a few weeks Not have an ostomy

15. Block WBC Binding to Integrins Anti-Integrin Coating Blockade of Adhesion Molecules: Blockade of Adhesion Molecules: Vedolizumab

16. Vedolizumab rhuMAb Beta7 PF-00547659 (MAdCAM-1 Antagonist) Leading Anti-Integrins In Development Blockade of Adhesion Molecules: Blockade of Adhesion Molecules: Vedolizumab

17. Vedolizumab Vedolizumab – antibody against one type of integrin Prevents binding of White Blood Cells (WBC) in the intestine Specific to the Intestine In Phase III testing in large number of patients Being Studied in both Ulcerative Colitis and Crohn’s Given via IV infusion (in the vein) once a month Developed by Millennium Pharmaceuticals

18. Blockade of Adhesion Molecules: Blockade of Adhesion Molecules: Vedolizumab Initial Ulcerative Colitis Study Week 6 Endpoint Initial Crohn’s Disease Study Week 8 Endpoint Vedolizumab

19. Vedolizumab GEMINI Study Clinicaltrials.gov ID: NCT01224171 Enrolling at the University of Michigan To participate, you must: Have active Crohn’s symptoms Have failed one medication in the past Not have any infections, cancer or an ostomy Be off anti-TNF medications and steroids, but may continue on azathioprine and prednisone Blockade of Adhesion Molecules: Blockade of Adhesion Molecules: Vedolizumab

20. rhuMAb Beta7 rhuMAb Beta7– antibody binding to alpha4beta7 and alphaEbeta7 Prevents White Blood Cells (WBC) entry into the intestines Also Prevents Lymphocytes from binding to the epithelium In Phase II Trials for Ulcerative Colitis Given via subcutaneous injection (shot under the skin) Developed by Genentech/Roche Pharmaceuticals Blockade of Adhesion Molecules: Blockade of Adhesion Molecules: rhuMAb Beta7

21. rhuMAb Beta7 Cheroutre and Madakamutil, Nat Rev Immunol 2004 Blockade of Adhesion Molecules: Blockade of Adhesion Molecules: rhuMAb Beta7

22. rhuMAb Beta7 Eucalyptus Study clinicaltrials.gov ID: NCT01336465 Enrolling at the University of Michigan To participate, you must: Have active Ulcerative Colitis symptoms Be off anti-TNF therapy Have no ostomy Be off all rectal therapies and anti-TNF therapies (may continue on azathioprine and prednisone) Blockade of Adhesion Molecules: Blockade of Adhesion Molecules: rhuMAb

23. IL-12/23LigandIL-12/23Ligand IL-12ReceptorIL-12Receptor Blockade of Cell-Activating Signals T-cell T-cells ACTIVATED Dendritic cell IL-17 Interferon

24. Ustekinumab Ustekinumab – antibody blocking IL-12/23 Interleukins Blocks IL-12/23 mediated Activation of T-cells, Agents normalize IL-12/23 mediated signaling, cellular activation, and and cytokine production, thereby reducing inflammation Currently approved for treatment of Psoriasis (tradename: Stelera®) IV induction then Subcutaneous every 4 weeks. Blockade of Cell-Activating Signals: ustekinumab

25. Blockade of Cell-Regulating Signals: Blockade of Cell-Regulating Signals: IL-12/23 Inhibitors CERTFI STUDY – Ustekinumab in Crohn’s Disease

26. ustekinumab UNITI Study Clinicaltrials.gov ID: NCT01369342 SOON to OPEN Enrollment at the University of Michigan To participate, you must: Have active Crohn’s disease symptoms Be off anti-TNF medication, but can stay on steroids and azathioprine Not have infections, cancer, or an ostomy Blockade of Cell-Activating Signals: ustekinumab

27. IL-12/23LigandIL-12/23Ligand IL-12ReceptorIL-12Receptor Blockade of Cellular Inflammation Controls T-cell Interleukins Interleukins Attach to Receptors JAK Binds to Activated Receptors JAK then Signals DNA Cell produces mediators of inflammation

28. Modulates signaling for several types of interleukins, Janus Kinases (JAK-1,2,3) mediate cellular response to many cytokines. JAK proteins are a MAJOR mechanism of directing the changes in cellular function to cause inflammation. Oral medication, Daily For Crohn’s Disease and Ulcerative Colitis Developed By Pfizer Pharmacudicals Tofacitinib (CP-690550) Dampening Cytokine Response: JAK-Inhibitors

29. Tofacitinib (CP-690550) Phase II Tofacitinib Study in Active Ulcerative Colitis Dampening Cytokine Response: JAK-Inhibitors

30. Tofacitinib (CP-690550) Phase II Tofacitinib Study in Active Crohn’s Disease Dampening Cytokine Response: JAK-Inhibitors

31. Other sites open for the Crohn’s disease patients NOW Coming very soon to the University of Michigan for UC patients To participate, you must: Have active UC symptoms Must have failed one medication in the past Must be off anti-TNF medications, but may continue on asacol, azathioprine and prednisone Not have an ostomy Tofacitinib (CP-690550) Dampening Cytokine Response: JAK-Inhibitors

32. Exciting Agents Early in Development

34. Why Participate in Clinical Trials? Obtain expert medical care at leading health care facilities with very close monitoring Gain access to start-of-the-art treatments Contributing to new medical knowledge Become a part of improving the future of IBD

35. Common Patient Concerns Do I have to be in a clinical trial?

36. Common Patient Concerns

37. Your Safety is Our First Concern Study Patients are very closely monitored by a large team Study Coordinators Principal Investigators Institutional Review Board Data Safety Monitoring Boards FDA

38. Common Patient Concerns Other Concerns Feeling like “an experiment” Involvement of placebo (or sham therapy) More time consuming that non-study treatment Costliness? Do I have to stay in once I sign up?

39. What to Consider Before Participating Read over the informed consent document before signing and ASK QUESTIONS! – What is the purpose of this study? – Has this medication been tested before? – What kind of tests are involved? – What kind of side effects should I watch for? – How will this trial affect my daily life? Consider and discuss with your doctor, family, friends the risks, benefits, and commitment that needs to be made in order to participate Discuss with your doctor to make sure you may be eligible

40. How to Get Involved Read more information online and find participating centers at www.clinicaltrials.gov www.clinicaltrials.gov For studies open at the University of Michigan visit www.UMClinicalStudies.orgwww.UMClinicalStudies.org Ask your gastroenterologist at your next appointment about opportunities to participate in research

41. What is a Clinical Trial? Voluntary research studies in humans How we test efficacy and safety of new medications – All medications must complete several phases of clinical trials to be approved for treatment to become widely available to all patients Inclusion/Exclusion Criteria and screening process

42. What is a Clinical Trial? Voluntary research studies in humans How we test efficacy and safety of new medications – All medications must complete several phases of clinical trials to be approved for treatment to become widely available to all patients Inclusion/Exclusion Criteria and screening process

43. I MMUNE S URVEILLANCE OF THE I NTESTINE