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Future Therapies for the Inflammatory Bowel Diseases Ryan W. Stidham, MD Crohn’s and Colitis Program University of Michigan Health System Ann Arbor, Michigan We’ve come a long way… 1700-1900 1930 1940 1950 1960 1970 Prednisone IBD is recognized Crohn’s and UC are described 1980 1990 2000 2010 Azathioprine Methotrexate Mesalamine Remicade Humira Cimzia Tysabri 2020 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 Future Therapies in IBD There is a great need for new 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. IBD Immunology 101 IBD Immunology 101 Mucosa Submucosa Blood Vessels IBD Immunology 101 Mucosa Submucosa Blood Vessels IBD Immunology 101 Mucosa Submucosa Blood Vessels Targets for Therapy • 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 Blockade of Cell Adhesion and Homing Cytokines CCL-25 Ligand CCR9 Receptor Blockade of Cell Adhesion and Homing Cytokines 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 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-Homing Signals: Anti-CCR9 Compound CCX282-B PROTECT-1 STUDY Symptom Response Achieved at Week 12 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 Blockade of Adhesion Molecules: Vedolizumab Block WBC Binding to Integrins Anti-Integrin Coating Blockade of Adhesion Molecules: Vedolizumab Leading Anti-Integrins In Development • Vedolizumab • rhuMAb Beta7 • PF-00547659 (MAdCAM-1 Antagonist) Blockade of Adhesion Molecules: Vedolizumab 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 Blockade of Adhesion Molecules: Vedolizumab Vedolizumab Initial Ulcerative Colitis Study Week 6 Endpoint Initial Crohn’s Disease Study Week 8 Endpoint Blockade of Adhesion Molecules: Vedolizumab 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: rhuMAb Beta7 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: rhuMAb Beta7 rhuMAb Beta7 Cheroutre and Madakamutil, Nat Rev Immunol 2004 Blockade of Adhesion Molecules: rhuMAb 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 Cell-Activating Signals IL-12 Receptor IL-12/23 Ligand T-cell Interferon Dendritic cell T-cells ACTIVATED IL-17 Blockade of Cell-Activating Signals: ustekinumab 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-Regulating Signals: IL-12/23 Inhibitors CERTFI STUDY – Ustekinumab in Crohn’s Disease Blockade of Cell-Activating Signals: ustekinumab 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 Cellular Inflammation Controls Interleukins Interleukins Attach to Receptors JAK Binds to Activated Receptors JAK then Signals DNA Cell produces mediators of inflammation T-cell Dampening Cytokine Response: JAK-Inhibitors Tofacitinib (CP-690550) • 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 Dampening Cytokine Response: JAK-Inhibitors Tofacitinib (CP-690550) Phase II Tofacitinib Study in Active Ulcerative Colitis Dampening Cytokine Response: JAK-Inhibitors Tofacitinib (CP-690550) Phase II Tofacitinib Study in Active Crohn’s Disease Dampening Cytokine Response: JAK-Inhibitors Tofacitinib (CP-690550) • 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 Exciting Agents Early in Development Exciting Agents Early in Development 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 Common Patient Concerns Do I have to be in a clinical trial? Common Patient Concerns Common Patient Concerns 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 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? 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 How to Get Involved Read more information online and find participating centers at www.clinicaltrials.gov For studies open at the University of Michigan visit www.UMClinicalStudies.org Ask your gastroenterologist at your next appointment about opportunities to participate in research 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 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 IMMUNE SURVEILLANCE OF THE INTESTINE