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