Ryan W Stidham MD Crohns and Colitis Program University of Michigan Health System Ann Arbor Michigan Weve come a long way Crohns and UC a re described IBD is recognized Prednisone ID: 150474
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Slide1
Future Therapies for the Inflammatory Bowel Diseases
Ryan W. Stidham, MD
Crohn’s and Colitis Program
University of Michigan Health System
Ann Arbor, MichiganSlide2
We’ve come a long way…
Crohn’s and UC
a
re described
IBD is recognized
Prednisone
Mesalamine
Remicade
Azathioprine
Methotrexate
Humira
Cimzia
Tysabri
1700-1900
1930
1940
1950
1960
1970
1980
1990
2000
2010
2020Slide3
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 MedicationsSlide4
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 IBDSlide5
IBD Immunology 101Slide6
Mucosa
Submucosa
Blood Vessels
IBD Immunology 101Slide7
Mucosa
Submucosa
Blood Vessels
IBD Immunology 101Slide8
IBD Immunology 101
Mucosa
Submucosa
Blood VesselsSlide9
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 TherapySlide10
CCL-25 Ligand
CCR9 Receptor
Blockade of Cell Adhesion and Homing Cytokines Slide11
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 Slide12
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 Slide13
Blockade of Cell-Homing Signals: Anti-CCR9
Compound
CCX282-B
Symptom Response Achieved at
Week 12
PROTECT-1 STUDYSlide14
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
a
ctive Crohn’s symptoms
Have failed at least one medication in the past
Not have Cancer, Hepatitis B, or HIV
N
ot have C. diff infection
B
e off anti-TNFs for a few weeks
Not have an ostomySlide15
Block WBC Binding to
Integrins
Anti-Integrin Coating
Blockade of Adhesion Molecules:
VedolizumabSlide16
Vedolizumab
rhuMAb
Beta7
PF-00547659 (MAdCAM-1 Antagonist)
Leading Anti-
Integrins In Development
Blockade of Adhesion Molecules:
VedolizumabSlide17
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 PharmaceuticalsSlide18
Blockade of Adhesion Molecules:
Vedolizumab
Initial Ulcerative Colitis Study
Week 6 Endpoint
Initial Crohn’s Disease Study
Week 8 Endpoint
VedolizumabSlide19
Vedolizumab
GEMINI Study
Clinicaltrials.gov
ID: NCT01224171
Enrolling at the University of Michigan
To participate, you must:H
ave active Crohn’s symptomsHave 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:
VedolizumabSlide20
rhuMAb
Beta7
rhuMAb
Beta7
– antibody binding
to alpha4beta7 and alphaEbeta7
Prevents White Blood Cells (WBC) entry into the intestinesAlso 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
Beta7Slide21
rhuMAb
Beta7
Cheroutre
and
Madakamutil
, Nat Rev Immunol 2004
Blockade of Adhesion Molecules:
rhuMAb
Beta7Slide22
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:
rhuMAbSlide23
IL-12/23
Ligand
IL-12
Receptor
Blockade of Cell-Activating Signals
T-cell
T-cells
ACTIVATED
Dendritic cell
IL-17
InterferonSlide24
U
stekinumab
U
stekinumab
–
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 Slide25
Blockade of Cell-Regulating Signals:
IL-12/23 Inhibitors
CERTFI STUDY –
Ustekinumab
in Crohn’s DiseaseSlide26
ustekinumab
UNITI
Study
Clinicaltrials.gov
ID: NCT01369342
SOON to OPEN Enrollment
at the University of MichiganTo participate, you must:
Have active Crohn’s disease symptomsBe off anti-TNF medication, but can stay on steroids and azathioprine
Not have infections, cancer, or an
ostomy
Blockade of Cell-Activating Signals: ustekinumab
Slide27
IL-12/23
Ligand
IL-12
Receptor
Blockade of Cellular Inflammation Controls
T-cell
JAK
Interleukins
Interleukins Attach to Receptors
JAK Binds to Activated Receptors
JAK then Signals DNA
Cell produces
mediators
of
inflammationSlide28
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-InhibitorsSlide29
Tofacitinib
(CP-690550)
Phase II
Tofacitinib
Study in Active Ulcerative Colitis
Dampening Cytokine Response: JAK-InhibitorsSlide30
Tofacitinib
(CP-690550)
Phase II
Tofacitinib
Study in Active Crohn’s Disease
Dampening Cytokine Response: JAK-InhibitorsSlide31
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
symptomsMust have failed one medication in the past
Must be off anti-TNF medications, but may continue on asacol, azathioprine and
prednisoneNot have an ostomy
Tofacitinib
(CP-690550)
Dampening Cytokine Response: JAK-InhibitorsSlide32
Exciting Agents Early in DevelopmentSlide33
Exciting Agents Early in DevelopmentSlide34
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
Slide35
Common Patient Concerns
Do I have to be in a
clinical trial?Slide36
Common Patient ConcernsSlide37
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 BoardData Safety Monitoring BoardsFDASlide38
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?Slide39
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 participateDiscuss with your doctor to make sure you may be eligibleSlide40
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 researchSlide41
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 processSlide42
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 processSlide43
Immune Surveillance of the Intestine