Transcript CCFA research priorities and Exchange

CCFA RESEARCH PROGRAMS,
PRIORITIES and IBD Exchange
Balfour Sartor, MD
Chief Medical Advisor
Marjorie Merrick
Vice President, Research and Scientific Programs
CCFA’s Mission and Vision Statements
Mission: To cure Crohn's disease and ulcerative
colitis, and to improve the quality of life of children
and adults affected by these diseases.
Vision: A future free from Crohn’s disease and
ulcerative colitis.
CCFA Has Invested $200 Million In Research
Since 1967. How Have Things Changed?
1967:
• Very little research was conducted in the field of
IBD.
• Few therapies were available (primarily prednisone
and sulfasalazine, segmental resection CD,
ileostomy after total proctocolectomy UC).
• No genes had been identified
• For many IBD patients, a stay in the hospital might
run into weeks or even months.
How Have Things Changed?
• CCFA, NIH, medical centers and pharmaceutical companies
around the world are actively conducting basic, clinical and
translational research in IBD.
• CCFA has supported over 1400 research grants and
currently funds approximately 200 ongoing and new grants
annually.
• There are multiple drugs now available, including the
biologics, and many experimental therapies in the pipeline.
• Over 163 genes have been associated with IBD.
• The average hospital stay for people with Crohn’s or colitis
has been reduced to approximately 9 days.
Unmet Clinical Needs in IBD
(Sartor perspective, not CCFA)
• Accurate prediction of disease course and
response to treatment in an individual patient
• Induction and maintenance of remission in
patients unresponsive to or intolerant of antiTNF mAb
• Induction of remission of mild to moderate ileal
Crohn’s disease without steroids or biologic
therapies
Unmet Clinical Needs in IBD (II)
• Sustained clinical remission in majority of patients that
require steroids or anti-TNFs for induction
• Optimal prevention of relapse in postoperative CD and
pouchitis in UC
• Identify clinically relevant subsets of patients with
predictable clinical responses- individualized therapy.
Mechanistic approach
• Cure of CD and UC and prevention of onset of IBD in
susceptible individuals
CCFA Research
• Approximately 200 active grants per year
(ongoing and new awards).
• Average of $16 million per year over past 4 yrs
• $21 million in 2014
CCFA Research Programs
Investigator- Initiated Research
Grants
- Senior Awards
- Career Development Awards
- Research Fellowships
Research Resources
- PROKIIDS network
- Clinical Research Alliance
- CCFA DNA Bank
- CCFA Microbiome Bioinformatics
- CCFA Data Management Center
Research Initiatives
- Microbiome Initiative
- Genetics Initiative
- RISK Stratification study
- OSCCAR
- CCFA Partners
IBD Exchange
Research Pilots
- Biomarkers
- Perioperative infections
- Mucosal healing UC
- PROKIIDS
- QI
CCFA Research Strategies
1. Fund the best peer-reviewed research available.
2. Train the next generation of IBD investigators
3. Help perpetuate the rapid progress in basic and
clinical IBD research of the last decade by
providing seed money to enable investigators to
generate data to become competitive at NIH
4. Facilitate early introduction of novel technology
that has the potential to lead to paradigm shifting
breakthroughs into IBD research
CCFA Research Strategies (II)
5. Identify host and microbial pathways that
provide novel therapeutic approaches, then
partner with pharmaceutical companies to develop
new drugs
6. Frequently update and prioritize research goals
(Challenges in IBD), then widely publicize these
research priorities
Challenges 2013
CCFA’s Strategic Plan for Research
Chairs: Ted Denson, Dermot McGovern
Genetics:
Microbiome:
Adaptive Immunity:
Innate Immunity:
Epithelial Cell Biology:
IBD Diagnosis:
Optimizing Therapy:
Epidemiology/
Environmental Factors:
Dermot McGovern, Subra Kugathasan
Balfour Sartor, Gary Wu, Vince Young
Theresa Pizarro, Ed deZoeten
Thad Stappenbeck, Scott Plevy, Clara Abraham
Asma Nusrat, Declan McCole, Christian Jobin,
Charles Parkos
Ted Denson, Corey Siegel, Peter Higgins
Hans Herfarth, Jeffrey Hyams
Ed Loftus, Mike Kappelman, Millie Long
Challenges 2013
1. Define clinically relevant subsets of patients with
IBD using genetic, immunologic, microbial, tissue
expression, and clinical profiles (to include drug
levels) that will predict aggressiveness of disease,
complications and response to treatment.
2. Understand how environmental factors enhance
risk of IBD through effects on microbial, epigenetic,
immunologic, mucosal barrier influences – with an
early focus on diet.
Challenges 2013 (continued)
3. Further understand reciprocal interactions (crosstalk) between genes, microbiota, epithelial cells,
innate and adaptive immune responses that
determine pathways mediating mucosal
homeostasis versus inflammation.
4. Determine which environmental triggers initiate,
perpetuate, and/or reactivate disease.
5. Determine optimal treatment strategies through
comparative effectiveness studies.
Resources Identified as Essential
1. Centralized and distributable infrastructure for
biobanking, data warehouse, and tissue/cell/microbial
repositories for integrated human investigation.
2. Prospective cohort studies of pediatric and adult IBD
patients with serial biospecimens collected throughout
the course of their diseases.
3. Infrastructure to recruit and follow patients from
childhood to adult life.
4. Access to data and biospecimens collected prior to and
following treatment with established and novel
therapeutics.
Resources Identified as Essential
5. Improved tools for measuring disease activity in IBD.
6. More specific in vivo tools including humanized mice
and lineage specific models for mechanistic
research.
7. Availability of new methodology for improved cell
lines and freshly isolated and viable mucosal cells.
8. Implementation of a series of workshops to improve
IBD research methodology and promote integrative
multidisciplinary approaches and resources.
Research Initiatives
Designed to fill important unmet needs in IBD research
based on priorities described in Challenges in IBD
Research:
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PROKIIDS IBD Research Network- RISK, PROTECT
CCFA Partners
Clinical Research Alliance
Genetics Initiative
Microbiome Initiative
IBD Exchange
Pediatric Risk Stratification Project
• 26 centers have enrolled ~1100 newly diagnosed pediatric
patients with Crohn’s disease (1754 overall pts: 70% Crohn’s
disease, 15% UC, 5% indeterminant colitis, 10% controls
• Goal: identify serum biomarkers, fecal bacteria, genes,
immunologic and clinical patterns that predict at the time of
diagnosis which child will develop severe, complicated vs. mild
Crohn’s disease and which individual will respond to each
medication
• Resources: Ileal and rectal biopsies on majority of pts
(Illumina deep sequencing 16srRNA), fecal samples, tissue
mRNA profiling (RNA seq), all pts genotyped (Immunochip),
serology, prospective serial clinical phenotyping and
therapeutic responses
Microbiome Consortium (2010- 2013)
• 7 multi-center, multi-disciplinary consortia studying large
cohorts of Crohn’s disease, UC, normal and non-IBD subjects
• Explore mechanisms by which genetic influences, AIEC, Paneth
cells influence intestinal bacterial composition and function,
IEC/ microbial interactions, viral triggers of disease onset/ flares
• Perform mechanistic studies of CD gene regulation of gut
bacteria in genetically engineered gnotobiotic mice
Renewal (2014-16).
Prospective cohorts ileal CD & UC serially sampled (bxs, stool
metabolomics), functional verification of candidate pathways to
identify targets, high throughput screens for candidate drugs
Microbiome: Anticipated Outcomes
• Identify key microbial components that initiate and perpetuate
disease
• Find biomarkers that can predict disease course
• Select subsets of patients that are likely (or unlikely) to
respond to a particular treatment
• Develop novel ways to manipulate the microbiota to both
treat and prevent disease (Better antibiotics, probiotics,
diets, fecal or microbial transplants)
• Develop intervention strategies to prevent disease in high risk
individuals (perhaps identified by their genetic and/ or
microbial profiles)
IBD Exchange Mission & Philosophy
• Mission - create an interconnected collection of patient
information, biospecimens and knowledge to advance our
understanding of the causes and lead to the discovery of a
cure for IBD.
• Philosophy - the community who takes advantage of the
resources will also contribute to building the resources by
depositing their data, discoveries and newly created
resources back into IBD EXCHANGE so that others can
benefit from the new knowledge that has been developed.
IBD Exchange Goals
1. Provide investigators with access to the resources needed
to support their research.
2. Facilitate sharing of knowledge more rapidly than relying on
publication in peer-reviewed journals.
3. Promote collaboration among investigators and sharing of
clinical data and biospecimens.
4. Serve as an educational venue for investigators and
patients with IBD.
IBD Exchange Strategies
1. Collect detailed clinical information on patients with IBD
including treatment, exposures, complications, outcomes
from prospectively followed cohorts of adults and children
with IBD,
2. Collect patient reported outcomes from prospectively
followed cohorts of patients with IBD
3. Create a biosample repository containing blood, feces,
urine, and tissue samples,
4. Create a knowledge environment to include a data
warehouse, specialty research cores, analytic tools,
educational tools for scientists, and educational tools for
patients
5. Promote novel research through a peer reviewed research
grants program.
Prospective Cohorts
Biobanks
Data Repository
Analytic Tools
Specialty Research
Cores
Research Grants
Year 4-5Exchange
Study
“y”
“PROTECT”
SHARE /
VEO /
Other HT
Projects
“RISK”
“Microbiome”
Partners 2
Other
CCFA
studies
Exchange
cohort
“Genetics
Initiative”
OSCCAR
Substudy
“x”
Spectrum of Initial IBDEX Cohorts
Patient Reported
Outcomes
Clinical Activity
Indices
Biosamples
Newly diagnosed
pediatric CD
Partners 2
RISK & VEO
RISK & VEO
Newly diagnosed
pediatric UC
Partners 2
Protect & VEO
Protect & VEO
Established adult
IBD
Partners 2/ PCORI
Exchange Cohort &
SHARE
Exchange Cohort,
SHARE, Microbiome
Newly diagnosed
adult IBD
OSCCAR, Partners 2 Exchange Cohort,
PCORI
OSCCAR & SHARE
Exchange Cohort,
OSCCAR & SHARE
Community based
International
Referral center based
Data Warehouse and Learning
Environment
Ancillary study
investigators
use data and
samples
IBDEX
cohorts
generate data
and samples
Investigators
funded by
CCFA and
Helmsley
generate data
and samples
IBD EX
Knowledge
Center
All newly generated data remains
linked to the samples that were
used to generate the data
Ancillary study
investigators
generate new
data