1. CCFA RESEARCH PROGRAMS, PRIORITIES and IBD Exchange
Balfour Sartor, MD
Chief Medical Advisor
Marjorie Merrick
Vice President, Research and Scientific Programs

2. 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.

3. Very little research was conducted in the field of IBD.
CCFA Has Invested $200 Million In Research Since 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.
Self-explanatory

4. 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.
Self-explanatory

5. 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 anti- TNF mAb
Induction of remission of mild to moderate ileal Crohn’s disease without steroids or biologic therapies

6. 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

7. 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 offers 2 levels of investigator-driven grants. Applications are accepted in January and July of each year and go through the rigorous peer-review process described in the previous slide.

8. CCFA Research Programs
Investigator- Initiated Research Grants
Senior Awards
Career Development Awards
Research Fellowships
Research Initiatives
Microbiome Initiative
Genetics Initiative
RISK Stratification study
OSCCAR
CCFA Partners IBD Exchange
Research Resources
PROKIIDS network
Clinical Research Alliance
CCFA DNA Bank
CCFA Microbiome Bioinformatics
CCFA Data Management Center
Research Pilots
Biomarkers
Perioperative infections
Mucosal healing UC
PROKIIDS QI

9. CCFA Research Strategies
Fund the best peer-reviewed research available.
Train the next generation of IBD investigators
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
Facilitate early introduction of novel technology that has the potential to lead to paradigm shifting breakthroughs into IBD research
CCFA uses these strategies to accomplish the goals of “predict” and “cure”.
We fund the best peer-reviewed research we can find, no matter where it is happening. Senior Research Awards have been funded in 15 countries around the globe. (Canada, England, Ireland, Switzerland, France, Germany, Sweden, Italy, Netherlands, Belgium, South Africa, Israel, Japan, Australia, New Zealand)
Our training award programs (Career Development and Research Fellowship Awards) support outstanding young investigators interested in pursuing a career in IBD research.
We provide seed money to enable investigators to generate data to become competitive for NIH grants.
We identify and support emerging areas of research and novel technology that has the potential to lead to new breakthroughs.

10. 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
CCFA uses these strategies to accomplish the goals of “predict” and “cure”.
We fund the best peer-reviewed research we can find, no matter where it is happening. Senior Research Awards have been funded in 15 countries around the globe. (Canada, England, Ireland, Switzerland, France, Germany, Sweden, Italy, Netherlands, Belgium, South Africa, Israel, Japan, Australia, New Zealand)
Our training award programs (Career Development and Research Fellowship Awards) support outstanding young investigators interested in pursuing a career in IBD research.
We provide seed money to enable investigators to generate data to become competitive for NIH grants.
We identify and support emerging areas of research and novel technology that has the potential to lead to new breakthroughs.

11. Challenges 2013 CCFA’s Strategic Plan for Research
Chairs: Ted Denson, Dermot McGovern
Genetics: Dermot McGovern, Subra Kugathasan
Microbiome: Balfour Sartor, Gary Wu, Vince Young
Adaptive Immunity: Theresa Pizarro, Ed deZoeten
Innate Immunity: Thad Stappenbeck, Scott Plevy, Clara Abraham
Epithelial Cell Biology: Asma Nusrat, Declan McCole, Christian Jobin, Charles Parkos
IBD Diagnosis: Ted Denson, Corey Siegel, Peter Higgins
Optimizing Therapy: Hans Herfarth, Jeffrey Hyams
Epidemiology/
Environmental Factors: Ed Loftus, Mike Kappelman, Millie Long
Since 1989, CCFA has brought together top IBD thought leaders to identify the most pressing unmet needs and unanswered questions in a variety of scientific areas. The resulting consensus paper, CHALLENGES IN IBD RESEARCH, outlines CCFA’s scientific strategic plan. The document is updated every 3-5 years, the most recent update was published in May 2013 in the IBD journal and posted CCFA’s website. Every project CCFA supports must address one or more of the priorities outlined in the document. The topics and workgroup chairs are listed on this slide.

12. Challenges 2013
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.
Understand how environmental factors enhance risk of IBD through effects on microbial, epigenetic, immunologic, mucosal barrier influences – with an early focus on diet.
The priorities listed in CHALLENGES 2013 are listed on this slide.

13. Challenges 2013 (continued)
Further understand reciprocal interactions (cross-talk) between genes, microbiota, epithelial cells, innate and adaptive immune responses that determine pathways mediating mucosal homeostasis versus inflammation.
Determine which environmental triggers initiate, perpetuate, and/or reactivate disease.
Determine optimal treatment strategies through comparative effectiveness studies.
Continued from previous slide.

14. Resources Identified as Essential
Centralized and distributable infrastructure for biobanking, data warehouse, and tissue/cell/microbial repositories for integrated human investigation.
Prospective cohort studies of pediatric and adult IBD patients with serial biospecimens collected throughout the course of their diseases.
Infrastructure to recruit and follow patients from childhood to adult life.
Access to data and biospecimens collected prior to and following treatment with established and novel therapeutics.
Essential resources are listed on this slide.
Infrastructure includes necessary technology, equipment, personnel (both scientific and administrative).
Ability to collect, analyze and distribute data and specimens is key component.

15. Resources Identified as Essential
Improved tools for measuring disease activity in IBD.
More specific in vivo tools including humanized mice and lineage specific models for mechanistic research.
Availability of new methodology for improved cell lines and freshly isolated and viable mucosal cells.
Implementation of a series of workshops to improve IBD research methodology and promote integrative multidisciplinary approaches and resources.
Essential resources continued.

16. Research Initiatives
Designed to fill important unmet needs in IBD research based on priorities described in Challenges in IBD Research:
PROKIIDS IBD Research Network- RISK, PROTECT
CCFA Partners
Clinical Research Alliance
Genetics Initiative
Microbiome Initiative
IBD Exchange
PRO-KIIDS IBD RESEARCH NETWORK
Francisco Sylvester and Mel Heyman – Co-chairs
Two ongoing studies:
RISK (Subra Kugathasan – PI) – CCFA funded study in newly diagnosed Crohn’s patients; 5 abstracts accepted to DDW; 4 manuscripts in progress; 17 ancillary studies approved
PROTECT (Ted Denson – PI ) NIH funded study in UC
CCFA Partners – Internet based registry of patient reported outcomes started in 2011
Bob Sandler – PI
Over 12,000 patients enrolled
17 abstracts, 4 publications, 4 abstracts at DDW
Clinical Research Alliance
Hans Herfarth and Peter Higgins – Co-chairs
Ongoing studies:
MERIT-UC (Hans Herfarth – PI)
PIANO (Uma Mahadevan – PI)
PUCCINI (Bruce Sands – PI)
Mucosal Healing in UC Pilot grant (Mark Osterman – PI)
Genetics
Ramnik Xavier and Skip Virgin – Consortium Co-chairs (in planning phase)
Microbiome
Phase 1-3: Jeff Gordon, PI – more than 50 publications to date
Jon Braun – Phase 4 Consortium chair
33 peer-reviewed publications, 15 submitted manuscripts, 9+ abstracts
OSCCAR (Ocean State Crohn’s and Colitis Area Registry)
Bruce Sands – PI
430 newly diagnosed patients enrolled
3 publications, 3 manuscripts submitted, 2 in progress; 14 abstracts, 2 oral presentations

17. 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
Building a multi-center research consortium is especially important if we are to help the approximately 140,000 children and adolescents under 18 to overcome Crohn’s and colitis. We already know that treating these youngsters is hampered by a significant lack of scientific data on the use of the various therapies in young people because drug trials are not consistently performed in adolescents, and rarely with children under the age of 14.
Like the Clinical Alliance, a multi-center consortia of leading pediatric researchers is urgently needed to enable researchers to address critical scientific knowledge gaps. CCFA’s Pediatric Research Network is starting with 7 centers in Hartford, Cincinnati, Atlanta, Philadelphia, Los Angeles, Milwaukee and Long Island, who have agreed to share data through a common database. These centers are collecting DNA, stool and serum samples from newly diagnosed patients under the age of 18 and will track these patients over time. For the initial study, the researchers hope to identify biomarkers that will help doctors to predict at the time of diagnosis which child will develop severe Crohn’s disease so that these children can be treated aggressively very early in the course of their disease. Early and aggressive treatment for children at high risk of developing severe disease may minimize symptoms and prevent future complications, as well as spare those who are likely to develop only mild to moderate disease to avoid the more powerful treatments that they really don’t need.

18. 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 ( ).
Prospective cohorts ileal CD & UC serially sampled (bxs, stool metabolomics), functional verification of candidate pathways to identify targets, high throughput screens for candidate drugs

19. 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)

20. 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.

21. IBD Exchange Goals
Provide investigators with access to the resources needed to support their research.
Facilitate sharing of knowledge more rapidly than relying on publication in peer-reviewed journals.
Promote collaboration among investigators and sharing of clinical data and biospecimens.
Serve as an educational venue for investigators and patients with IBD.

22. IBD Exchange Strategies
Collect detailed clinical information on patients with IBD including treatment, exposures, complications, outcomes from prospectively followed cohorts of adults and children with IBD,
Collect patient reported outcomes from prospectively followed cohorts of patients with IBD
Create a biosample repository containing blood, feces, urine, and tissue samples,
Create a knowledge environment to include a data warehouse, specialty research cores, analytic tools, educational tools for scientists, and educational tools for patients
Promote novel research through a peer reviewed research grants program.

23. Prospective Cohorts Biobanks Specialty Research Cores
Data Repository
Analytic Tools
Specialty Research Cores
Research Grants

24. SHARE / VEO / Other HT Projects
Year 4-5Exchange
Study “y”
Partners 2
“PROTECT”
SHARE / VEO / Other HT Projects
“RISK”
Exchange cohort
“Microbiome”
Substudy “x”
Other CCFA studies
“Genetics
Initiative”
OSCCAR

25. Spectrum of Initial IBDEX Cohorts
Patient Reported Outcomes
Clinical Activity Indices
Biosamples
Newly diagnosed pediatric CD
Partners 2
RISK & VEO
Newly diagnosed pediatric UC
Protect & VEO
Established adult IBD
Partners 2/ PCORI
Exchange Cohort & SHARE
Exchange Cohort, SHARE, Microbiome
Newly diagnosed adult IBD
OSCCAR, Partners 2
PCORI
Exchange Cohort, OSCCAR & SHARE
Community based International Referral center based

26. Data Warehouse and Learning Environment
Ancillary study investigators use data and samples
IBDEX cohorts generate data and samples
IBD EX Knowledge Center
Investigators funded by CCFA and Helmsley generate data and samples
Ancillary study investigators generate new data
All newly generated data remains linked to the samples that were used to generate the data