BREAKTHROUGHS in IBD
          Research:
               Helping You Today

              Stephan R. Targan, MD
          D...
Today s
              Today’s Goals
• Highlight the Past history of IBD research
• Understand Today’s breakthroughs in IBD...
Goals of Research

• CURE!
  – Cause & prevention
• Develop new & improved treatments
• Increase quality of life
         ...
IBD Population
  1956–1970
  19 6 19 0
IBD Population
 1970–Present
 19 0 P
Milestones in Research
Then & Now
Then: 1967
Cancer            No surveillance


Treatment
T t     t         Diet, bowel rest, steroids, sulfasal...
Then & Now
Now: 2010
Cancer            Routine, periodic colonoscopy

                  Steroids, 5-aminosalicylic acid (5...
Then & Now
Now: 2010
Research    Each year, CC f
                       CCFA funds more than 200 current and ongoing
     ...
Today s
             Today’s Goals
• Highlight the Past history of IBD research
• Understand Today’s breakthroughs in rese...
Important Breakthroughs
• Unraveling IBD-related genetics
             IBD related
• Importance of the IL23/17 pathway in
...
KIF21B

                  IBD Related Genetics 2010                                      IL18RAP
                         ...
Unraveling Genetics



   • I
     Impact
          t
     – Leap forward in understanding IBD
     – Rapid discovery of n...
IL23/17 Pathway Breakthrough
              y           g

                                                                ...
IL23/17 Pathway Breakthrough

     • Impact
       – 10–15 clinical trials focus on this pathway
       – Treatment can be...
Understanding the Relationship
    of Bacteria & G
      fB     i    Genetics
                        i
• Genetics impact ...
Breakthroughs in Current
    Areas of Study
Current Areas of Study
• Causation Factors
  –   Genetics
  –   Immunologygy
  –   Microbiology
  –   Environment
• Diagno...
Causat o acto s
 Causation Factors

              Genetics




              IBD
Environment
                         Immu...
Genetics
• Current research:
  – R l of genes i IBD
    Roles f      in
     • Mapping the IBD
       genome
     • Diseas...
Genetics

Dark ages → Genetic revolution              Genetic explosion
1940/50 – Familial association              2001 –...
Immunology:
        Study of the Immune System

• Immunological biomarkers:
  markers in the blood, stool
                ...
Immunology
• Antibody biomarkers
  – IBD patients have antibodies to normal bacteria in the
    body
  – Associated with t...
Microbiology:
      Study of Microbial Community
              (Microbiome)
              (Parasites, Viruses & Bacteria)
...
Microbiology:
                             Probiotics
•   Escherichia coli
     – I d i and maintaining remission as mesal...
Microbiology:
                      Bacteria
• Mycobacterium avium paratuberculosis (MAP)
  – Found in milk
  – Does not a...
Environmental Triggers
 Infections                                Antibiotics




NSAIDs
                                 ...
Diagnosis
          1967                      2010
• Barium enema          •   Colonoscopy
• Rigid sigmoidoscopy   •   Cap...
Treatments
Treatments
• Biologic therapies target specific proteins and
  enzymes in the immune system relating to the
  body’s infla...
Pediatrics
• CCFA Pediatric Network
• Preventing growth issues
   – Immunomodulatory
     treatments act as surgery
     s...
What does this all mean to me?
Today s
              Today’s Goals
• Highlight the Past history of IBD research
• Understand Today’s breakthroughs in res...
Problem 2010
 Too Many Targets
Not enough Patients
Clinical Trials
• Clinical trials study: treatment, prevention,
  diagnostics, screening and quality of life
• Clinical tr...
Clinical Trials:
               Risks & Benefits
       Risks                      Benefits
• Test treatments may not   • ...
Clinical Trials

• Talk to your doctor about clinical trials
  as a treatment option
• Fi d a clinical t i l
  Find     li...
Why Do We Need More
              Research?
              R      h?
Although we have made very significant advances…

• Th...
Question and Answer S
Q   ti     dA       Session
                        i
CCFA Teleconference
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CCFA Teleconference

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Brief synopsis of IBD Research and current Breakthroughs

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CCFA Teleconference

  1. 1. BREAKTHROUGHS in IBD Research: Helping You Today Stephan R. Targan, MD Director, Division of Gastroenterology Inflammatory Bowel and Immunobiology Research Institute Cedars Sinai Cedars-Sinai Medical Center Professor of Medicine University of California, Los Angeles David Geffen School of Medicine Los Angeles, California
  2. 2. Today s Today’s Goals • Highlight the Past history of IBD research • Understand Today’s breakthroughs in IBD research • Discuss the Future of IBD research – next steps
  3. 3. Goals of Research • CURE! – Cause & prevention • Develop new & improved treatments • Increase quality of life q y
  4. 4. IBD Population 1956–1970 19 6 19 0
  5. 5. IBD Population 1970–Present 19 0 P
  6. 6. Milestones in Research
  7. 7. Then & Now Then: 1967 Cancer No surveillance Treatment T t t Diet, bowel rest, steroids, sulfasalazine, antibiotics Di t b l t t id lf l i tibi ti Surgery Ileostomy For many patients, a stay in the hospital might run into Hospitalization weeks or even months Research Minimal research was conducted in IBD
  8. 8. Then & Now Now: 2010 Cancer Routine, periodic colonoscopy Steroids, 5-aminosalicylic acid (5-ASA), Treatment immunomodulators, immunomodulators biologic therapies, antibiotics, total therapies antibiotics parenteral nutrition (TPN), enteral feeding Pipeline 80+ treatments are currently in clinical trials Surgery J-pouch, laparoscopic resection, stricturoplasty Hospitalization Average reduced to approximately 9 days, if at all
  9. 9. Then & Now Now: 2010 Research Each year, CC f CCFA funds more than 200 current and ongoing research grants Since 1967, the CCFA has supported the training of 218 Research Fellows and 122 Career Development Awards CCFA 1989 Challenges in IBD Agenda transformed direction and pace of IBD research around the world Clinical Research Alliance created Pediatric Research Network created DNA Bank created CCFA funded over $150 million worth of research and been some part of each significant breakthrough, either in training the researcher, or at some p g point funding the g research study
  10. 10. Today s Today’s Goals • Highlight the Past history of IBD research • Understand Today’s breakthroughs in research • Discuss the Future of IBD research next steps research–next
  11. 11. Important Breakthroughs • Unraveling IBD-related genetics IBD related • Importance of the IL23/17 pathway in Crohn s Crohn’s disease & ulcerative colitis • Understanding the relationship of genetics and bacteria in a host
  12. 12. KIF21B IBD Related Genetics 2010 IL18RAP IL12B UC a CD 1q24 LYRM4 CDKAL1 and 1q32 1 32 BTNL2 6q21 SLC26A3 HLA-DRB1 7p12 HLA-DQA 8q24 JAK2 CCNY 10p11 STAT3 IL23R 13q14 PTPN22 19p13 ITLN2 1q24 21q21 GCKR ITLN1 PUS10 6q25 PTPN22 CD Specific 13q14 IL12B There is still a long way to go… CDKAL1 CCR6 SLC22A23 7p12 CCR6 8q24 11q13 NKX2-3 JAK2 LRRK2/MUC19 PTPN2 C11orf30 13q14 CCL2/CCL7 ZNF365 LRRK2/MUC19 ORMDL3 NOD2 IRGM ORMDL3 18q11 19p13 19 13 5q31 IL23R PTGER4 STAT3 ICOSLG MHC TNFSF15 ATG16L1 MST1 ICOSLG 21q21 Prior 2005 2006 2007 2008 2009 Anderson CA, et al. Gastroenterology. 2009;136:523.
  13. 13. Unraveling Genetics • I Impact t – Leap forward in understanding IBD – Rapid discovery of new therapeutic targets
  14. 14. IL23/17 Pathway Breakthrough y g IL17RA IL-23 p40 p19 IL12RB1 IL-23R IL17A TYK2 P JAK2 Cytoplasm NFκB and Nucleus MAPK pathway p y STAT3 STAT3 Activation of P P Anti-apoptotic Transcription proteins and pro-inflammatory cytokines Extracellular Space Activated T-cell
  15. 15. IL23/17 Pathway Breakthrough • Impact – 10–15 clinical trials focus on this pathway – Treatment can be targeted specifically to IL23/17 pathway – Different variants of pathway may be able to predict response or nonresponse
  16. 16. Understanding the Relationship of Bacteria & G fB i Genetics i • Genetics impact the types of bacteria present in a host intestine • Population of bacteria in the g impact the p gut p host metabolically • Impact – Specialized treatments and therapies to manipulate an individual’s vast array of bacteria
  17. 17. Breakthroughs in Current Areas of Study
  18. 18. Current Areas of Study • Causation Factors – Genetics – Immunologygy – Microbiology – Environment • Diagnosis • Treatment • Pediatrics
  19. 19. Causat o acto s Causation Factors Genetics IBD Environment Immune System y
  20. 20. Genetics • Current research: – R l of genes i IBD Roles f in • Mapping the IBD genome • Disease progression • Disease severity • Gene mutations Ge e utat o s • Reaction to medical treatments Related Early Onset Genes Genes
  21. 21. Genetics Dark ages → Genetic revolution Genetic explosion 1940/50 – Familial association 2001 – NOD 2 1994 – HLA association 2001 – IBD/5 (OCTN) 1996 – Familial pattern 2006 – MDR1, IL-23R 1996 – Chromosome 16 2007 – ATG16L1, NCF4, PHOX2B 1996 – Ch Chromosomes 3 7 12 3, 7,12 2008 – XBP1 2010 – 20 CD specific genes/ 13 UC specific genes
  22. 22. Immunology: Study of the Immune System • Immunological biomarkers: markers in the blood, stool , and other bio-matter – Identify subsets of IBD – Determine disease characteristics in children
  23. 23. Immunology • Antibody biomarkers – IBD patients have antibodies to normal bacteria in the body – Associated with types of inflammation response – DO NOT cause inflammation – May increase risk for: • Early onset • Aggressive disease
  24. 24. Microbiology: Study of Microbial Community (Microbiome) (Parasites, Viruses & Bacteria) • B Beneficial b t i fi i l bacteria VS • Harmful bacteria (probiotics & prebiotics) – Cause diseases – Promote intestinal cell – Cause inflammation healing – Stimulate anti- inflammatory antigens – Inhibit pro-inflammatory cytokine production
  25. 25. Microbiology: Probiotics • Escherichia coli – I d i and maintaining remission as mesalamine i patients with UC Inducing d i t i i i i l i in ti t ith UC, also similar side effect profile • Lactobacillus – Anti-inflammatory effects • Saccharomyces boulardii – Decrease in relapse of Crohn’s disease – Risk of fungemia • Bifidobacterium – Fermented milk may decrease symptoms in patients with CD Probiotics & prebiotics studies continue. Consult your doctor when using individually, or ideally, look for a clinical trial.
  26. 26. Microbiology: Bacteria • Mycobacterium avium paratuberculosis (MAP) – Found in milk – Does not appear to play a role in the etiology of Crohn’s disease
  27. 27. Environmental Triggers Infections Antibiotics NSAIDs Diet IBD Smoking Stress St NSAIDs=nonsteroidal anti-inflammatory drugs.
  28. 28. Diagnosis 1967 2010 • Barium enema • Colonoscopy • Rigid sigmoidoscopy • Capsule endoscopy • Small bowel x-ray • CT • MRI • Serologic panel • Virtual colonoscopy
  29. 29. Treatments
  30. 30. Treatments • Biologic therapies target specific proteins and enzymes in the immune system relating to the body’s inflammatory response • Targeted outcomes – Sustained remissions – Steroid sparing – Mucosal healing – Reduction in hospitalizations & surgeries – Improved quality of life
  31. 31. Pediatrics • CCFA Pediatric Network • Preventing growth issues – Immunomodulatory treatments act as surgery sparing – Limit steroids – Enteral nutrition in CD • Treatments – Biologic agents hold promise of growth enhancement • Surgery – Steroids increase risk for surgery
  32. 32. What does this all mean to me?
  33. 33. Today s Today’s Goals • Highlight the Past history of IBD research • Understand Today’s breakthroughs in research • Discuss the Future of IBD research – next steps
  34. 34. Problem 2010 Too Many Targets Not enough Patients
  35. 35. Clinical Trials • Clinical trials study: treatment, prevention, diagnostics, screening and quality of life • Clinical trials are studied in phases – Phase I trials: • What method of drug delivery and dosage is safest? • What are the drug’s side effects? – Phase II trials: • Is the drug effective in treating IBD? – Ph Phase III t i l trials: • Is the drug more effective and/or does it have fewer side effects than the current standard treatment? – Phase IV trials: • O Ongoing research t gain additional i f i h to i dditi l information i l di th d ' ti including the drug's risks, benefits, and optimal use
  36. 36. Clinical Trials: Risks & Benefits Risks Benefits • Test treatments may not • Be an active participant be as effective as in your care standard treatment • Gain access to new • May receive a placebo treatments • May require more of y q • Obtain expert medical p your time and attention care • All costs may not be • Help others covered
  37. 37. Clinical Trials • Talk to your doctor about clinical trials as a treatment option • Fi d a clinical t i l Find li i l trial – Call CCFA’s Information Resource Center 888.MY.GUT.PAIN – Visit: www.ccfa.org/clinicaltrials – Visit: www.clinicaltrials.gov
  38. 38. Why Do We Need More Research? R h? Although we have made very significant advances… • There are many forms of these diseases, so there will not be just one cure • We need to expand our understanding of the essential nature of Crohn’s and colitis • We need to develop innovative treatments to induce remission, prevent relapses, prevent complications • S i Science and t h l d technology are poised t i d to make rapid progress – and that progress will depend on the amount of support & funding available
  39. 39. Question and Answer S Q ti dA Session i

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