Immunologic Mechanisms of Pipeline Drugs in IBD and the Role of GWAS

CAUSES OF IBD AND NEW MECHANISMS OF TREATMENT Shrinivas Bishu, MD Assistant professor Crohn’s and Colitis Center University of Michigan Ann Arbor, MI Talk Outline

 Background: inflammatory bowel disease (IBD) basics  What are the cause(s) of IBD?  Why do we need to understand the immune system  Gut microbiota  The basics of the immune system  The gut microbiota  Currently approved biologic agents  Upcoming agents and how they work  Anti-adhesion therapies  JAK/STAT inhibitors  Anti-cytokine therapies  What does this mean for me?  Am I eligible for these therapies?  Can you target therapies to my disease?

Clinical trials in CD 814 total trials UC clinical trials 636 total trials Inflammatory Bowel Disease (IBD)

 Incidence1:  Crohn’s Disease: ~ 1.7 x10^6 persons  Ulcerative Colitis: ~ 2.3 x 10^6 persons

 Progression to Surgery2,3  CD ~ 25% at 5 years; 44% at 9 years  UC ~ 10% at 5 years

1:Cosnes J, et al. Gastro 2011 2:Vester-Andersen, et al. AJG 2013 3:Peyrin-Biroulet L, et al. Gut 2011

Gastrointestinal Tract

• Inflammatory Bowel Disease(s) • Ulcerative Colitis • Colon • Crohn’s Disease • Pan GI tract

• Extra-intestinal disease • Arthritis • Eye • Liver • Skin IBD: Endoscopy

Normal:

Ulcerative Colitis:

Crohn’s Disease: Talk Outline

 History:  Descriptions as early as 117, 300, 1745, 1769 WE Crohn’s DONdisease: 1909, ’1913T KNOW  1859: first formal description of UC (Sir Samuel Wilks; surgeon general of the Union army) All 1932: firsthope formal description is of not CD (Dr. Croh lostn)  Billions of dollars spent in research  Federal government (NIH) Very Medical/Patient Very societies (AGA, good ACG, CCFA) clues  Pharmaceutical companies IBD genes: genome wide association studies (GWAS)

 Over 50% of genes are in immune pathways  Many genes are enriched (expressed) in immune cells and tissues IBD pathogenesis

 IBD pathogenesis  Complex; likely multiple “diseases”  Clues  Genes (GWAS) and environment  Host immune system and intestinal microbiota  New therapies are targeting these pathways Talk Outline

 Background: inflammatory bowel disease (IBD) basics  What are the cause(s) of IBD?  The basics of the immune system  The gut microbiota  Currently approved biologic agents  Upcoming agents and how they work  Anti-adhesion therapies  JAK/STAT inhibitors  Anti-cytokine therapies  What does this mean for me?  Am I eligible for these therapies?  Can you target therapies to my disease? The Immune System

 Protect the host (you) from bacteria, fungi, viruses, parasites  Underactive; susceptible to infections and cancer  Overactive; auto-immune conditions  Most important in areas where you see infectious agents  Lungs  Skin  Intestines

 Composed of:  Lymphoid organs  Cells The Immune System: Lymphoid Organs

 Lymphoid organs  Spleen  Lymph nodes

 Specialized cells activate the immune response  Capture bacteria and viruses and “present” them to cells that respond The Immune System: Cells

 Cells that “capture” bacteria and viruses  Dendritic Cells  Cells that do the killing “effector cells”  T-cells: HIV  B-cells: vaccines

Dendritic Cells T-Cells B-Cells Talk Outline

The Gut Microbiota

 Human GI tract is colonized with trillions of bacteria  Spatial distribution Good and Bad bacteria

 If the GI tract is colonized with bacteria;  How does your body differentiate good from bad bacteria?

https://www.youtube.com/watch?v=oJz4vFaP1c A Adaptive Immune System

• Dendritic Cells drive T-cell ‘lineage commitment’ • Secondary lymphoid organs (SLOs); Peyer’s Patch

Medzhitov, R. Nature Reviews Immunology 1, 135-145 (November 2001) Zou W, Restifo PN. Nature Reviews Immunology 10, 248-256 (April 2010) Mucosal Immune System

 Target dendritic cells  Target adaptive responses (T-cells)  Target mucosal responses Talk Outline

 Target movement of immune cells  Target activation of immune cells  Target survival of immune cells  Dendritic cells  T-cells Pipeline Agents

Block movement of immune cells

Block survival of immune cells

Block movement of immune cells

Block activation of immune cells Upcoming Therapies Crohn’s Disease Ulcerative Colitis Anti-adhesion therapies

 T-cells need to get to sites of inflammation  T-cells are activated by dendritic cells in lymph nodes  Prevent the T-cells from leaving the lymph node  “Stop the guns from reaching the battle”  https://vimeo.com/102644808

Entvyio

JAK/SMAD7 inhibitors

Block T-cell survival T-cell proliferation

http://movie-usa.glencoesoftware.com/video/10.1084/jem.20041236/video-9 Anti-cytokine therapies

 Cytokines are required for:  T-cell lineage commitment  Innate cell effector function  T-cell (Adaptive immune) effector function Anti-cytokine therapies

Block immune cell activation Talk Outline

 Identify pathways?  Identify patients at risk?  Genotype-phenotype correlations  Disease progression

 Provide rationale for developing biomarkers?

 “Personalized medicine” Future

 Can different therapeutic modalities be combined?  JAK inhibitor + mucosal protective agent  αTNF + anti-adhesion therapy  Risk of infection  Risk of lymphoma induction  GWAS studies to identify patients that may benefit by targeting pathways (IL23 risk allele -> JAK inhibitor)