The sphingosine-1-phosphate (S1P) pathway: A new therapeutic frontier in IBD

1. The sphingosine-1-phosphate (S1P) pathway: A new therapeutic frontier inIBD Isaria sinclarii

2. DISCLOSURES • Nothing to Disclose

3. S1P pathway in intestinal lymphocyte traffic: • Sphingosine-1-phosphate (S1P) is a bioactive lipid derived from cell membrane sphingomyelin. • S1P signals through 5 GPCR’s: S1P1-S1P5 • The synthetic agonist Fingolimod (FTY720) was derived from Myriocin, extracted from the fungus Isaria sinclarii • Fingolimod binds to S1P1,3,4,5 • Binding to S1P3 may induce severe bradycardia • S1P1 is predominantly involved in the immunologic role of the pathway

4. FTY720 (Gilenya): the first oral agent for the treatment of MS

5. Lymphocyte traffic: a precedent for a pathogenetic link between MS and IBD Natalizumab

6. S1P gradients regulate lymphocyte egress and recirculation Retention Afferent Lymph Lymph node Low [S1P] High [S1P] Blood

7. Receptos developed potent and selective S1P1 agonistsMore selective than FTY720 and KRP203 • Initial screening hits and compound optimization was performed at The Scripps Research Institute (Dr Hugh Rosen and Dr Ed Roberts) • Medicinal chemistry campaign of ~700 compounds improved potency, selectivity and pharmacokinetics

8. RPC 1063 attenuated CD4+CD45RBhi colitis in SCID miceHistopathology – lymphopenia required for suppression of inflammation No Transfer • Histopathology scored: • Inflammation • Erosion • Gland loss • Hyperplasia • Efficacy equivalent to anti-TNF antibody Vehicle 1.2mpk RPC1063 One-way ANOVA Slide provided by Fiona Scott One-way ANOVA

9. Rivera-Nieves et al Gastroenterology 2003; 124: 972. A Mouse Model of Crohn’s-like Chronic Ileitis: The SAMP1 mouse strains Matsumoto et al Gut 1998; 43:71. • Terminal ileitis • develops spontaneously • 100% penetrance • segmental • transmural • granulomas • perianal disease • Lymphocytes play a pivotal role

10. RPC1063 attenuates ileitis in SAMP1YitFc mice TOUCHSTONE is multi-center, double-blind, randomized, placebo-controlled study investigating the effect of two doses of RPC1063 (an S1P1-selective agonist) versus placebo. Its primary objective is to test the efficacy of RPC1063 for the induction of clinical remission in patients with moderately to severely active UC at eight weeks (ClinicalTrials.gov Identifier: NCT01647516).

11. The S1P pathway is dysregulated in IBD

12. Working Hypothesis: Inflammation alters the S1P gradient and promotes T cell retention HOMEOSTASIS Chronic inflammation High tissue[S1P] Low tissue[S1P] High blood [S1P] High blood [S1P]

13. What is the mechanism of action?Traffic, vascular tone, cytokines or all S1P1 CD31 Lyve 1

14. Potential Points of control by S1P1-selective agonists • S1P1 agonists induce degradation of S1P1 (Functional antagonism) and allow pathogenic T cell egress and recirculation. . • S1P1 agonists enhance the endothelial barrier function at postcapillary venules decreasing recruitment of pathogenic T cells into intestine. Chronic inflammation Chronic inflammation + S1P1 agonist High tissue[S1P] High tissue[S1P] High blood [S1P] High blood [S1P]

15. Thanks UCSD En-Hui Behrens Laikon Hospital Athens Scripps Research Institute Giorgos Bamias Hugh Rosen Pedro González-Cabrera Receptos Fiona Scott Robert Peach Bryan Clemons