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

DISCLOSURES Nothing to Disclose

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

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

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

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

Gonzalez-Cabrera, Mol Pharm, 2008 Receptos developed potent and selective S1P1 agonists More 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 EC50 (nM) S1P1 cAMP S1P2 S1P3 Ca++ S1P4 β-arrestin S1P5 CYM-5181 Schurer, NatChemBiol, 2008 6.1 8,500 660 >1,000 (5% efficacy) 345 CYM-5442 Gonzalez-Cabrera, Mol Pharm, 2008 2.8 4,340 3,250 (12% efficacy) 136 RPC1063 0.16 >10,000 5,590 (31% efficacy) 55 1859 0.21 2,170 (20% efficacy) 170 1570 0.06 FTY720-P 0.29 614 8.8 1,814 (100% efficacy) 0.14 KRP203-P 0.23 12 (94% efficacy) 3.2

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

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

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).

The S1P pathway is dysregulated in IBD

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

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

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]

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