1. The sphingosine-1-phosphate (S1P) pathway:
A new therapeutic frontier in IBD
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 5

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

7. 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

8. 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

9. 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

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: NCT ).

11. The S1P pathway is dysregulated in IBD

12. 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]

13. What is the mechanism of action
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