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 agentfor the treatment of MS

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

Natalizumab

Afferent Lymph

Blood

Retention

S1P gradients regulate lymphocyte egress and recirculation

High [S1P]

Low [S1P]

Lymph node

RECEPTOS DDW 2012 7

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

Receptos developed potent and selective S1P1 agonistsMore selective than FTY720 and KRP203

EC50 (nM) S1P1cAMP

S1P2cAMP

S1P3Ca++

S1P4β-arrestin

S1P5β-arrestin

CYM-5181Schurer, NatChemBiol, 2008

6.1 8,500 660 >1,000(5% efficacy)

345

CYM-5442Gonzalez-Cabrera, Mol Pharm, 2008

2.8 >1,000 4,340 3,250(12% efficacy)

136

RPC1063 0.16 >10,000 >10,000 5,590(31% efficacy)

55

1859 0.21 >10,000 >10,000 2,170(20% efficacy)

170

1570 0.06 >10,000 >10,000 >10,000 55

FTY720-P 0.29 614 8.8 1,814(100% efficacy)

0.14

KRP203-P 0.23 >10,000 >10,000 12(94% efficacy)

3.2

RECEPTOS DDW 2012 8

Histopathology scored:

Inflammation

Erosion

Gland loss

Hyperplasia

Efficacy equivalent to anti-TNF antibody

RPC 1063 attenuated CD4+CD45RBhi colitis in SCID miceHistopathology – lymphopenia required for suppression of inflammation

Vehicle

1.2mpk RPC1063

No Transfer

One-way ANOVA

One-way ANOVASlide provided by Fiona Scott

The SAMP1 mouse strains

•Terminal ileitis•develops spontaneously•100% penetrance•segmental•transmural•granulomas •perianal disease•Lymphocytes play a pivotal role

A Mouse Model of Crohn’s-like Chronic Ileitis:

Matsumoto et al Gut 1998; 43:71.

Rivera-Nieves et al Gastroenterology 2003; 124: 972.

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

HOMEOSTASIS Chronic inflammation

High blood [S1P]

Low tissue[S1P] High tissue[S1P]

High blood [S1P]

Working Hypothesis: Inflammation alters the S1P gradient and promotes T cell retention

What is the mechanism of action?Traffic, vascular tone, cytokines or all

S1P1CD31Lyve 1

Chronic inflammation

High tissue[S1P]

High blood [S1P]

High tissue[S1P]

High blood [S1P]

Potential Points of control by S1P1-selective agonists• S1P1 agonists induce degradation of S1P1 (Functional antagonism) and

allow pathogenic T cell egress and recirculation. .

Chronic inflammation + S1P1 agonist

• S1P1 agonists enhance the endothelial barrier function at postcapillary venules decreasing recruitment of pathogenic T cells into intestine.

ThanksUCSD En-Hui Behrens Laikon Hospital AthensScripps Research Institute Giorgos BamiasHugh RosenPedro González-Cabrera

ReceptosFiona ScottRobert PeachBryan Clemons