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
S1P gradients regulate lymphocyte egress and recirculation
Retention
Afferent Lymph
Lymph node
Low [S1P]
High [S1P]
Blood
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
cAMP
Ca
CYM-5181
6.1
8,500
660
2.8
>1,000
4,340
RPC1063
0.16
>10,000
>10,000
1859
0.21
>10,000
>10,000
1570
0.06
>10,000
>10,000
>10,000
55
FTY720-P
0.29
614
8.8
1,814
0.14
KRP203-P
0.23
>10,000
>10,000
Schurer, NatChemBiol, 2008
CYM-5442
Gonzalez-Cabrera, Mol Pharm, 2008
RECEPTOS DDW 2012
S1P2
7
S1P3
++
S1P4
S1P5
β-arrestin
β-arrestin
>1,000
(5% efficacy)
3,250
(12% efficacy)
5,590
(31% efficacy)
2,170
(20% efficacy)
(100% efficacy)
12
(94% efficacy)
345
136
55
170
3.2
RPC 1063 attenuated CD4+CD45RBhi colitis in SCID mice
Histopathology – lymphopenia required for suppression of inflammation
Histopathology scored:
No Transfer
Inflammation
Erosion
Gland loss
Hyperplasia
Vehicle
Efficacy equivalent to
anti-TNF antibody
1.2mpk RPC1063
One-way ANOVA
Slide provided by Fiona Scott
RECEPTOS DDW 2012
One-way ANOVA
8
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
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
Working Hypothesis: Inflammation alters the S1P
gradient and promotes T cell retention
HOMEOSTASIS
Low tissue[S1P]
High blood [S1P]
Chronic inflammation
High tissue[S1P]
High blood [S1P]
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
High tissue[S1P]
High blood [S1P]
Chronic inflammation + S1P1 agonist
High tissue[S1P]
High blood [S1P]
Thanks
UCSD
En-Hui Behrens
Scripps Research Institute
Hugh Rosen
Pedro González-Cabrera
Receptos
Fiona Scott
Robert Peach
Bryan Clemons
Laikon Hospital Athens
Giorgos Bamias