The sphingosine-1-phosphate (S1P) pathway:

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

• Nothing to Disclose

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S1P pathway in intestinal lymphocyte traffic

• Sphingosine-1-phosphate (S1P) is a bioactive
  lipid derived from cell membrane sphingomyelin.
• S1P signals through 5 GPCRs 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

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FTY720 (Gilenya) the first oral agent for the
treatment of MS
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Lymphocyte traffic a precedent for a
pathogenetic link between MS and IBD
Natalizumab
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S1P gradients regulate lymphocyte egress and
recirculation
Retention
Afferent Lymph
Lymph node
Low S1P
High S1P
Blood
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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

EC50 (nM) S1P1 cAMP S1P2 cAMP S1P3 Ca S1P4 ß-arrestin S1P5 ß-arrestin
CYM-5181 Schurer, NatChemBiol, 2008 6.1 8,500 660 gt1,000 (5 efficacy) 345
CYM-5442 Gonzalez-Cabrera, Mol Pharm, 2008 2.8 gt1,000 4,340 3,250 (12 efficacy) 136
RPC1063 0.16 gt10,000 gt10,000 5,590 (31 efficacy) 55
1859 0.21 gt10,000 gt10,000 2,170 (20 efficacy) 170
1570 0.06 gt10,000 gt10,000 gt10,000 55
FTY720-P 0.29 614 8.8 1,814 (100 efficacy) 0.14
KRP203-P 0.23 gt10,000 gt10,000 12 (94 efficacy) 3.2
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RPC 1063 attenuated CD4CD45RBhi colitis in SCID
miceHistopathology 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
One-way ANOVA
Slide provided by Fiona Scott
One-way ANOVA
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A Mouse Model of Crohns-like Chronic Ileitis
The SAMP1 mouse strains
Matsumoto et al Gut 1998 4371.

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

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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).
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The S1P pathway is dysregulated in IBD
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Working Hypothesis Inflammation alters the S1P
gradient and promotes T cell retention
HOMEOSTASIS
Chronic inflammation
High tissueS1P
Low tissueS1P
High blood S1P
High blood S1P
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What is the mechanism of action?Traffic,
vascular tone, cytokines or all
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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
Chronic inflammation S1P1 agonist
High tissueS1P
High tissueS1P
High blood S1P
High blood S1P
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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

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