title: Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity.
abstract: Sphingosine1-phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P1 receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non-selective S1P modulator, FTY720 (fingolimod, Gilenya™). The purpose of this study was to assess RPC1063 for its therapeutic utility in autoimmune diseases.
  
  
  
  The specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P1 receptor expression, was characterized in vitro. The oral pharmacokinetic (PK) parameters and pharmacodynamic effects were established in rodents, and its activity in three models of autoimmune disease (experimental autoimmune encephalitis, 2,4,6-trinitrobenzenesulfonic acid colitis and CD4(+) CD45RB(hi) T cell adoptive transfer colitis) was assessed.
  
  
  
  RPC1063 was specific for S1P1 and S1P5 receptors, induced S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7(+) T lymphocytes in vivo. RPC1063 showed high oral bioavailability and volume of distribution, and a circulatory half-life that supports once daily dosing. Oral RPC1063 reduced inflammation and disease parameters in all three autoimmune disease models.
  
  
  
  S1P receptor selectivity, favourable PK properties and efficacy in three distinct disease models supports the clinical development of RPC1063 for the treatment of relapsing multiple sclerosis and inflammatory bowel disease, differentiates RPC1063 from other S1P receptor agonists, and could result in improved safety outcomes in the clinic.
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: F L
authors.initials: FL
authors.lastname: Scott
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Clemons
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Brooks
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Brahmachary
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Powell
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Dedman
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: H G
authors.initials: HG
authors.lastname: Desale
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Timony
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Martinborough
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Rosen
authors.affiliation: Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: E
authors.initials: E
authors.lastname: Roberts
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: M F
authors.initials: MF
authors.lastname: Boehm
authors.affiliation: Receptos Inc, San Diego, CA, USA.
authors.forename: R J
authors.initials: RJ
authors.lastname: Peach
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced / Q000188:drug therapy*; D004195:Disease Models, Animal; D005260:Female; D007189:Indans / Q000494:pharmacology*; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000276:immunology; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049349:Receptors, Lysosphingolipid / Q000819:agonists*; D014302:Trinitrobenzenesulfonic Acid
chemical_list: D007189:Indans; C571327:Mog protein, mouse; D063308:Myelin-Oligodendrocyte Glycoprotein; D010069:Oxadiazoles; D049349:Receptors, Lysosphingolipid; D014302:Trinitrobenzenesulfonic Acid; C000607776:ozanimod