Ozanimod (RPC1063) is a potent sphingosine‐1‐phosphate receptor‐1 (S1P₁) and receptor‐5 (S1P₅) agonist with autoimmune disease‐modifying activity

Abstract

BACKGROUND AND PURPOSESphingosine1-phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P 1 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. EXPERIMENTAL APPROACHThe specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P 1 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. KEY RESULTSRPC1063 was specific for S1P 1 and S1P 5 receptors, induced S1P 1 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. CONCLUSIONS AND IMPLICATIONSS1P 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.

Progression of type 1 diabetes from the prediabetic stage is controlled by interferon-α signaling

“…Fourth, CYM-5442 therapy enhanced the expression of negative immune regulating surface molecules on autoreactive T cells, further limiting the ability of any autoimmune T-cell that might enter the islets from killing β cells. The selective and potent S1PR1 agonist CYM-5442 (27, 28) is a predecessor compound to the clinical agonist ozanimod (29), now completing phase 3 clinical trials for multiple sclerosis (30) and ulcerative colitis (31). S1PR1 agonists are clinically effective immunomodulators because of multistep interdiction of immunopathology.…”

Next generation of small molecules in inflammatory bowel disease

“…The compound is currently being evaluated for the treatment of immune-mediated inflammatory diseases,81 such as multiple sclerosis82 and IBD. In a recent double-blind, placebo-controlled phase II clinical trial (the TOUCHSTONE study), Sandborn et al evaluated the efficacy and safety of induction and maintenance therapy with ozanimod in patients with moderate-to-severe UC 83.…”

Sphingosine 1-Phosphate Receptor Modulators and Drug Discovery

“…Ozanimod is an oral selective S1P 1/5 dual modulator, and induces lymphopenia and regulates immune response (Scott et al ., 2016). In three models of autoimmune diseases that is, experimental autoimmune encephalitis, TNBS-induced colitis, and CD4 + CD45RBhi T cell adaptive transfer colitis, oral ozanimod diminished inflammation parameters.…”

“…In three models of autoimmune diseases that is, experimental autoimmune encephalitis, TNBS-induced colitis, and CD4 + CD45RBhi T cell adaptive transfer colitis, oral ozanimod diminished inflammation parameters. This finding supports the clinical development of ozanimod for multiple sclerosis (Cohen et al ., 2016a; Scott et al ., 2016). …”