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P032 Pharmacokinetic Properties of RPC1063, a Selective S1P1 and S1P5 Receptor Agonist, Significantly Contribute to Efficacy in Animal Models of Inflammatory Bowel Disease

F. Scott1, B. Clemons1, H. Dedman2, R. Powell2, E. Martinborough3, G. Timony2, M. Boehm3, R. Peach*1

1Receptos, Biology, San Diego, United States, 2Receptos, Preclinical Sciences, San Diego, United States, 3Receptos, Chemistry, San Diego, United States


Pharmacologic activation of the sphingosine 1-phosphate 1 receptor (S1P1R) leads to immunomodulatory effects as a consequence of disruption of lymphocyte egress from secondary lymphoid organs. RPC1063, an S1P1,5R agonist, is in clinical development as an oral monotherapy for inflammatory bowel disease (IBD) and relapsing multiple sclerosis (RMS). The aim of this study was to assess RPC1063 and other novel S1P1,5R modulators with similar potencies but varying pharmacokinetic (PK) profiles for their efficacy in a TNBS model of IBD. RPC1063 was further assessed in a CD4+CD45RBhi T cell adoptive transfer model in SCID mice.


In the TNBS model, 14 compounds were assessed in 7 separate studies. Compounds were administered by orally to Sprague-Dawely (SD) rats once a day at 1 mg/kg for 7 days, with the first dose 2 hours post-TNBS instillation. Prednisolone served as a positive control. RPC1063 was further assessed at 0.1, 0.3 and 1 mg/kg. Improvements in body weight, colon shortening, weight, thickening, length:weight ratio, ulcer number and size, strictures and adhesions were quantified. Circulating lymphocytes were quantified at the end of the study. Plasma PK parameters were determined in separate studies by oral gavage in SD rats. For the adoptive transfer model, RPC1063 was administered after establishment of disease at 1.2 mg/kg PO and continued for 21 days. An anti-TNF antibody (300 µg 1x/week, IP) served as a positive control. Experimental end points included body weight change and histopathology. Statistical analysis was by Student T-test or One-way ANOVA, and correlations determined by calculating Pearson r.


In the TNBS model, 3/14 compounds, including RPC1063, significantly ameliorated (p<0.05) all 8 disease parameters. There were significant correlations between efficacy and volume of distribution (Pearson r=0.6, P=0.027), Cmax (Pearson r=-0.6, P=0.035), and exposure (AUC; Pearson r=-0.8, P=0.001). RPC1063 significantly suppressed colitis in both disease models. Histopathological analysis in the adoptive transfer model established that RPC1063 preserved intestinal architecture and significantly reduced inflammation, gland loss, erosion and epithelial hyperplasia.


RPC1063 is a selective S1P1,5R agonist that demonstrates significant efficacy in two animal models of IBD. Importantly, optimal PK properties of RPC1063, including a high volume of distribution, appear requisite for maximal efficacy in models of IBD. This data supported the decision to evaluate RPC1063 in humans where it has demonstrated a strong safety and efficacy profile during the induction stage of a phase 2 ulcerative colitis clinical trial and in a phase 2 RMS clinical trial.