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79 Effects of an oral selective sphingosine 1-phosphate receptor modulator in a mouse model of sle
  1. KR Taylor1,
  2. M Steinberg1,
  3. RJ Peach1,
  4. H Rosen2,
  5. GJ Opiteck1,
  6. M Stokes1,
  7. BR Clemons1 and
  8. FL Scott1
  1. 1Receptos- Inc., Research, San Diego- California, USA
  2. 2Scripps Research Institute, The Rosen Laboratory, La Jolla- California, USA

Abstract

Background and aims Ozanimod (RPC1063) is a specific and potent small molecule modulator of S1P1,5R that has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Its metabolite, RP-101075, shares ozanimod’s specificity profile at the S1P receptor family in vitro, and its pharmacokinetic (PK) and pharmacodynamic profile in vivo.

Methods The (NZB×NZW)F1 model was used in therapeutic dosing mode to assess the benefit of an S1P1,5R modulator in systemic lupus erythematosus (SLE), compared to cyclophosphamide.

Results As predicted for an S1P1,5R modulator, treatment with 0.3, 1 and 3 mg/kg RP-101075 resulted in a dose-dependent reduction in circulating T and B cells, achieving 62%–99% decrease across all doses tested. Compared to vehicle treated animals, 3 mg/kg RP-101075 reduced proteinuria over the duration of the study (34±5 vs 18±1 U*week; p<0.0001), and blood urea nitrogen (36±5 vs 21±3 mg/dL; p<0.0001). Additionally, RP-101075 reduced kidney disease in a dose dependent manner, as quantified by histological assessment of mesangial expansion, endo- and exo-capillary proliferation, interstitial infiltrates and fibrosis, glomerular deposits and tubular atrophy. In addition, RP-101075 significantly reduced expression of fibrotic and immune genes in the kidneys, with minimal effect on IFN-inducible genes. Of particular note, RP-101075 lowered the number of plasmacytoid dendritic cells, a major source of IFNα in lupus patients, and all B and T cell subsets in the spleen.

Conclusions Given that RP-101075 shares the pharmacokinetic profile of ozanimod and reduces circulating lymphocytes similarly, ozanimod warrants clinical evaluation as a potential treatment for SLE.

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