Etrasimod (APD334), an Oral, Next‐Generation Sphingosine‐1‐Phosphate Receptor Modulator Inhibits the Development of Colitis in Lymphoid‐Null Mice Injected with Colitogenic CD4+ T Cells
Authors: Adams John W. , Solomon Michelle , Lehmann‐Bruinsma Karin , Carroll Chris , He Hongmei , Behan Dominic , Al‐Shamma Hussien 
Published: November 2023

Objective

Etrasimod (APD334) is a next‐generation oral sphingosine‐1‐phosphate (S1P) modulator with an optimized S1P receptor activity profile currently in Phase 2 clinical trials for the treatment of ulcerative colitis (UC). Etrasimod selectively targets S1P receptor subtypes 1, 4 and 5 which have been implicated in decreasing intestinal inflammation. Etrasimod does not activate S1P2 or S1P3 receptor subtypes, which are associated with cardiac, pulmonary and tumor‐related side effects. This study was designed to evaluate the efficacy of etrasimod in the treatment of intestinal inflammation in the adoptive transfer model of UC.

Methods

Colitogenic CD4+CD45RBhigh T cells were isolated from the spleens of wild type BALB/c female mice and transferred into female severe combined immune deficient (SCID) mice to induce colon inflammation and pathology reminiscent of human UC. Animals were sorted into 6 treatment groups, 5 receiving colitogenic T cells. These 5 include a vehicle group, a positive control group treated with FTY‐720 (1mg/kg), and 3 groups treated with etrasimod (1, 3 and 10mg/kg). The sixth group infected with unsorted cells served as baseline control. All treatments began on the day of T cell transfer, with single daily doses administered for the duration of the study. After 5 weeks, all animals were sacrificed, and colon weight to length ratios were recorded prior to processing for histology and tissue expression analysis.

Results

Approximately 3 weeks after transfer, SCID mice that received CD4+ CD45RBhigh T cells progressively developed symptoms of colitis, including weight loss and diarrhea, compared with mice that received unsorted cells. Treatment with etrasimod (1–10mg/kg) and FTY720 (1mg/kg) significantly inhibited weight loss and overt signs of colon inflammation including diarrhea. This was confirmed by post mortem analysis, wherein etrasimod and FTY720 treated animals had significantly reduced colon weight to length ratios. Consistent with these measures, histological analysis revealed a thickened mucosa, and an increase in inflammatory immune cell infiltration of the colons of vehicle treated mice that received sorted colitogenic T cells. By contrast, a marked decrease in mucosal thickness and number of infiltrating immune cells was observed in colons of mice treated with etrasimod and FTY‐720. Finally, these findings were confirmed with qPCR analysis of colon tissue homogenates, in which elevated markers of T cell and macrophage infiltrates such as CD4, CD11b and TNFa in vehicle treated animals were significantly blunted in animals treated with etrasimod and FTY720.

Conclusions

Etrasimod, a potent orally bioavailable S1P modulator, inhibits experimental colitis induced by adoptive transfer of naive colitogenic T cells into lymphoid‐null mice. These findings suggest that etrasimod may modulate systemic and local immune cells in the treatment of UC by selectively targeting S1P receptor subtypes 1, 4 and 5 while avoiding receptors associated with safety issues.

Support or Funding Information

Research Support: Arena Pharmaceuticals