Efficacy and Safety of S1P1 Receptor Modulator Drugs for Patients with Moderate-to-Severe Ulcerative Colitis

Abstract

Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) that negatively impacts patients' quality of life. In the last decades, the therapeutic options available for the management of patients with moderate to severe UC have increased significantly, including not only biological drugs but also small molecules. However, there is a persistent need to develop new drugs that act on new targets while minimizing the risk of adverse events. Sphingosine-1-phosphate (S1P) is a membrane-derived lysophospholipid. The S1P gradient between tissues and the circulatory system has a key role in regulating the trafficking of immune cells as autoreactive B and T lymphocytes. S1P receptor modulators could be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including UC, by reducing lymphocyte egress from the lymph nodes to the bloodstream. Several S1P receptor modulators have been developed and tested in UC. Ozanimod is already approved by Food and Drug Administration (FDA) and European Medical Agency (EMA), while etrasimod and VTX002 are still under approval. Oral administration route, rapidity and reliable safety profile are the main advantages of this class of drugs. The aim of this review is to summarize the available evidence for the efficacy, safety, and pharmacokinetics of ozanimod, etrasimod, and VTX002 in UC.

Keywords: IBD; S1P1 receptor modulators; VTX-002; etrasimod; inflammatory bowel disease; ozanimod; ulcerative colitis.

Figure 1

Selective action of ozanimod, etrasimod and VTX002 towards sphingosine 1-phosphate (S1P) receptors (S1PR1-5). S1P is a membrane-derived lysophospholipid widely expressed in all tissues. S1P plays a key role in regulating the trafficking of multiple immune cells, including T and B cells. The concentration of S1P is relatively low in lymphoid organs compared with the lymph, forming an S1P gradient that, in normal conditions, allows T and B cells to egress from the lymph node to peripheral tissues, activating immune response [33,34]. The biological effects of S1P are mediated via five specific G-protein-coupled receptors, S1PR1–5. S1PR1, S1PR2 and S1PR3 are ubiquitously expressed, and S1PR4 and S1PR5 have a more restricted expression in the hematopoietic and central nervous system, respectively [24]. S1PR1 activation is involved in lymphocyte trafficking, T cell regulation, and promotion of tumor growth and metastasis in a STAT3-dependent manner. S1PR2 and S1PR3 promote cell migration and proliferation and modulate barrier function. S1PR2 regulates macrophage activation and retention and exerts protumorigenic or antitumorigenic effects. S1PR3 also promotes leukocyte rolling. S1PR4 mediates cytoskeletal rearrangement and plasmacytoid dendritic cell differentiation and activation. S1PR5 is involved in monocyte egress from bone marrow and tumorigenesis [24,25,26]. S1PRs regulate immune cell trafficking, activation and differentiation, and for this reason, it has become a new target for the treatment of immune-mediated disease.