Sphingosine 1‐phosphate receptor modulators in multiple sclerosis treatment: A practical review

Abstract

Four sphingosine 1‐phosphate (S1P) receptor modulators (fingolimod, ozanimod, ponesimod, and siponimod) are approved by the US Food and Drug Administration for the treatment of multiple sclerosis. This review summarizes efficacy and safety data on these S1P receptor modulators, with an emphasis on similarities and differences. Efficacy data from the pivotal clinical trials are generally similar for the four agents. However, because no head‐to‐head clinical studies were conducted, direct efficacy comparisons cannot be made. Based on the adverse event profile of S1P receptor modulators, continued and regular monitoring of patients during treatment will be instructive. Notably, the authors recommend paying attention to the cardiac monitoring guidelines for these drugs, and when indicated screening for macular edema and cutaneous malignancies before starting treatment. To obtain the best outcome, clinicians should choose the drug based on disease type, history, and concomitant medications for each patient. Real‐world data should help to determine whether there are meaningful differences in efficacy or side effects between these agents.

Selective Activation of GPCRs: Molecular Dynamics Shows Siponimod Binds but Fails to Activate S1PR2 Unlike S1PR1

“…As a result, lymphocytes are confined within lymphoid tissues 8,9 . This mechanism makes S1PR1 a valuable target for treating autoimmune diseases such as Multiple Sclerosis (MS) [10][11][12] , tackling transplant rejections, and addressing conditions like Pulmonary Fibrosis 11,13,14 . The receptor subtypes S1PR1, S1PR2 and S1PR3 are primarily expressed in the cardiovascular, central nervous, and immune systems, whereas the expression of S1PR4 and S1PR5 is re-stricted to the immune and nervous systems 15,16 .…”

“…20,21 Hence, this limits the clinical use of Fingolimod. In contrast, second-generation S1P receptor modulators such as Siponimod, Ozanimod, and Ponesimod are more selective for S1PR1 and S1PR5 over S1PR2, S1PR3, and S1PR4, resulting in fewer side effects 9,11,12 . Understanding the mechanisms of action of these next-generation drugs is crucial for developing strategies to enhance drug selectivity in GPCR therapeutics.…”