Sphingosine 1-phosphate (S1P) receptor modulators possess a unique mechanism of 
action as disease-modifying therapy for multiple sclerosis (MS). Subtype 1 S1P 
receptors are expressed on the surfaces of lymphocytes and are important in 
regulating egression from lymph nodes. The S1P receptor modulators indirectly 
antagonize the receptor's function and sequester lymphocytes in lymph nodes. 
Fingolimod was the first S1P agent approved in the USA in 2010 for relapsing MS 
after two phase III trials (FREEDOMS and TRANSFORMS) demonstrated potent 
efficacy, and good safety and tolerability. Post-marketing experience, as well 
as a third phase III trial (FREEDOMS II), also showed favorable results. More 
selective S1P receptor agents-ponesimod (ACT128800), siponimod (BAF312), 
ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303-are still in 
relatively early stages of development, but phase I and II trials showed 
promising efficacy and safety. However, these observations have yet to be 
reproduced in phase III clinical trials.