Fingolimod (FTY720, Gilenya), an immunosuppresive agent with activity purported to be mediated by binding of it’s phosphorylated derivative to the sphingosine-1-phosphate receptor 1 (S1P1), was approved earlier in the year as the first orally administered disease modifying therapy for the treatment of relapsing forms of multiple sclerosis. Activation of S1P1 induces internalisation and degradation of the receptor resulting in functional antagonism and subsequent attenuation of circulating lymphocyte levels. An alternative approach to modulation of the S1P receptor family involves inhibition of sphingosine 1-phosphate lyase (S1PL), an enzyme which degrades sphingosine 1-phosphate in cells, resulting in raised levels of S1P and subsequent functional antagonism of the S1P receptors. In this recent J.Med.Chem. paper, workers at Lexicon Pharmaceuticals describe the discovery of LX2931, their first clinical candidate S1PL inhibitor, and a backup candidate (LX2932) for the treatment of rheumatoid arthritis. Interestingly, the effects of S1PL inhibition seem to be limited to lymphoid tissue and hence compounds like LX2931 offer the potential of immunosuppression with fewer side effects compared to agents (e.g. Fingolimod) exhibiting a broader tissue activity profile.
LX2931 demonstrated robust activity in rodent models of rheumatoid arthritis and effectively, and reversibly, lowered peripheral lymphocyte counts in volunteers. The compound was well tolerated and a Phase IIa 12-week trial in RA patients was initiated on the basis of the data presented in this publication. Just last week, Lexicon published the top-line data from this trial and whilst the lower dose groups (70 and 110mg, once daily) failed to demonstrate an effect (ACR20) over that seen with placebo, there was a response at week 12 (60% versus 49% for placebo) in the 150mg per day dose group. The drug was also well tolerated and Lexicon are now looking for partners to continue development. The high placebo response in this trial complicates the interpretation of these data but the safety profile and lack of any significant drug-drug interactions may offer the potential to explore the effects of higher doses in the clinic (although it’s not clear that the Phase I data would currently support this?).