Siponimod is a next generation sphingosine 1-phosphate (S1P) receptor modulator that acts selectively on S1P1 and S1P5, with no requirement for phosphorylation in vivo. It has a half life of about 30 hours and eliminated within 7 days. Fingolimod is the current-generation S1P receptor modulator, which is approved for the treatment for RRMS and targets S1P receptor subtypes 1, 3, 4 & 5. Elimination can take up to 2 months. S1P receptor modulators target MS by binding to S1P1 expressed on lymphocytes and selectively retain a subset of lymphocytes in lymphoid tissues. In this double-blind, adaptive dose-ranging phase 2 study, the researchers aimed to determine the dose-response relation of siponimod as regards the effects on brain MRI lesion activity and characterise safety and tolerability in people with relapsing-remitting MS. Patients were randomly selected in cohort 1 (188 patients) to receive once daily siponimod 10mg, 2mg, or 0.5mg or placebo for 6 months. Patients were randomly allocated to cohort 2 (109) to receive siponimod 1.25mg, 0.25mg or placebo once daily for 3 months. The primary endpoint of this study was dose-response, which was assessed by percentage reduction in monthly number of combined unique active lesions (CUALs) at 3 months for siponimod versus placebo. The results from this study demonstrated that siponimod 10mg reduced the number of CUALs at 3 months by 82% compared with placebo. Siponimod 2mg seemed to achieve close to this level of efficacy.
These results suggest that S1P receptor modulator, with selectivity for subtypes 1 and 5, may be effective in RRMS. For secondary MRI outcomes(reduction in monthly new gadolinium-enhancing lesions and monthly new or newly enlarged T2 lesions), efficacy was much the same with the 10mg and 2mg doses, but the 0.5mg dose showed submaximum reductions versus placebo. The safety profile was overall manageable, especially at the lower doses. The highest incidences of adverse events were seen in the siponimod 10mg and 2mg groups. In light of the potential safety benefits of S1P1 and S1P5 receptor selectivity and a fast washout, siponimod is a promising candidate for further development in phase 3 studies.
Authors: Selmaj K, Li DK
Source: Lancet Neurol. 2013 Jun 11.
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