BACKGROUND: Siponimod is an oral selective modulator of sphingosine 1-phosphate 
receptor types 1 and type 5, with an elimination half-life leading to washout in 
7 days. We aimed to determine the dose-response relation of siponimod in terms 
of its effects on brain MRI lesion activity and characterise safety and 
tolerability in patients with relapsing-remitting multiple sclerosis.
METHODS: In this double-blind, adaptive dose-ranging phase 2 study, we enrolled 
adults (aged 18-55 years) with relapsing-remitting multiple sclerosis at 73 
medical centres in Europe and North America. We tested two patient cohorts 
sequentially, separated by an interim analysis at 3 months. We randomly 
allocated patients in cohort 1 (1:1:1:1) to receive once-daily siponimod 10 mg, 
2 mg, or 0·5 mg, or placebo for 6 months. We randomly allocated patients in 
cohort 2 (4:4:1) to siponimod 1·25 mg, siponimod 0·25 mg, or placebo once-daily 
for 3 months. Randomisation was done with a central, automated system and 
patients and investigators were masked to treatment assignment. The primary 
endpoint was dose-response, assessed by percentage reduction in monthly number 
of combined unique active lesions at 3 months for siponimod versus placebo; this 
endpoint was analysed by a multiple comparison procedure with modelling 
techniques in all patients with at least one MRI scan up to 3 months. We 
assessed safety in all patients who received at least one dose of study drug. 
This study is registered with ClinicalTrials.gov, number NCT00879658.
FINDINGS: Between March 30, 2009, and Oct 22, 2010, we recruited 188 patients 
into cohort 1 and 109 patients into cohort 2. We showed a dose-response relation 
(p=0·0001) across the five doses of siponimod, with reductions in combined 
unique active lesions at 3 months compared with placebo of 35% (95% CI 17-57) 
for siponimod 0·25 mg (51 patients included in the primary endpoint analysis), 
50% (29-69) for siponimod 0·5 mg (43 patients), 66% (48-80) for siponimod 1·25 
mg (42 patients), 72% (57-84) for siponimod 2 mg (45 patients), and 82% (70-90) 
for siponimod 10 mg (44 patients). In patients treated for 6 months, 37 (86%) of 
43 patients who received siponimod 0·5 mg had adverse events (eight serious), as 
did 48 (98%) of 49 patients who received siponimod 2 mg (four serious), 48 (96%) 
of 50 patients who received siponimod 10 mg (three serious), and 36 (80%) of 45 
controls (none serious). For individuals treated to 3 months, 38 (74%) of 51 
patients who received siponimod 0·25 mg had adverse events (none serious), as 
did 29 (69%) of 42 patients who received siponimod 1·25 mg (two serious) and 13 
(81%) of 16 controls (none serious).
INTERPRETATION: Therapeutic effects of siponimod on MRI lesion activity in 
model-based analyses and its tolerability in relapsing-remitting multiple 
sclerosis warrant investigation in a phase 3 trial.
FUNDING: Novartis Pharma AG.