Phase 2 siponimod trial results

Siponimod the new finglimod me-too drug. The difference is that it is being tested in SPMS. #MSBlog #MSResearch

Epub: Selmaj et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. Lancet Neurol. 2013 Jun 10. doi:pii: S1474-4422(13)70102-9. 10.1016/S1474-4422(13)70102-9.

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. This study 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 RRMSers.

METHODS: In this double-blind, adaptive dose-ranging phase 2 study, they enrolled adults (aged 18-55 years) with RRMS at 73 medical centres in Europe and North America. They tested two MSer cohorts sequentially, separated by an interim analysis at 3 months. They randomly allocated MSers 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. They randomly allocated MSers 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 MSers 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 MSers with at least one MRI scan up to 3 months. They assessed safety in all MSers who received at least one dose of study drug. This study is registered with, number NCT00879658.

FINDINGS: Between March 30, 2009, and Oct 22, 2010, they recruited 188 MSers into cohort 1 and 109 MSers into cohort 2. They 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 MSers included in the primary endpoint analysis), 50% (29-69) for siponimod 0·5 mg (43 MSers), 66% (48-80) for siponimod 1·25 mg (42 MSers), 72% (57-84) for siponimod 2 mg (45 MSers), and 82% (70-90) for siponimod 10 mg (44 MSers). In MSers treated for 6 months, 37 (86%) of 43 MSers who received siponimod 0·5 mg had adverse events (eight serious), as did 48 (98%) of 49 MSers who received siponimod 2 mg (four serious), 48 (96%) of 50 MSers 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 MSers who received siponimod 0·25 mg had adverse events (none serious), as did 29 (69%) of 42 MSers 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.

“Siponimod is the next generation of fingolimod (Gilenya). Both these drugs are spingosine-1-phosphate receptor modulators. There are a number of different type of receptors and S1P1 receptor and S1P5 receptors are thought to be important in the action of the drugs. Fingolimod also targets S1P3 and S1P4 receptors.”

“The good news is that Siponimod is currently being tested in SPMS. The trial programme is trying to address the needs of SPMSers. I think this study have more than a 50% chance of being positive.”

NCT01665144: Evaluate the safety and efficacy of Siponimod (BAF312) versus placebo in a variable treatment duration in patients with secondary progressive multiple sclerosis.

CoI: multiple. I am member of the steering committee of the Siponimod progressive clinical trial programme and a result I receive financial compensation for my time on this committee. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.


  • Good news to hear it is being trialled in SPMS – can you give us any more details, eg where/when/when will it report?
    Thanks as always

  • Oh sorry I hadn't realised that was a link to the trial info! Please ignore my previous question 🙂

  • Isn't fingolimod being trialled in PPMS, and aren't the results due soon? Surely if fingolimod works in the former then it'll work in SPMS?

    MouseDoc has little faith in fingolimod's awaited efficaciousness in PPMS. How say you, Prof G?

    • Prof G is glass half full. We need to wait and see what happens in MS, in animals we have a fair idea, but some element ofPPMSrespondstoimmuno therapy this arm should show benefit.

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