title: Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study.
abstract: 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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  Novartis Pharma AG.
authors.affiliation: Department of Neurology, Medical University of Lodz, Lodz, Poland. kselmaj@afazja.am.lodz.pl
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
authors.forename: David K B
authors.initials: DK
authors.lastname: Li
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.forename: Olaf
authors.initials: O
authors.lastname: Stüve
authors.forename: Peter
authors.initials: P
authors.lastname: Rieckmann
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.forename: Tjalf
authors.initials: T
authors.lastname: Ziemssen
authors.forename: Lixin Zhang
authors.initials: LZ
authors.lastname: Auberson
authors.forename: Harald
authors.initials: H
authors.lastname: Pohlmann
authors.forename: Francois
authors.initials: F
authors.lastname: Mercier
authors.forename: Frank
authors.initials: F
authors.lastname: Dahlke
authors.forename: Erik
authors.initials: E
authors.lastname: Wallström
mesh_terms: D000293:Adolescent; D000328:Adult; D001384:Azetidines / Q000627:therapeutic use*; D001499:Bayes Theorem; D001593:Benzyl Compounds / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects / Q000473:pathology; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; D049349:Receptors, Lysosphingolipid; C578989:siponimod