title: Safety and Efficacy of Siponimod (BAF312) in Patients With Relapsing-Remitting Multiple Sclerosis: Dose-Blinded, Randomized Extension of the Phase 2 BOLD Study.
abstract: OBJECTIVE
  This dose-blinded extension of the phase 2 BOLD (BAF312 on MRI Lesion Given Once Daily) Study in relapsing-remitting multiple sclerosis provides evidence on disease activity and safety of a range of siponimod doses for up to 24 months.
  
  
  OBJECTIVE
  To assess the safety and efficacy of siponimod for up to 24 months during the dose-blinded extension of the BOLD Study.
  
  
  METHODS
  At extension baseline in a randomized clinical trial, patients taking siponimod continued at the originally assigned dose and patients taking placebo were rerandomized to the 5 siponimod doses. Initial treatment was titrated over 10 days. A total of 252 eligible patients were treated at specialized multiple sclerosis centers for this study conducted from August 30, 2010, through June 3, 2013.
  
  
  METHODS
  Siponimod at 10-mg, 2-mg, 1.25-mg, 0.5-mg, and 0.25-mg doses.
  
  
  METHODS
  Safety assessment included blood tests, documentation of adverse events at regular scheduled visits and Holter monitoring; key efficacy measures were annualized relapse rate and magnetic resonance imaging lesion activity.
  
  
  RESULTS
  Among the 252 eligible patients, the mean (SD) ages were 37.2 (8.4) years, 35.2 (9.1) years, 34.0 (7.6) years, 35.1 (9.2) years, and 36.8 (9.1) years in the 0.25-mg, 0.5-mg, 1.25-mg, 2-mg, and 10-mg groups. Of the 252 patients, 184 (73%) entered the extension and received siponimod (10 mg: n = 33; 2 mg: n = 29; 1.25 mg: n = 43; 0.5 mg: n = 29; and 0.25 mg: n = 50); 159 (86.4%) completed the dose-blinded extension. The incidence of adverse events was similar across treatment groups (10 mg: 87.9%; 2 mg: 89.7%; 1.25 mg: 88.4%; 0.5 mg: 96.6%; and 0.25 mg: 84.0%). Nine patients reported serious adverse events (2 mg: 3/29 [10.3%], 1.25 mg: 1/43 [2.3%], 0.5 mg: 4/29 [13.8%], and 0.25 mg: 1/50 [2.0%]; no serious adverse event was reported for more than 1 patient and no new safety signals occurred compared with the BOLD Study. Dose titration mitigated symptomatic bradycardic events. Reductions in mean (95% CI) gadolinium-enhancing T1 lesion counts from the last BOLD assessment were sustained in the 10-mg, 2-mg, 1.25-mg, and 0.5-mg dose groups (0 [0-0], 0.1 [0-1.9], 0.1 [0-2.6], and 0.1 [0-2.8] at month 24, respectively). At the 3 highest vs 2 lowest doses, the estimated new/newly enlarging T2 lesion counts (95% CIs) were lower during months 6 to 12 (0.5 [0.2-1.3], 0.4 [0.2-1.1], and 0.2 [0.1-0.6] vs 1.3 [0.6-2.8] and 1.4 [0.7-2.7]), months 12 to 18 (0.4 [0.1-1.1], 0.4 [0.1-1.3], and 0.4 [0.2-1.0] vs 1.0 [0.4-2.6] and 3.6 [1.7-7.6]), and months 18 to 24 (0 [0-not estimable], 0.9 [0.1-7.6], and 0.1 [0-1.7] vs 1.6 [0.3-7.7] and 2.0 [0.4-9.5]). Annualized relapse rates (95% CIs) up to month 24 were similarly lower for the 3 highest doses: 0.22 (0.12-0.40) for 10 mg, 0.20 (0.10-0.38) for 2 mg, and 0.14 (0.08-0.26) for 1.25 mg vs 0.33 (0.19-0.56) for 0.5 mg and 0.33 (0.21-0.50) for 0.25 mg.
  
  
  CONCLUSIONS
  For up to 24 months of siponimod treatment, multiple sclerosis disease activity was low and there were no new safety signals; investigation in phase 3 trials is encouraged.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01185821.
authors.affiliation: Neurologic Clinic and Policlinic, Department of Medicine, University Hospital Basel, Basel, Switzerland2Department of Clinical Research, University Hospital Basel, Basel, Switzerland3Department of Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada5Department of Medicine (Neurology), University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: David K B
authors.initials: DK
authors.lastname: Li
authors.affiliation: University of Texas Southwestern Medical Center, Dallas.
authors.forename: Olaf
authors.initials: O
authors.lastname: Stüve
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hartung
authors.affiliation: The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: Technical University of Munich, Munich, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.affiliation: Sozialstiftung Bamberg Hospital, Bamberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Rieckmann
authors.affiliation: MS Centre of Catalonia, Vall d´Hebron University Hospital, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Center of Clinical Neuroscience, University of Technology Dresden, Dresden, Germany.
authors.forename: Tjalf
authors.initials: T
authors.lastname: Ziemssen
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Brian
authors.initials: B
authors.lastname: Hunter
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Sophie
authors.initials: S
authors.lastname: Arnould
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Erik
authors.initials: E
authors.lastname: Wallström
authors.affiliation: Department of Neurology, Medical University of Lodz, Lodz, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
mesh_terms: D000328:Adult; D001384:Azetidines / Q000627:therapeutic use*; D001593:Benzyl Compounds / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000000981:diagnostic imaging / Q000188:drug therapy*; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; C578989:siponimod