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Original Investigation
September 2016

Safety and Efficacy of Siponimod (BAF312) in Patients With Relapsing-Remitting Multiple SclerosisDose-Blinded, Randomized Extension of the Phase 2 BOLD Study

Author Affiliations
  • 1Neurologic Clinic and Policlinic, Department of Medicine, University Hospital Basel, Basel, Switzerland
  • 2Department of Clinical Research, University Hospital Basel, Basel, Switzerland
  • 3Department of Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland
  • 4Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada
  • 5Department of Medicine (Neurology), University of British Columbia, Vancouver, British Columbia, Canada
  • 6University of Texas Southwestern Medical Center, Dallas
  • 7Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  • 8The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada
  • 9Technical University of Munich, Munich, Germany
  • 10Sozialstiftung Bamberg Hospital, Bamberg, Germany
  • 11MS Centre of Catalonia, Vall d´Hebron University Hospital, Barcelona, Spain
  • 12Center of Clinical Neuroscience, University of Technology Dresden, Dresden, Germany
  • 13Novartis Pharma AG, Basel, Switzerland
  • 14Department of Neurology, Medical University of Lodz, Lodz, Poland
JAMA Neurol. 2016;73(9):1089-1098. doi:10.1001/jamaneurol.2016.1451
Abstract

Importance  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.

Design, Setting, and Participants  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.

Interventions  Siponimod at 10-mg, 2-mg, 1.25-mg, 0.5-mg, and 0.25-mg doses.

Main Outcomes and Measures  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 and Relevance  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.

Trial Registration  clinicaltrials.gov Identifier: NCT01185821

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