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Original Investigation |

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

Ludwig Kappos, MD1,2,3; David K. B. Li, MD4,5; Olaf Stüve, MD6; Hans-Peter Hartung, MD7; Mark S. Freedman, MD8; Bernhard Hemmer, MD9; Peter Rieckmann, MD10; Xavier Montalban, MD11; Tjalf Ziemssen, MD12; Brian Hunter, PhD13; Sophie Arnould, PhD13; Erik Wallström, MD13; Krzysztof Selmaj, MD14
[+] 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.
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Published online

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

Figures in this Article

Figures

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Figure 1.
CONSORT Flow Diagram for the Extension Study
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Figure 2.
Efficacy End Points Up to Month 24 (Dose-Blinded Extension Full Analysis Set)

A, Estimated number of gadolinium (Gd)-enhancing T1 lesions. Based on at least 1 scan up to the respective time points. A negative binomial regression model adjusted for treatment group, age, and baseline (BL) Gd-enhancing T1 lesion count was used to estimate Gd-enhancing T1 and new/newly enlarged T2 lesion counts and their associated 95% CIs. For extension month 18 data, a post hoc analysis of Gd-enhancing T1 lesion counts was conducted (see eTable 3 in the Supplement). Pairwise comparisons between siponimod, 0.25 mg, and other doses were made with a negative binomial regression model using the log link, adjusted for BL Gd-enhancing T1 lesion count, age, and treatment group. At extension month 18, there was a greater number of patients with magnetic resonance imaging assessments than at extension month 24 owing to the study design. B, Estimated number of new/newly enlarging T2 lesions. Considering variable durations of study drug interruption between the end of the BOLD (BAF312 on MRI Lesion Given Once Daily) Study and the start of the extension, the 0- to 6-month interval was not considered for analysis. The numbers in parts A and B are the numbers of patients with a magnetic resonance imaging scan. C, The annualized relapse ratewas estimated using a negative binomial regression model adjusted for treatment, age, BL Expanded Disability Status Scale score, BL Gd-enhancing T1 lesion count, and number of relapses in the previous 2 years, with log(time in study in years) as the offset variable, using the log link. D, Mean absolute lymphocyte counts per treatment group (dose-blinded extension set). Only data while taking treatment (defined as measurements up to and including 10 days after the date of the last dose of extension study drug) are summarized. Data shown in part D are mean values ±2 SDs.

aPatients in the 0.25-mg and 1.25-mg groups received treatment for only 3 months during the BOLD Study.

bP < .001.

cP < .01.

dBaseline is defined as the last nonmissing pretreatment measurement in the BOLD Study.

eExtension BL (EBL) is the last available measurement before the first dose of extension study drug.

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Figure 3.
Effect on Heart Rate During Dose-Blinded Titration

Mean change from baseline in Holter electrocardiogram hourly mean heart rate during dose-blinded titration in patients with washout (dose-blinded extension set). The treatment displayed is the dose received on that day, which is derived from the titration schedule in the protocol. According to this schedule, on extension day 1 and day 2, all patients received siponimod, 0.25 mg. In line with the dose titration schedule, on extension day 7, patients received a siponimod dose equivalent to their assigned dose group, except for patients in the 10-mg dose group, who received 3 mg and reached the 10-mg dose on day 10. The values are the number of patients within the subgroup with at least 1 postdose measurement recorded during the visit for which a corresponding baseline measurement was available. Baseline is defined as the last nonmissing pretreatment measurement in the BOLD (BAF312 on MRI Lesion Given Once Daily) Study. Patients with washout are those patients with more than 7 days’ study drug interruption between the date of the last intake of study drug in the BOLD Study and the date of first dose of extension study drug, and all patients randomized to placebo in the BOLD Study. bpm indicates beats per minute.

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