Research Article| Volume 37, ISSUE 11, P2489-2505.e2, November 01, 2015

Effects of Therapeutic and Supratherapeutic Doses of Siponimod (BAF312) on Cardiac Repolarization in Healthy Subjects



      The International Conference on Harmonisation E14 guideline mandates an intensive cardiac safety evaluation in a clinical thorough QT study, typically in healthy subjects, for all new non-antiarrhythmic drugs with systemic bioavailability. This thorough QT study investigated the effects of therapeutic (2 mg) and supratherapeutic (10 mg) doses of siponimod (BAF312) on cardiac repolarization in healthy subjects.


      The study was a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled, multiple oral dose study. Eligible subjects were randomly assigned to 3 groups to receive siponimod (up-titration to 2 and 10 mg over 18 days), placebo (Days −1 to 18), or moxifloxacin 400 mg Days 10 and 18). Triplicate ECGs were extracted at prespecified time points from Holter ECGs recorded from 1 hour predose until 24 hours postdose at baseline and on-treatment assessment Days 10 and 18. The primary pharmacodynamic variable was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF) at steady-state conditions. In addition, the pharmacokinetic parameters of siponimod and its main circulating metabolite M3 and its metabolite M5 were evaluated.


      Of the 304 enrolled subjects, 281 (92.4%) were included in the pharmacodynamic analysis and 270 (88.8%) completed the study. The upper bounds of the 2-sided 90% confidence intervals (CIs) for ΔΔQTcF at both siponimod doses were within the regulatory threshold of 10 milliseconds (ms) at all predefined on-treatment time points, with the absence of any dose-related effects. The highest observed upper limits of the 2-sided 90% CIs of 9.8 and 9.6 ms for therapeutic and supratherapeutic doses, respectively, were both observed at 3 hours postdose. No treatment-emergent QTc values >480 ms and no QTc increases of >60 ms from baseline were observed. Similar results were obtained with individualized heart rate correction of cardiac repolarization (QTcI). Assay validity was demonstrated by maximum ΔΔQTcF of >5 ms after 400 mg moxifloxacin on both on-treatment assessment days. The selected supratherapeutic dose produced approximately 5-fold higher exposures (Cmax and AUC) than the therapeutic dose, and was considered appropriate to investigate the effects of siponimod on QT/QTc at substantial multiples of the anticipated maximum therapeutic exposure.


      The findings provide evidence that siponimod is not associated with a significant arrhythmogenic potential related to QT prolongation.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Gergely P.
        • Nuesslein-Hildesheim B.
        • Guerini D.
        • et al.
        The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate.
        Br J Pharmacol. 2012; 167: 1035-1047
        • Baumruker T.
        • Billich A.
        • Brinkmann V.
        FTY720, an immunomodulatory sphingolipid mimetic: translation of a novel mechanism into clinical benefit in multiple sclerosis.
        Expert Opin Investig Drugs. 2007; 16: 283-289
        • Brinkmann V.
        • Davis M.D.
        • Heise C.E.
        • et al.
        The immune modulator FTY720 targets sphingosine 1-phosphate receptors.
        J Biol Chem. 2002; 277: 21453-21457
        • Cohen J.A.
        • Barkhof F.
        • Comi G.
        • et al.
        Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis.
        N Engl J Med. 2010; 362: 402-415
        • Kappos L.
        • Radue E.W.
        • O׳Connor P.
        • et al.
        A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis.
        N Engl J Med. 2010; 362: 387-401
        • Selmaj K.
        • Li D.K.
        • Hartung H.P.
        • et al.
        Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study.
        Lancet Neurol. 2013; 12: 756-767
        • Matloubian M.
        • Lo C.G.
        • Cinamon G.
        • et al.
        Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1.
        Nature. 2004; 427: 355-360
        • Mazurais D.
        • Robert P.
        • Gout B.
        • et al.
        Cell type-specific localization of human cardiac S1P receptors.
        J Histochem Cytochem. 2002; 50: 661-670
        • Means C.K.
        • Brown J.H.
        Sphingosine-1-phosphate receptor signalling in the heart.
        Cardiovasc Res. 2009; 82: 193-200
        • Gergely P.
        • Wallström R.
        • Nuesslein-Hildesheim B.
        • et al.
        Phase I study with the selective S1P1/S1P5 receptor modulator BAF312 indicates that S1P1 rather than S1P3 mediates transient heart rate reduction in humans.
        Mult Scler. 2009; 15: s125-s126
        • Legangneux E.
        • Gardin A.
        • Johns D.
        Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects.
        Br J Clin Pharmacol. 2013; 75: 831-841
        • Fenichel R.R.
        • Malik M.
        • Antzelevitch C.
        • et al.
        Drug-induced torsades de pointes and implications for drug development.
        J Cardiovasc Electrophysiol. 2004; 15: 475-495
        • Morganroth J.
        Cardiac repolarization and the safety of new drugs defined by electrocardiography.
        Clin Pharmacol Ther. 2007; 81: 108-113
        • Roden D.M.
        Drug-induced prolongation of the QT interval.
        N Engl J Med. 2004; 350: 1013-1022
      1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals For Human Use. ICH Harmonised Tripartite Guideline: The Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs. May 2005. Accessed 2015.

        • Food and Drug Administration HHS
        International Conference on Harmonisation; guidance on E14 Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs; availability. Notice.
        Fed Regist. 2005; 70: 61134-61135
      2. Guidance for Industry: E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs. 2005. Accessed 2015

        • Mason J.W.
        • Florian Jr, J.A.
        • Garnett C.E.
        • et al.
        Pharmacokinetics and pharmacodynamics of three moxifloxacin dosage forms: implications for blinding in active-controlled cardiac repolarization studies.
        J Clin Pharmacol. 2010; 50: 1249-1259
        • Magnano A.R.
        • Talathoti N.
        • Hallur R.
        • et al.
        Sympathomimetic infusion and cardiac repolarization: the normative effects of epinephrine and isoproterenol in healthy subjects.
        J Cardiovasc Electrophysiol. 2006; 17: 983-989