title: Effects of Therapeutic and Supratherapeutic Doses of Siponimod (BAF312) on Cardiac Repolarization in Healthy Subjects.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The findings provide evidence that siponimod is not associated with a significant arrhythmogenic potential related to QT prolongation.
authors.affiliation: Novartis Pharma AG, Basel, Switzerland. Electronic address: kasra.shakeri-nejad@novartis.com.
authors.forename: Kasra
authors.initials: K
authors.lastname: Shakeri-Nejad
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Vassilios
authors.initials: V
authors.lastname: Aslanis
authors.affiliation: Novartis Healthcare Limited, Hyderabad, India.
authors.forename: Uday Kiran
authors.initials: UK
authors.lastname: Veldandi
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Louise
authors.initials: L
authors.lastname: Mooney
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Nicole
authors.initials: N
authors.lastname: Pezous
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Bruno
authors.initials: B
authors.lastname: Brendani
authors.affiliation: SeaView Research Inc., Miami, Florida.
authors.forename: Axel
authors.initials: A
authors.lastname: Juan
authors.affiliation: Celerion, Tempe, Arizona.
authors.forename: Mark
authors.initials: M
authors.lastname: Allison
authors.affiliation: Elite Research Institute, Miami, Florida.
authors.forename: Robert
authors.initials: R
authors.lastname: Perry
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Eric
authors.initials: E
authors.lastname: Legangneux
mesh_terms: D000293:Adolescent; D000328:Adult; D001384:Azetidines / Q000008:administration & dosage / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D024841:Fluoroquinolones / Q000494:pharmacology; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced*; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D055815:Young Adult
chemical_list: D001384:Azetidines; D001593:Benzyl Compounds; D024841:Fluoroquinolones; C578989:siponimod; D000077266:Moxifloxacin
keywords: BAF312; cardiac repolarization; healthy subjects; moxifloxacin; siponimod; thorough QT