Abstract
Purpose
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.
Findings
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.
Implications
The findings provide evidence that siponimod is not associated with a significant
arrhythmogenic potential related to QT prolongation.
Key words
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Article info
Publication history
Published online: October 27, 2015
Accepted:
September 13,
2015
Identification
Copyright
© 2015 Elsevier HS Journals, Inc. Published by Elsevier Inc. All rights reserved.
