Elsevier

Clinical Therapeutics

Volume 37, Issue 11, 1 November 2015, Pages 2489-2505.e2
Clinical Therapeutics

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

https://doi.org/10.1016/j.clinthera.2015.09.006Get rights and content

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.

Introduction

Siponimod (BAF312) is a selective sphingosine 1-phosphate (S1P) receptor modulator that is currently being developed for the treatment of secondary progressive multiple sclerosis.1 The therapeutic efficacy of S1P receptor modulation in multiple sclerosis has been reported using fingolimod.2, 3, 4, 5 Siponimod has shown nanomolar affinity for S1P1/5 receptors, inducing a profound and long-lasting internalization of S1P1 receptors.1, 6 The internalization of S1P1 receptors renders lymphocytes unresponsive to S1P, depriving them of an obligatory signal to egress from the lymph nodes and recirculate into the central nervous system, which, in turn, reduces neuroinflammation.7 Siponimod metabolism is well characterized. Siponimod is eliminated from the systemic circulation mainly due to metabolism and subsequent biliary and fecal excretion. The predominant hepatic enzymes responsible for siponimod metabolism are CYP2C9 (>70%) and, to a lesser extent, CYP3A4 (20%). After oral administration, siponimod is metabolized to M5 mainly by hydroxylation. M5 (hydroxylated metabolite) is converted to M3 by glucuronidation. These 2 metabolites have been tested for the agonistic activity on S1P1 receptors in vitro and were found to have a weak agonistic activity (M5, EC50: 470 [71] nmol/L and M3, EC50: >10,000 nmol/L) as compared with the parent compound (siponimod, EC50: 1.1 [0.41] nmol/L) (unpublished data on file, Novartis Pharma AG, Basel, Switzerland).

Expression of S1P1 receptors in atrial, septal, and ventricular cardiomyocytes and in the endothelial cells of cardiac vessels in humans implicates their role in the regulation of heart rate (HR).8, 9 Transient, dose-dependent decreases in HR and occasional asymptomatic first- and second-degree atrioventricular blocks (AVB) have been reported with S1P receptor modulators.4, 5 Consistent with the effects of S1P receptor modulators on HR, previous studies with siponimod identified a transient, dose-dependent decrease in HR at treatment initiation.1, 6, 10 However, the established dose-titration regimen of siponimod was able to attenuate the onset of bradyarrhythmic effects typically observed with other S1P receptor modulators.11

Drugs that prolong cardiac repolarization are associated with an increased risk of polymorphic ventricular tachycardia (Torsades de Pointes).12, 13, 14 Hence, intensive cardiac safety evaluation is mandated by the International Conference on Harmonisation (ICH) E14 guideline in a clinical thorough QT (TQT) study, typically in healthy subjects, for all new non-antiarrhythmic drugs with systemic bioavailability.15, 16, 17 In accordance with the regulatory guidelines, the present study assessed the effect of siponimod on cardiac repolarization, as evidenced by the QT and corrected QT interval (QTc) at steady state after administration of the therapeutic dose of 2 mg and a supratherapeutic dose of 10 mg in healthy subjects. The primary objective was to assess whether the effects of therapeutic and supratherapeutic doses of siponimod on the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF) exceeded the 5-ms regulatory threshold level of concern, as evidenced by an upper bound of a 2-sided 90% CI or a 1-sided 95% CI for the largest mean QTc effect of 10 ms. Secondary objectives included the evaluation of the effects on other ECG variables, including QTcI, HR, PR, and QRS and of morphologic ECG changes related to cardiac repolarization (abnormal ST segment, T or U waves). The pharmacokinetic (PK) properties of siponimod; PK and pharmacodynamic (PD) relationship of plasma concentrations of siponimod (and its main circulating metabolite M3, as well as its active metabolite M5) and the ECG variables; and the overall safety profile and tolerability of siponimod were also assessed.

Section snippets

Study Design

This was a randomized, double-blind, placebo-, and moxifloxacin-controlled, multiple oral dose study conducted in parallel groups of healthy adult male and female subjects. The study consisted of a screening period of up to 42 days, a 2-day baseline period, a treatment period of up to 18 days, and an end-of-study evaluation at approximately 14 to 21 days after the last administration of study drug (Figure 1). On baseline Day −1, all subjects underwent pre-dose safety assessments and received

Subject Disposition and Demographics

Of the 304 enrolled subjects, 281 (92.4%) were included in the PD analysis, and 270 (88.8%) completed the study. A CONSORT flow chart is shown in Figure 2. Main reasons for discontinuation included protocol deviations (n = 23), withdrawal of consent (n = 6), AEs (n = 2), administrative issues (n = 2), and loss to follow-up (n = 1). Mean (SD) age and body mass index of the study population were 35.0 (7.6) years (range 18−45 years) and 26.1 (2.6) kg/m2 (range 18.0−30.0 kg/m2), respectively. A

Discussion

Clear robust data on the effect of new chemical entities on ECG parameters and, in particular, on cardiac repolarization, as measured by the QTc interval, are a key regulatory requirement during drug development. The preclinical and clinical safety data did not reveal a potential of siponimod to adversely affect cardiac repolarization and cause QT prolongation. An in vitro study reported no significant inhibition of hERG channels (9% inhibition) stably expressed in HEK293 cells with siponimod

Conclusions

The results of this TQT study found no clinically significant arrhythmogenic potential at therapeutic and supratherapeutic doses of siponimod related to QT prolongation. The absence of outliers of significance in the categorical analysis of QTcF and the negative concentration-response further support the limited QT-prolonging potential of siponimod. The absence of relevant morphologic ECG changes indicated the lack of a relevant effect of siponimod on cardiac repolarisation. All observed ECG

Author contributions

Kasra Shakeri-Nejad, Vassilios Aslanis, Uday Kiran Veldandi, Louise Mooney, Nicole Pezous, Bruno Brendani, and EricLegangneux conceptualized and designed the study, analyzed and interpreted data from the study. Nicole Pezous conducted statistical analysis of the data. Axel Juan, Mark Allison, and Robert Perry were investigators for the clinical conduct of the study. All authors made significant contribution to data interpretation and writing/revision of the manuscript.

Conflict of Interest

All authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author). Axel Juan, Mark Allison, and Robert Perry, declare no support from any organization for the submitted work. Axel Juan was an employee of SeaView Research Inc., Miami, Florida, during the conduct of study, Mark Allison was an employee of Celerion, Tempe, Arizona, during the conduct of study. Robert Perry was an employee of Elite Research

Acknowledgments

The authors would like to thank Dr Pierre Jordaan (Organ Safety Expert, Novartis Pharma AG, Basel) for critically reviewing the manuscript. The authors would also like to acknowledge Rahul Birari (Medical communications, Novartis Healthcare Pvt. Ltd) for providing medical writing support, which encompassed preparation of a first draft, formatting, referencing, preparing tables and figures, incorporating the authors’ revisions, and submission all under the direction of the authors and Hashem

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