Effects of Therapeutic and Supratherapeutic Doses of Siponimod (BAF312), a Selective S1P1,5 Receptor Modulator, on Cardiac Repolarization: Results of a Thorough QTc (TQT) Study (P2.232)

OBJECTIVE: To assess if the placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF) effect of therapeutic (2mg) and supratherapeutic (10mg) doses of siponimod (BAF312) exceeds the regulatory threshold level of concern, defined as 5ms, as evidenced by upper bound of the two-sided 90% CI for the largest mean QTc effect of 10ms. BACKGROUND: Siponimod is a next generation selective sphingosine 1-phosphate -1 and -5 receptor modulator, currently in Phase 3 development for the treatment of secondary progressive multiple sclerosis. This TQT study investigated siponimod effects on cardiac repolarization in healthy subjects. DESIGN/METHODS: This was a randomized, double-blind, parallel-group, placebo- and moxifloxacin-controlled multiple-dose study. Eligible subjects (N=304) were randomized in three groups to receive siponimod (up-titration to 2mg and 10mg over 18 days), placebo (Days -1-18) or moxifloxacin 400mg (Days 10 and 18). Primary assessments were 12-lead Holter recording (1h pre-dose until 24h post-dose) at baseline, Day 10 and Day 18 and associated triplicate ECG extractions. RESULTS: 270/304 subjects completed the study. Siponimod 2mg and 10mg doses resulted in upper bounds of the two-sided 90% CI mean ΔΔQTcF below 10ms at all time-points. Maximum mean ΔΔQTcF effect was 7.8ms and 7.2ms at 3h post-dose. Categorical analysis revealed no treatment-emergent QTc values above 480ms and no QTc increases of above 60ms from baseline. Positive correlations between siponimod plasma concentration and QTc were characterized by flat regression lines. Assay sensitivity was demonstrated and maximum mean ΔΔQTcF effect of moxifloxacin 400mg at 3h post-dose were 11.69ms on Day 10 and 12.62ms on Day 18. Adverse events were mild to moderate in intensity. CONCLUSIONS: Siponimod was not associated with clinically significant QT-prolongation and the results did not indicate arrhythmogenic potential. Morphologic ECG changes did not demonstrate significant effects on cardiac repolarization. Absence of significant dose response, a weak concentration effect, and no significant categorical analysis outliers support this conclusion. Study Supported by: Novartis Pharma AG Disclosure: Dr. Shakeri-Nejad has received personal compensation for activities with Novartis as an employee. Dr. Mooney has received personal compensation for activities with Novartis as an employee. Dr. Aslanis has received personal compensation for activities with Novartis. Dr. Veldandi has received personal compensation for activities with Novartis as an employee. Dr. Pezous has received personal compensation for activities with Novartis as an employee. Dr. Legangneux has received personal compensation for activities with Novartis.