Effect of laquinimod, a novel immunomodulator in development for treatment of multiple sclerosis, on cardiac repolarization in healthy subjects: A thorough QT/QTc study

Laquinimod (TV‐5600, Teva Pharmaceuticals) is a quinoline‐3‐carboxamide derivative in clinical development as a once daily oral treatment for Relapsing Remitting multiple sclerosis (MS), Primary Progressive MS, Crohn's disease and Huntington's disease. Objective: The primary objective of this study was to define the effect of laquinimod, on cardiac safety by assessing its effect vs placebo on the 12‐lead electrocardiogram (ECG) with a focus on QTc duration. Moxifloxacin was also included to demonstrate assay sensitivity. Method: This randomized, double‐blind study included 4 parallel‐ groups of healthy subjects. Subjects received a dose of either 0.6 or 1.2 mg/day laquinimod for 14 days, placebo for 14 days, or 13 days of placebo followed by a single dose of 400 mg moxifloxacin on Day 14. Continuous ECGs were recorded on Day 1 (baseline) and Days 14 to 17 and 4 ECGs were extracted at predefined time points. The primary endpoint was an analysis of variance of the time‐matched change from baseline in individual placebo corrected QTc (ddQTcI) providing an estimate for each time point and its 2‐sided 90% confidence interval (CI). Blood samples at each time point were collected for laquinimod pharmacokinetics. Linear mixed effects modeling was used to quantify the relationship between laquinimod plasma concentration and ddQTcI. Safety assessments included adverse event monitoring, vital signs, clinical laboratory tests and physical examinations. Results: A total of 200 subjects were randomized and 195 were included in the ECG analysis. The upper limits of the 2‐sided 90% CI for ddQTcI for both laquinimod doses were below 10 ms at all time points, whilst the lower limits for moxifloxacin exceeded 5 ms providing assay sensitivity. Laquinimod did not affect heart rate, PR or QRS interval durations. The relationship between ddQTcI and laquinimod plasma concentration showed no signal of change in ddQTcI from baseline with increasing laquinimod levels. The safety and tolerability of laquinimod were consistent with the known safety profile of laquinimod in healthy subjects and MS patients. Conclusions: Laquinimod does not affect the ECG and especially cardiac repolarization and is well tolerated at doses of 0.6 and 1.2 mg/day.