P014 Analysis of QT Interval Prolongation of Amiselimod in Healthy Subjects: A Phase 1 Randomized Controlled Trial

P014

Analysis of QT Interval Prolongation of Amiselimod in Healthy Subjects: A Phase 1 Randomized Controlled Trial

Hanauer Stephen1, O'Reilly Terry2, Lester Robert2, Slatkin Neal3, Lee Jimin4, Franklin Howard3, Bulawski Angela4, Israel Robert4
1 Feinberg School of Medicine, Chicago, United States, 2 Celerion, Tempe, United States, 3 Salix Pharmaceuticals, Bridgewater, United States, 4 Bausch Health US, LLC, Bridgewater, United States

BACKGROUND: Amiselimod, a selective sphingosine 1-phosphate receptor modulator, is in development for the treatment of inflammatory bowel disease. Unlike fingolimod, amiselimod does not appear to impact early changes in heart rate or increase the risk of bradycardia.1 This phase 1 analysis assessed the potential for amiselimod and its active metabolite, MT-1303-P, to invoke QT interval prolongation.

METHODS: A randomized, double-blind, multiple-dose, placebo-controlled, parallel study with a nested crossover design evaluated the effects of multiple amiselimod doses on QT prolongation. Healthy adults were randomized in a 2:1:1 ratio during a 28-day treatment period accordingly: a single dose of placebo followed by amiselimod (titrated daily doses of 0.4 to 1.6 mg to achieve steady-state concentrations); a single dose of moxifloxacin 400 mg followed by placebo; or placebo followed by a single dose of moxifloxacin 400 mg. Moxifloxacin prolongs QT interval duration and therefore served as a positive control to determine assay sensitivity. A full 24-hour continuous 12-lead electrocardiogram recording (extracted in triplicate) and time-matched pharmacokinetic samples were taken at baseline, day 1, day 13, and day 26. The primary endpoint compared the QT mean difference between amiselimod/MT-1303-P and placebo in the time-matched change from baseline (ddQTc). The QT interval was corrected for effect of heart rate by Fridericia's method (QTcF). The analysis used a linear mixed-effects model with the change from time-matched baseline QTcF as the dependent variable. A 2-sided 90% confidence interval (CI) was calculated as the difference in treatment QTcF, which was fitted across all time points on days 13 and 26. The relationship between amiselimod/MT-1303-P plasma concentrations (Cmax) and time-matched treatment differences in QTcF change from baseline between amiselimod and placebo was quantified using a linear mixed-effects modeling approach.

RESULTS: This analysis included 183 subjects (amiselimod n=92; moxifloxacin n=91). Approximately 40% were female, >80% were white, and the mean (standard deviation) age was 39.0 (8.8) years. Statistical modeling of change from baseline dQTcF between amiselimod and placebo for day 13 and day 26 showed that the upper limits of the 90% CIs of the differences of LS means were <10 msec for all postdose time points, indicating that amiselimod did not have a significant effect on QT interval prolongation. For moxifloxacin, the lower limits of the 90% CIs of the differences between moxifloxacin and placebo of LS means for all 4 time points were >5 msec, confirming assay sensitivity. No subject in any treatment group had a QTcF >500 msec or a change from baseline in QTcF >60 msec at any timepoint. Predicted ddQTcF at the geometric mean Cmax of amiselimod/MT-1303P were slightly higher on day 26 than day 13. However, at the geometric mean Cmax of amiselimod/MT-1303-P following oral dosing to steady-state concentrations for the 0.4 mg amiselimod dose (day 13) and 0.8 mg amiselimod dose (day 26), the upper limits of the 90% CIs were well below 10 msec, indicating that QTcF prolongation was not observed.

CONCLUSION(S): In this cardiodynamic analysis, amiselimod did not invoke a significant effect on QT interval prolongation.
1. Harada T, et al. Br J Clin Pharmacol. 2017;83(5):1011-1027.