Absence Of A Relevant Effect On Cardiac Repolarization In A QT/QTc (TQT) Study of RPC1063, A Novel, Selective S1P1 Receptor Agonist, In Healthy Adult Volunteers (P2.229)

Objective: Assess whether RPC1063 increases the corrected QT (QTc) interval compared to placebo (PBO). Background: RPC1063 is an orally available, potent, selective sphingosine-1-phosphate 1 receptor (S1P1R) agonist. Stimulation of S1P1R may improve pathological processes in multiple sclerosis and is associated with decrease in heart rate (HR) on initial dosing. Fingolimod, a non-selective S1PR agonist, demonstrated prolongation of QTc. S1P3R is expressed on mouse heart conduction tissue and may be responsible for QTc prolongation. Methods: This was a single-center, double-blind, randomized, placebo- and positive-controlled, parallel-group, nested crossover for positive control, TQT study of RPC1063. 124 healthy male and female subjects, aged 18-45 years were randomized in a 1:1 ratio to RPC1063 (0.25 to 2 mg dose titration regimen [DT]) or placebo. Moxifloxacin (MFX) 400 mg served as a positive control. QT assessments were performed at Baseline (BL), Day 10 and Day 14, and Days 2 and 17 (MFX). 24-hour continuous ECG monitoring was also performed for cardiac monitoring and HR characterization at BL, Day 1, and during dose escalation. Standard safety assessments were also included. Results: The upper 95% 1-sided confidence limit for QTc change from BL was always below 10 msec at both 1mg and 2mg doses, meeting pre-specified criteria to rule out a relevant QT effect of RPC1063. Assay sensitivity was demonstrated with QTc change from BL >5 msec following MXF treatment. DT was well tolerated, attenuated first dose effects, and minimized decreases in HR. Generally, RPC1063 treatment was well tolerated. AEs, including cardiac AEs, were generally similar in RPC1063 and control groups, and similar to those seen previously with RPC1063. Most common AEs were administration site reaction, headache, orthostatic hypotension, dizziness, musculoskeletal chest pain and constipation. No SAEs occurred in the study. Conclusions: The study confirmed the absence of a relevant effect of RPC1063 on QTc prolongation. Disclosure: Dr. Hartung has received personal compensation for activities with Receptos Inc., as an employee. Dr. Olson has nothing to disclose. Dr. Peach has received personal compensation for activities with Receptos Inc. as an employee. Dr. Peach holds stock and/or stock options from Receptos Inc. Dr. Boehm has received personal compensation for activities with Receptos Inc. as an employee. Dr. Boehm holds stock and/or stock options in Receptos Inc. Dr. Mendzelevski has received personal compensation for activities with Novartis, Teva Neuroscience, Galderma, Astex Pharmaceuticals, MediWould, Mersana Therapeutics, Nabriva Therapeutics, and Xention. Dr. Smith has received personal compensation for activities with Receptos as an employee. Dr. Smith holds stock and/or stock options in Receptos. Dr. Pan has received personal compensation for activities with Receptos as a consultant. Dr. Timony has received personal compensation for activities with Receptos Inc. as an employee. Dr. Timony holds stock and/or stock options in Receptos Inc. which sponsored research in which Dr. Timony was involved as an investigator. Dr. Gujrathi has received personal compensation for activities with Receptos as an employee. Dr. Gujrathi holds stock and/or stock options in Receptos.