Safety and Tolerability of Orally Administered RPC1063, a Novel S1P1 Receptor Modulator, in Healthy Adult Volunteers, Results of a Phase 1 Study (P01.178)

OBJECTIVE: To assess safety and tolerability of oral RPC1063 as single and multiple daily doses in healthy adults. BACKGROUND: RPC1063 is an oral, potent, selective sphingosine-1-phosphate receptor (S1P1R) modulator. Stimulation of the S1P1R results in sequestration of lymphocytes, which improves MS. DESIGN/METHODS: Randomized, double-blind, placebo-controlled, single and multiple ascending dose escalation, first-in-human study of RPC1063. Subjects were 88 healthy male and female subjects aged 18-55 years. The study included a single ascending dose (SAD) portion, multiple ascending dose portions for 7(MAD-7) and 28day(MAD-28), and a dose titration cohort. Cohorts included 8 subjects assigned to RPC1063 (6) or placebo (2). Doses were 0.3-3 mg(SAD), 0.3-2 mg(MAD-7), and 0.3-1.5 mg(MAD-28). RESULTS: Generally, RPC1063 treatment was well-tolerated. The most common AEs with RPC1063 were headache(9), somnolence(6), nausea(6), dizziness(5), fatigue(4), abdominal pain(3), and pruritus(3). No severe AEs were observed. AEs were generally similar in the placebo group. One MAD-28 subject receiving 1.5 mg had second degree, Mobitz-type-1-atrioventricular block on Day 1 of dosing and was discontinued; all other subjects completed the study. In the 3 mg SAD, 2 subjects experienced 2-second-sinus-pause during periods of sinus bradycardia, and 1 subject experienced intermittent bradycardia. These AEs resolved without medical intervention. A mild dose-dependent reduction in heart rate (HR) was observed with RPC1063. Dose titration appeared to attenuate reduction in HR. Two subjects in the 2 mg MAD-7 cohort had mild asymptomatic PFT abnormalities that resolved without medical intervention. Lymphocyte counts, used as a pharmacodynamic (PD) marker, decreased from baseline by 34% and 65% at doses of 0.3 and 1 mg, respectively. No apparent drug-related effects were observed for other clinical laboratory or ophthalmologic exams. CONCLUSIONS: RPC1063 was generally well tolerated, with a robust PD effect on lymphocyte counts seen at all doses. The emerging favorable safety and PD profile of RPC1063 support its continued development in patients with MS. Disclosure: Dr. Olson has received personal compensation for activities with Receptos as an employee. Dr. Olson holds stock and/or stock options in Receptos. Dr. Hartung has received personal compensation for activities with Receptos as an employee. Dr. Hartung holds stock and/or stock options in Receptos. Mr. Timony has received personal compensation for activities with Receptos, Inc. as an employee. Mr. Timony holds stock and/or stock options in Receptos, Inc. Dr. Peach has received personal compensation for activities with Receptos Inc. 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 from Receptos Inc. Dr. Rosen has received personal compensation for activities with Receptos Inc. as a consultant. Dr. Rosen holds stock and/or stock options in Receptos Inc. Dr. Smith has received personal compensation from Receptos. Dr. Smith holds stock and/or stock options in Receptos. Dr. Pan has received personal compensation for actvities with Receptos as a consultant. Ms. Brooks has received personal compensation for activities with Receptos Inc. as an employee. Ms. Brooks holds stock and/or stock options in Receptos Inc. Dr. Gujrathi has received personal compensation for activities with Receptos. Dr. Gujrathi holds stock and/or stock options in Receptos.