The Preclinical Safety Profile of RPC1063, a Selective and Potent Sphingosine 1-Phosphate 1 Receptor (S1P1R) Agonist (P01.158)

OBJECTIVE: Evaluate the preclinical safety profile of the selective S1P1R agonist RPC1063. BACKGROUND: RPC1063 is being developed to treat relapsing multiple sclerosis (RMS). RPC1063 demonstrates 269-fold selectivity for S1P1R over S1P5R, and greater than 20,000-fold selectivity over S1P2R, S1P3R and S1P4R; potential tolerability advantages conferred by selectively for S1P1R are discussed. DESIGN/METHODS: RPC1063 was administered orally in rat and monkey GLP toxicology studies of up to 9-months duration. Reduction in absolute lymphocyte count (ALC), an established bio-marker for activity of S1PR modulators in RMS, was used to set the lowest doses to a pharmacologically active dose (PAD; defined as an ∼50% decrease in ALC at trough). RESULTS: No observed adverse effect levels (NOAEL) were established in all toxicology studies at a PAD, which was the lowest dose level in both species (0.2 mg/kg/d in rats and 0.1 or 0.15 mg/kg/d in monkeys). Hematology findings were limited to dose-related and rapidly reversible decreases in ALC, a change consistent with the pharmacologic mechanism. Clinical chemistry findings were unremarkable; no changes were observed in liver parameters. NOAELs were driven by mild and fully reversible histopathology findings in the lung (histiocytosis) and kidney (anisocytosis). RPC1063 C max and AUC at the animal NOAELs exceeded the clinical exposures at a dose producing ∼70% reduction in ALC (based upon Phase I data) by > 150-fold, suggesting a broad safety margin. Publically available chronic toxicology data of the non-selective S1PR modulator fingolimod (Gilenya®) demonstrate findings in multiple species that were not observed with RPC1063 including fibrotic changes in heart and lung. The findings unique to fingolimod, which also has S1P3R agonist activity, are consistent with fibrotic events described in the literature related to signaling through S1P3R. CONCLUSIONS: A favorable preclinical safety profile has been established for RPC1063. The absence of fibrotic changes with RPC1063 is consistent with selectivity of RPC1063 towards S1P1R. Disclosure: 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. 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. Powell has received personal compensation for activities with Receptos Inc. Dr. Powell holds stock and/or stock options in Receptos, Inc. Dr. Dedman has received personal compensation for activities with Receptos Inc. as an employee. Dr. Dedman holds stock and/or stock options in Receptos Inc. Dr. Scott has received personal compensation for activities with Receptos Inc. as an employee. Dr. Scott holds stock options in Receptos Inc. Dr. Martinborough has received personal compensation for activities with Receptos Inc as an employee. Dr. Martinborough 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 an advisor. Dr. Rosen 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.