Abstract Details

Title Metabolites of RPC1063 Contribute to In Vivo Efficacy

Topic MS and Related Diseases

Presentation(s) P05 - (-)

Poster/Presentation
Number 157

Objective

Background BACKGROUND: RPC1063 is a potent, selective small molecule sphingosine 1-phosphate-1 receptor (S1P1R) agonist in clinical development for treating relapsing multiple sclerosis. RPC1063 is efficacious in preclinical models of experimental autoimmune encephalomyelitis (EAE).

Design/Methods DESIGN/METHODS: Metabolites of RPC1063 were identified, and the potency and specificity on the S1PR family assessed. The metabolite/parent ratio, pharmacokinetics and bio-distribution were determined in vivo. Efficacy in MOG(35-55) peptide induced mouse EAE was assessed and lymphopenia monitored as a pharmacodynamic biomarker. Toxicity risk was assessed on hERG channel, CYPs and a CEREP panel.

Results RESULTS: After dosing RPC1063, RP101075 was identified in all preclinical species and human subjects, while RP101442 was present in human, monkey, rat and rabbit, but not detected in mouse or dog. On average, the M/P ratio for RP101075 and RP101442 is 0.85 and 0.15, respectively. Like RPC1063, RP101075 and RP101442 cross the blood brain barrier, with brain to blood ratios of 10, 31 and 4, respectively. In vitro, RP101075 and RP101442 are as potent (EC50 0.185 nM and 0.131 nM respectively) as RPC1063 (EC50 0.156 nM) on the S1P1R for inhibition of cAMP production. RP101075 and RP101442 are also highly selective for S1P1R, a profile shared with the parent molecule. In preclinical species, RP101075 and RP101442 produce robust, dose dependent lymphopenia. RP101075 (0.1 and 0.3mpk) and RP0101442 (0.4 and 0.8mpk) had therapeutic benefit in MOG35-55 peptide induced mouse EAE, achieving efficacy equivalent to RPC1063 and FTY720 (GilenyaTM). Finally, there was no significant activity on a broad CEREP panel, CYP enzymes or in hERG channel assays with RPC1063, RP101075 or RP101442.

Conclusions CONCLUSIONS: RPC1063 shows a favorable profile for the treatment of relapsing multiple sclerosis with significant metabolites likely to contribute to disease efficacy.

Authors/Disclosures
Fiona Scott, PhD (Receptos Inc.) PRESENTER	No disclosure on file
	No disclosure on file
Antoine Gueguen, MD (Fondation Oph. A. De Rothschild, Service De Neurologie)	An immediate family member of Dr. Gueguen has received personal compensation for serving as an employee of ABBVIE. Dr. Gueguen has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for ALEXION. Dr. Gueguen has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Jonhson&Jonhson. Dr. Gueguen has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Johnson&Johnson. The institution of Dr. Gueguen has received research support from BrainEver. The institution of Dr. Gueguen has received research support from Pixyl. The institution of Dr. Gueguen has received research support from Kalsiom. The institution of Dr. Gueguen has received research support from Ministére de la Santé, France.
	No disclosure on file
Robert J. Peach, PhD (Receptos)	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file

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