Assessing RPC1063: A Potent S1P1R Agonist's Preclinical Safety Evaluation

The study aimed to assess the safety of RPC1063, a selective S1P1R agonist being developed for treating relapsing multiple sclerosis (RMS). The drug showed significant selectivity for S1P1R compared to other receptors, which may offer better tolerability. Toxicology studies were conducted on rats and monkeys over a period of 9 months, focusing on the reduction in absolute lymphocyte count (ALC) as an indicator of S1PR modulator activity.

The lowest doses were set to a pharmacologically active dose (PAD), which resulted in approximately a 50% decrease in ALC. The PAD was identified as 0.2 mg/kg/day for rats and 0.1 or 0.15 mg/kg/day for monkeys. No adverse effects were observed at this PAD, with the only findings being mild and reversible histopathological changes in the lung and kidney.

Clinical chemistry results were normal, with no liver parameter changes. The maximum concentration (Cmax) and area under the curve (AUC) of RPC1063 at the no observed adverse effect levels (NOAEL) in animals were more than 150 times higher than the clinical exposures at a dose that resulted in about a 70% reduction in ALC.

In contrast to RPC1063, chronic toxicology data for the non-selective S1PR modulator fingolimod showed fibrotic changes in multiple species, which were not seen with RPC1063. This difference is attributed to fingolimod's S1P3R agonist activity, which is linked to fibrotic events.

The conclusion of the study was that RPC1063 demonstrated a favorable preclinical safety profile, with the lack of fibrotic changes aligning with its selective action on S1P1R. Several individuals involved in the study received personal compensation and held stock or stock options in Receptos, Inc., the company developing RPC1063.