Abstract Details

Title Comparative Gastric Irritation of the Fumaric Acid Esters Dimethyl Fumarate (DMF) and XP23829 in Rat and Monkey

Topic MS and Related Diseases

Presentation(s) P01 - (-)

Poster/Presentation
Number 159

Objective

Background BACKGROUND: XP23829 and DMF are both prodrugs of monomethyl fumarate (MMF). DMF was shown to be effective in treatment of relapsing-remitting multiple sclerosis (MS) and psoriasis, but can cause gastrointestinal (GI) adverse effects. XP23829 has similar efficacy to DMF in animal models of MS and psoriasis, but shows less gastric irritation in acute (4 day) studies in rats.

Design/Methods DESIGN/METHODS: XP23829 was administered to CD rats (15/sex/dose) at 0 (vehicle), 150, 250, or 500 mg/kg/day and monkeys (3/sex/group) at 0 (vehicle), 25, 75, or 200 mg/kg/day for 4 weeks in GLP toxicity studies. DMF was administered to parallel groups at similar MMF exposures. GI toxicity was assessed by gross necropsy and histopathology. Toxicokinetics were assessed in parallel cohorts. Tissue distribution of 14C-labeled DMF and XP23829 (both labeled in fumarate) were compared in rats by whole body autoradiography.

Results RESULTS: DMF caused dose-dependent GI irritation in rats and monkeys after 4 weeks. In rats, 300 mg/kg/day DMF caused ulceration, necrosis and loss of mucosa of glandular stomach. At similar MMF exposure, XP23829 showed no adverse effects on glandular stomach. In monkeys, DMF showed greater gastric mucosal hyperplasia than XP23829. Both prodrugs were converted rapidly to MMF after absorption; DMF and XP23829 were not detected in the blood. Radioactivity in stomach mucosa was observed 24 hours after dosing 14C-labeled DMF but not for XP23829.

Conclusions CONCLUSIONS: DMF caused significantly greater local gastric irritation after 4 weeks in rats and monkeys. DMF, but not XP23829, remains localized in gastric mucosa 24 hours after oral dosing of rats. XP23829 may have the potential for a lower risk of GI side effects in clinical use compared to DMF.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
David Wustrow, PhD (XenoPort Inc.)	No disclosure on file
Brian E. McGeeney, MD (Boston University)	No disclosure on file
Kenneth Cundy, PhD	No disclosure on file

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