A comparison of XP23829 with DMF, the active ingredient of BG-12 (CMSC - ACTRIMS 2012) - Jun 1, 2012 - Mice treated with DMF at 15 and 90 mg/kg-eq of MMF showed a 29% and 32% reduction in last day disease score (LDDS) compared to vehicle-treated animals; Animals treated with XP23829 at 11 and 90mg/ kg-eq MMF had reductions in LDDS of 57% and 69%, respectively
Preclinical-animal • Multiple Sclerosis
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Annual Meeting of the Consortium of Multiple Sclerosis Center, ACTRIMS 2012, 30 May – 2 Jun 12; San Diego, CA
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Abstract # SC03
Background: A formulation of dimethyl fumarate (DMF), BG-12, has shown promising activity in two phase 3 clinical trials in relapsing-remitting multiple sclerosis (RRMS). Gastrointestinal (GI) disturbances accounted for a significant portion of the adverse events. After oral dosing, DMF is rapidly converted to monomethyl fumarate (MMF). Objectives: Recently we identified a novel MMF prodrug, XP23829. This study compared the efficacy of XP23829 and DMF in the experimental autoimmune encephalomyelitis (EAE) model in mouse and in GI irritation models in the rat. Methods: EAE: Female C57BL/6 mice were injected subcutaneously with an emulsion of phosphate-buffered saline containing 200 µg MOG35-55 peptide and complete Freund’s adjuvant containing Mycobacterium tuberculosis. Pertussis toxin was administered IP on days 0 and 2 post-immunization. Animals were dosed twice a day orally with compounds from days 3 to 27. Disease scores were determined daily. GI Irritation: Rats were dosed with XP23829 or DMF for 2 weeks, and PK samples were collected on day 14. Signs of GI irritation were evaluated at necropsy. Results: Mice treated with DMF at 15 and 90 mg/kg-eq of MMF showed a 29% and 32% reduction in last day disease score (LDDS) compared to vehicle-treated animals. Animals treated with XP23829 at 11 and 90 mg/kg-eq MMF had reductions in LDDS of 57% and 69%, respectively. Doses of DMF as low as 90 mg-eg MMF/kg/day caused dose-related gastric irritation that was observed at necropsy. This irritation was not observed with XP23829 at doses as high as 134 mg-eq MMF/kg/day. This dose of XP23829 produced approximately two-fold higher Cmax and area under the curve concentrations of MMF than the lowest dose of DMF that caused GI irritation. Conclusions: Animals receiving XP23829 in the EAE model had delayed disease onset and lower disease scores than animals receiving equivalent doses of DMF. XP23829 was able to achieve greater systemic concentrations of MMF without GI irritation than DMF. Further development of XP23829 is warranted
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