Dimethyl Fumarate and Monomethyl Fumarate are Distinguished by Non-Overlapping Pharmacodynamic Effects In Vivo (P1.206)

OBJECTIVE: Determine if the pharmacodynamic and therapeutic effects of dimethyl fumarate (DMF) and monomethyl fumarate (MMF) are completely overlapping, or if distinct responses are induced in naive and experimental autoimmune encephalomyelitis (EAE) mice. BACKGROUND: Delayed-release DMF is approved in the U.S., Canada, and Australia for the treatment of relapsing MS. It is unknown exactly how delayed-release DMF exerts clinical effects; however, DMF promotes anti-inflammatory and neuroprotective responses, both of which may impact MS pathophysiology. DMF is rapidly metabolized in vivo to MMF, and both are pharmacologically active. It is unknown if delayed-release DMF therapeutic effects are mediated through DMF, MMF, or some combination of the two. Understanding the pharmacodynamic properties of DMF and MMF would provide important insights into the delayed-release DMF mechanisms of action. DESIGN/METHODS: Naive C57BL/6 mice were dosed orally with vehicle, DMF, or MMF and pharmacodynamic responses were evaluated in multiple tissues and whole blood. Differentially expressed genes and immune cell surface markers were identified by comparing DMF- or MMF-treated mice to matched vehicle controls. Mice in which EAE was induced by myelin oligodendrocyte glycoprotein (MOG) were evaluated for DMF or MMF therapeutic effects, and pharmacodynamic responses were also evaluated. RESULTS: In naive animals, pharmacodynamic responses to DMF versus MMF exhibited some overlap, but multiple distinct responses to each treatment were also evident. In EAE animals, similar patterns of pharmacodynamic effects were observed, with some overlapping responses, but also numerous distinct responses unique to either DMF or MMF. DMF produced a more robust clinical effect on disease score compared to MMF. CONCLUSIONS: DMF and MMF induce some common pharmacodynamic responses, but are also clearly differentiated from each other. This indicates that DMF and MMF are not therapeutically equivalent. Thus, DMF cannot be considered simply, or only as a prodrug of MMF, as it has distinct pharmacological properties. Study Supported by: Biogen Idec, Inc. Disclosure: Dr. Brennan has received personal compensation for activities with Biogen Idec as an employee. Dr. Allaire has received personal compensation for activities with Biogen Idec as an employee. Dr. Allaire holds stock and/or stock options in Biogen Idec, which sponsored research in which Dr. Allaire was involved as an investigator. Dr Allaire holds stock and/or stock options in Biogen Idec. Dr. Huss has received personal compensation in an editorial capacity for Biogen Idec. Dr. Huss holds stock and/or stock options in Biogen Idec. Dr. Cullen has received personal compensation for activities with Biogen Idec as an employee. Dr. Thai has received personal compensation for activities with Biogen Idec as an employee. Dr. Szak has received personal compensation for activities with Biogen Idec as an employee. Dr. Szak holds stock and/or stock options in Biogen Idec stock, which sponsored research in which Dr. Szak was involved as an investigator. Dr. Thomas has received personal compensation for activities with Biogen Idec as an employee. Dr. Gianni has received personal compensation for activities with Biogen Idec as an employee. Dr. Carulli has received personal compensation for activities with Biogen Idec as an employee. Dr. Fontenot has received personal compensation for activities with Biogen Idec as an employee. Dr. Fontenot holds stock and/or stock options in Biogen Idec. Dr. Wipke has received personal compensation for activities with Biogen Idec as an employee. Dr. Rhodes has received personal compensation for activities with Biogen Idec as an employee. Dr. Rhodes has received research support from Biogen Idec. Dr. Scannevin has received personal compensation for activities with Biogen Idec as an employee. Dr. Scannevin holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Scannevin was involved as an investigator.