Safety, Tolerability, and Pharmacokinetics of BG-12 Administered with and without Aspirin: Key Findings from a Randomized, Double-Blind, Placebo-Controlled Trial in Healthy Volunteers (P04.136) (2012)

Objective: To evaluate the safety, tolerability, and pharmacokinetics of BG-12 (dimethyl fumarate) administered with or without aspirin. Background Oral BG-12 is currently being evaluated for treatment of relapsing-remitting multiple sclerosis (RRMS). In the Phase 3 study DEFINE, BG-12 240 mg BID and TID demonstrated efficacy on clinical and magnetic resonance imaging disease activity versus placebo. Common adverse events reported in BG-12-treated patients included flushing and gastrointestinal (GI)-related events. Most patients reported events that were mild or moderate in severity and reduced substantially in incidence after the first month of treatment. Design/Methods: In this double-blind placebo-controlled study, healthy volunteers were randomized to 4 days of treatment with BG-12 (or matching placebo) with or without aspirin 325 mg. Standard pharmacokinetic measures were obtained, measured by monomethyl fumarate (MMF) on days 1 and 4 of dosing. Flushing and GI events were assessed using several patient-reported severity scales. Potential flushing mediators were also explored. Results: Fifty-six subjects were enrolled and completed the study. BG-12 (as measured by MMF) concentration versus time profiles did not show evidence of accumulation and were not affected by aspirin administration. Mean flushing scores were mild and decreased over the 4-day treatment period in the BG-12-treated groups. Administration of aspirin further reduced flushing incidence and intensity. GI-related symptoms were infrequent and mild in intensity in all groups. A prostaglandin D 2 metabolite was elevated in some individuals treated with BG-12 and may be associated with flushing. Conclusions: With 4 days of BG-12 dosing, there was no accumulation of MMF, mean flushing scores were mild in intensity across all groups, and the incidence and severity of flushing decreased over the dosing period. Aspirin pretreatment further decreased the incidence and severity of flushing and did not adversely affect GI events. Overall, the safety and pharmacokinetic profiles of BG-12 were unaffected by aspirin administration. Supported by: Biogen Idec Inc. Disclosure: Dr. Sheikh has received personal compensation for activities with Biogen Idec as an employee. Dr. Nestorov has received personal compensation for activities with Biogen Idec. Dr. Russell has nothing to disclose. Dr. O9Gorman has received personal compensation for activities with Biogen Idec as an employee. Dr. Huang has received personal compensation for activities with Biogen Idec as an employee. Dr. Milne has received personal compensation for activities with Roche USA as a consultant. Dr. Milne9s laboratory has received research support from Biogen Idec. Dr. Stecher has received personal compensation for activities with Biogen Idec as an employee. Dr. Novas has received personal compensation for activities with Biogen Idec. Dr. Dawson has received personal compensation for activities with Biogen Idec Inc. as an employee.