title: BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety.
abstract: BACKGROUND
  Multiple sclerosis (MS) is a chronic inflammatory disease, affecting more than 2.5 million people worldwide with more 400,000 cases in the United States alone. There has been considerable improvement in the treatment of MS, with the introduction of disease-modifying drugs; however, new oral therapies may provide additional benefit by providing an alternative treatment modality and the potential for improved adherence by avoiding the injection-associated side effects and anxiety encountered with some first-line agents. BG-12 (dimethyl fumarate) is an oral agent approved in the United States for the treatment of relapsing forms of MS.
  
  
  METHODS
  We review published literature about what is known about the mechanism of action of BG-12, and key efficacy and safety findings from three clinical studies in patients with relapsing-remitting MS (RRMS).
  
  
  RESULTS
  Data from preclinical studies have demonstrated that BG-12 may promote anti-inflammatory and cytoprotective activities that are mediated, at least in part, by the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway. Studies in animals have shown a protective effect of BG-12 on neuronal, axonal and myelin integrity. Results from a phase 2 study and two randomized double-blind placebo-controlled phase 3 studies, CONFIRM and DEFINE, have shown that BG-12 provides clinical and radiologic efficacy in patients with RRMS. At 2 years, BG-12 240 mg twice and three times daily reduced annualized relapse rate (CONFIRM primary endpoint) by 44% and 51% and the risk of relapse (DEFINE primary endpoint) by 49% and 50%, respectively, compared with placebo (all p < 0.001). BG-12 was generally well tolerated and had an acceptable safety profile, with a similar incidence of adverse events across treatment groups.
  
  
  CONCLUSIONS
  BG-12 may have cytoprotective and anti-inflammatory properties that contribute to its efficacy among patients with RRMS. Findings from phase 2 and 3 studies further support BG-12 as an effective initial therapy. ClinicalTrials.gov ID: NCT00168701; NCT00420212: NCT00451451.
authors.affiliation: Mellen Center for Multiple Sclerosis Treatment and Research , Cleveland Clinic, Cleveland, OH , USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
authors.forename: Mariko
authors.initials: M
authors.lastname: Kita
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Cohan
authors.forename: Lily Jung
authors.initials: LJ
authors.lastname: Henson
authors.forename: Javier
authors.initials: J
authors.lastname: Zambrano
authors.forename: Robert H
authors.initials: RH
authors.lastname: Scannevin
authors.forename: John
authors.initials: J
authors.lastname: O'Gorman
authors.forename: Mark
authors.initials: M
authors.lastname: Novas
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Dawson
authors.forename: J Theodore
authors.initials: JT
authors.lastname: Phillips
mesh_terms: D000328:Adult; D000818:Animals; D000069462:Dimethyl Fumarate; D004311:Double-Blind Method; D005260:Female; D005650:Fumarates / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy*; D051267:NF-E2-Related Factor 2 / Q000819:agonists; D051381:Rats
chemical_list: D005650:Fumarates; D007166:Immunosuppressive Agents; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000069462:Dimethyl Fumarate