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.

Scope:

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).

Findings:

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.

Keywords::

• BG-12
• Clinical trial phase 2
• Clinical trial phase 3
• Dimethyl fumarate
• Multiple sclerosis
• NF-E2-related factor 2

Transparency

Declaration of funding

This review was sponsored by Biogen Idec (Cambridge, MA, USA). Writing and editorial support was provided by Emily Seidman of CircleScience (Tytherington, UK) and funded by Biogen Idec.

Declaration of financial/other relationships

R.J.F. has received consultant fees from Allozyne, Avanir, Biogen Idec, Novartis, Questcor, and Teva, and grant and research support from Novartis. M.K. has received research support from Biogen Idec in connection with the CONFIRM trial and travel expenses related to speaking from Biogen Idec. S.L.C. has received consulting fees, honoraria, and research support from Biogen Idec and consulting fees and/or honoraria from Novartis, Acorda, Genzyme, Sanofi Aventis. L.J.H., Principal Investigator for DEFINE at Swedish Medical Center; received consulting fees from Biogen Idec, Genzyme, Novartis, Pfizer, Questcor, Sanofi Aventis, Serono, and Teva, and research support from Biogen, Genzyme, Novartis, Sanofi Aventis, and TCELNA. J.T.P. has received honoraria from Acorda, Biogen Idec, Genzyme, Novartis, and Teva; research support from Biogen Idec and Roche. J.Z., R.H.S., J.O’G., M.N., and K.T.D. are employees of Biogen Idec.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

The authors thank CircleScience, Tytherington, UK, supported by Biogen Idec Inc., for their assistance in the preparation of this manuscript, funded by Biogen Idec.

Previous presentation: These data have been previously presented at: European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Lyon, France, 10–13 October 2012; Consortium of Multiple Sclerosis Centers (CMSC), San Diego, CA, 30 May–2 June 2012; American Academy of Neurology (AAN), New Orleans, LA, 21–28 April 2012; European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Amsterdam, Netherlands, 19–22 October 2011; American Academy of Neurology (AAN), Honolulu, HI, 9–16 April 2011; European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Gothenburg, Sweden, 13–16 October 2010; European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), Dusseldorf, Germany, 9–12 September 2009.