Efficacy and safety of BG-12 (dimethyl fumarate) and other disease-modifying therapies for the treatment of relapsing–remitting multiple sclerosis: a systematic review and mixed treatment comparison

Abstract

Objective:

Currently, direct comparative evidence or head-to-head data between BG-12 (dimethyl fumarate) and other disease-modifying treatments (DMTs) is limited. This study is a systematic review and data synthesis of published randomized clinical trials comparing the efficacy and safety of existing DMTs to BG-12 for relapsing–remitting multiple sclerosis (RRMS).

Methods:

A systematic review was conducted by searching MEDLINE, EMBASE, and the Cochrane Library for English-language publications from 1 January 1960 to 15 November 2012. Clinicaltrials.gov, metaRegister of Controlled Trials, and conference proceedings from relevant annual symposia were also hand searched. Two independent reviewers collected and extracted data, with discrepancies reconciled by a third reviewer. Included studies were randomized controlled trials (RCTs) of DMTs (interferon [IFN] beta-1a, IFN beta-1b, glatiramer acetate [GA], BG-12, fingolimod, natalizumab, and teriflunomide) in adults with RRMS. Mixed treatment comparisons were conducted to derive the relative effect size for the included treatments. Annualized relapse rate (ARR), disability progression, and safety outcomes were assessed.

Results:

BG-12 240 mg twice a day (BID) significantly reduces ARR compared to placebo (rate ratio: 0.529 [95% CI: 0.451–0.620]), IFNs (0.76 [95% CI: 0.639–0.904]), GA (0.795 [95% CI: 0.668–0.947]), and teriflunomide 7 mg and 14 mg (0.769 [95% CI: 0.610–0.970] and 0.775 [95% CI: 0.614–0.979]), and does not show a significant difference when compared to fingolimod. Only natalizumab was significantly superior to BG-12 in reducing ARR. BG-12 also demonstrated favorable results for disability and safety outcomes.

Conclusion:

Based on indirect comparison, BG-12 offers an effective oral treatment option for patients with RRMS with an overall promising efficacy and safety profile compared to currently approved DMTs. Key limitations of the systematic review were the large heterogeneity in patients enrolled and the variability in the definition of outcomes in included trials.

Keywords::

• Efficacy
• Mixed treatment comparison
• Multiple sclerosis
• Relapsing
• remitting
• RRMS
• Safety

Transparency

Declaration of funding

This study was funded by Biogen Idec US. Biogen is developing BG-12 for patients with multiple sclerosis.

The authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors, and are fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development. M.H., R.J.F., and E.H. contributed to the manuscript review. N.C.K. contributed to the interpretation of results and manuscript review. S.A. conceptualized the study design. B.D. contributed to study design and methodology, interpretation of results, and manuscript review. S.P.S. contributed to methodology, interpretation of results, and manuscript review. M.K.S. and A.T. performed the data collection, analysis, and contributed to manuscript review.

Declaration of financial/other relationships

N.C.K., S.A., S.P.S., and B.D. have disclosed that they are employees of Biogen Idec. M.H., R.J.F., and E.H. receive honoraria from Biogen Idec. E.H. is also supported by the Czech Ministry of Education (MSM 0021620849, PRVOUK-P26/LF1/4). M.K.S. and A.T. are employees of HERON, a company that received funding from Biogen Idec to conduct this study.

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

With thanks to the evidence review team at HERON Health PVT for their assistance with data collection during the study. With thanks also to Ebony Samuels, Catherine Kielar, and Sarah Collington at HERON Evidence Development UK for their assistance with the preparation of the manuscript.

Previous presentation: Data from the current study has been presented in poster form at the American Academy of Neurology’s 65th annual meeting in San Diego, 16–23 March 2013.

Notes

*Avonex is a registered trade name of Biogen Idec MA Inc., United States

^†Betaseron is a registered trade name of Bayer Schering Pharma, Germany

^‡Extavia is a registered trade name of Novartis AG, Switzerland

^§Rebif is a registered trade name of Ares Trading SA, Switzerland

^∥Copaxone is a registered trade name of Teva Pharmaceutical Industries Ltd, Israel

^⊥Tysabri is a registered trade name of Elan Pharmaceuticals Inc., United States

^††Aubagio is a registered trade name of Genzyme, a Sanofi company, United States

^‡‡Novantrone is a registered trade name of EMD Serono, Switzerland

^§§Gilenya is a registered trade name of Novartis AG, Switzerland

^⊥⊥Tecfidera is a registered trade name of Biogen Idec MA Inc, United States