TECFIDERA™ was recently approved by the U.S. Food and Drug Administration for the treatment of subjects with relapsing forms of multiple sclerosis. TECFIDERA™ contains dimethyl fumarate (DMF), which has the following structure:

The first Phase 3 study, DEFINE (ClinicalTrials.gov identifier NCT00420212), demonstrated that DMF significantly reduced clinical relapses, accumulation of disability progression, and lesion number and volume compared with placebo after two years of treatment. See, e.g., Gold R, et al. N Engl J Med 2012; 367: 1098-107. These findings were supported by the results of the second phase 3 study, CONFIRM, which additionally evaluated subcutaneous glatiramer acetate as an active reference treatment (rater-blind). See, e.g., Fox R J, et al. N Engl J Med 2012; 367: 1087-97.
Preclinical and clinical data suggest dimethyl fumarate (DMF) has beneficial effects on neuroinflammation, neurodegeneration, and toxic-oxidative stress. See, e.g., Linker R. A., et al., Brain 2011; 134:678-92 and Scannevin R. H., et al., J Pharmacol Exp Ther 2012, 341:274-284. The beneficial effects of DMF and its primary metabolite, monomethyl fumarate (MMF), appear to be mediated, at least in part, through activation of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) antioxidant response pathway, an important cellular defense. Nrf2 is expressed ubiquitously in a range of tissues and, under normal basal conditions, is sequestered in the cytoplasm in a complex with Keap1 protein. However, when cells are under oxidative stress and overloaded with reactive oxygen or nitrogen species (ROS or RNS), or electrophilic entities, Nrf2 rapidly translocates to the nucleus, forms heterodimer with small protein Maf, then binds to the antioxidant response element resulting in increased transcription of several antioxidant and detoxifying genes including NQO-1, HO-1, and SRXN1. See, e.g., Nguyen et al., Annu Rev Pharmacol Toxicol 2003; 43:233-260; McMahon et al., Cancer Res 2001; 61:3299-3307. Sustained oxidative stress has been implicated in the pathogenesis of a variety of neurodegenerative diseases such as multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, and Parkinson's disease. For reviews, see, e.g., van Muiswinkel et al., Curr. Drug Targets CNS—Neurol. Disord, 2005; 4:267-281; Burton N. C. et al., Comprehensive Toxicology, 2010, 59-69.
DMF quickly gets absorbed in vivo and converted to MMF. The half-life of MMF was shown to be approximately 1 hour (0.9 h in rat at 100 mg/Kg oral dose). Both DMF and MMF are metabolized by esterases which are ubiquitous in the GI tract, blood and tissues.
DMF has demonstrated an acceptable safety profile in the DEFINE and CONFIRM studies. However, tolerability issues such as flushing and gastrointestinal events were observed. While these events are generally mild to moderate in severity, there remains a desire to reduce such events to further increase patient compliance and improve patient's quality of life. These mild adverse events could be the result of off-target events induced either by DMF or MMF and or the metabolites derived from them. For example, recent reports (Hanson et al., J. Clin. Invest. 2010, 120, 2910-2919; Hanson et al., Pharmacol. Ther. 2012, 136, 1-7.) indicate that MMF induced flushing is due to the activation of the G-protein-coupled receptor HCA2 (Hydroxy-carboxylic acid receptor 2, GPR109A).
There is a need for DMF analogs having an improved pharmacokinetic profile.
USPTO Backgrounds
USPTO Backgrounds