BG00012 - A Novel Oral Therapy in Development for the Treatment of Multiple Sclerosis

BG00012 - A Novel Oral Therapy in Development for the Treatment of Multiple Sclerosis

Fox Robert J
US Neurological Disease 2007 - Issue II
Published: October 2008
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Multiple sclerosis (MS) is an inflammatory disease of the brain and spinal cord characterized by focal areas of demyelination and neuronal destruction. Historically, disease-modifying therapies used to treat MS have been administered by injection, exerting their effects through generalized immunomodulatory and anti-inflammatory mechanisms.1 These injection therapies are only moderately effective in reducing relapses and disability progression,2–5 and many patients discontinue therapy due to tolerability concerns, fear, and/or inconvenience of frequent injections.6,7 Thus, there is an unmet medical need in MS for safe and effective oral therapies with novel mechanisms of action.

Similar to MS, psoriasis is an autoimmune-mediated disorder. Fumaric acid esters (FAEs) have been used for the treatment of psoriasis in Europe for over 20 years, and a formulation of FAEs—dimethyl fumarate and ethylhydrogen fumarate (Fumaderm®)—has been approved for the treatment of severe chronic plaque psoriasis in Germany since 1994.8–12 BG00012 is an oral formulation of dimethyl fumarate that may exert a combination of anti-inflammatory and neuroprotective biological effects. Pilot and phase II clinical studies of Fumaderm and BG00012, respectively, in patients with MS have shown positive results, and BG00012 holds promise to be one of the first oral therapies available for the treatment of relapsing MS.

This article discusses the potential mechanisms of action of BG00012 and reviews the available clinical data of its efficacy and safety in patients with MS. In addition, two phase III clinical trials of BG00012 in patients with relapsing–remitting MS that are currently recruiting patients are described.

Potential Mechanisms of Action in Multiple Sclerosis
MS is an autoimmune-mediated disorder characterized by inflammation, destruction of myelin, loss of oligodendrocytes, axonal damage, and subsequent neuronal loss in the central nervous system (CNS).13–16 Although the pathogenesis of MS is not completely understood, blood–brain barrier (BBB) breakdown has been postulated as an early event in the disease process.17 It is believed that interactions between adhesion molecules on activated leukocytes and their complementary receptors on endothelial cells of the vessel wall promote leukocyte migration across the BBB.18 In the CNS, immune cells initiate a series of events that lead to upregulation of the expression of endothelial adhesion molecules, recruitment of additional lymphocytes and monocytes, and production of inflammatory cytokines.19,20 In addition, there is accumulating scientific evidence that oxidative stress may play a major role in the neuronal damage that occurs in MS.21 For example, activated macrophages and microglial cells may degrade myelin and damage oligodendrocytes by generating oxygen or nitrogen free radicals, producing excitatory amino acids, and releasing proteolytic and lipolytic enzymes.22

FAEs have been shown to affect aspects of the inflammatory cascade thought to be involved in MS. Data from in vitro studies showed that dimethyl fumarate and related FAEs increase the production and induce the expression of anti-inflammatory cytokines, such as interleukin (IL)-10, IL-4, and IL-5.23–26 Other in vitro studies demonstrated that dimethyl fumarate and its primary metabolite, monomethyl fumarate, can both inhibit expression of pro-inflammatory cytokines such as IL-6, IL-1β, and tumour necrosis factor (TNF)-α, as well as inhibiting the secondary effects of inflammatory cytokines such as IL-1β and TNF-α.25,27–31 Hence, it is thought that dimethyl fumarate can induce a shift from a T helper (Th)-1 (pro-inflammatory) to a Th-2 (anti-inflammatory) T-cell response.32

In addition to exerting anti-inflammatory effects, BG00012 may modulate metabolic homeostasis and cellular response to oxidative stress, a possible cause of cell and tissue damage in persistent inflammation (see Figure 1).


Figure 1: BG00012 May Induce Detoxification and Cellular Protection

BG00012 May Induce Detoxification and Cellular Protection

BG00012 induces the cleavage of the cytosolic regulatory protein kelch-like ECH-associated protein 1 (Keap1) from the transcription factor nuclear factor E2-related factor 2 (Nrf2) in the cell cytoplasm. This cleavage allows Nrf2 to move into the nucleus and interact with other nuclear transcription factors (i.e. Jun and Maf family proteins) to upregulate the antioxidant response element (ARE). A protean of Phase II genes is induced through the ARE, and these lead to cellular detoxification, repair, and normalization of energy metabolism.
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