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
Published: European Neurological Review - Volume 3 - Issue I
download article

| More
dots

Multiple sclerosis (MS) is an inflammatory disease of the brain and spinal cord characterised 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 generalised 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 characterised 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 proinflammatory cytokines such as IL-6, IL-1β and tumour necrosis factor (TNF)-α and inhibit 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). Dimethyl fumarate is a well-known inducer of phase II detoxification genes, and treatment of cultured astroglia and microglia with FAEs has been shown to upregulate the Phase II detoxification enzyme NAD(P)H:quinone oxidoreductase-1 (NQO-1).30 The NQO-1 gene is a prototypical transcriptional target for the nuclear factor E2-related factor 2 (Nrf2), a transcription factor that controls Phase II detoxifying gene expression and is critical for oxidative stress response and immune homeostasis.31,33,34 Recent studies have demonstrated that BG00012 and monomethyl fumarate can activate Nrf2 in vitro.35 The Nrf2 pathway has been implicated as a mediator of a range of neuroprotective effects in the CNS, including inhibition of oxidative and excitotoxic neuronal damage,36–40 protection of the BBB41 and regulation of myelin maintenance.42 Hence, the current body of experimental evidence suggests that BG00012 may provide a dual neuroprotective and anti-inflammatory therapeutic effect not targeted by contemporary MS therapies (see Figure 2).

12345next ›last »
References:
  1. Yong VW, Differential mechanisms of action of interferon-β and glatiramer acetate in MS, Neurology, 2002;59:802–8.
  2. IFNB Multiple Sclerosis Study Group, Interferon beta-1a is effective in relapsing-remitting multiple sclerosis. I. Clinical results of a multicenter, randomized, double-blind, placebocontrolled trial, Neurology, 1993;43:655–61.
  3. Jacobs LD, Cookfair DL, Rudick RA, et al., Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis, Ann Neurol, 1996;39:285–94.
  4. PRISMS (Prevention of Relapses and Disability by Interferon β-1a Subcutaneously in Multiple Sclerosis) Study Group, Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis, Lancet, 1998;352: 1498–1504.
  5. Johnson KP, Brooks BR, Cohen JA, et al., Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, doubleblind, placebo-controlled trial, Neurology, 1995;45:1268–76.
  6. Mohr DC, Boudewyn AC, Likosky W, et al., Injectable medication for the treatment of multiple sclerosis: the influence of self-efficacy expectations and injection anxiety on adherence and ability to self-inject, Ann Behav Med, 2001;23:125–32.
  7. O’Rourke KET, Hutchinson M, Stopping beta-interferon therapy in multiple sclerosis: an analysis of stopping patterns, Mult Scler, 2005;11:46–50.
  8. Bayard W, Hunziker T, Krebs A, et al., Peroral long-term treatment of psoriasis using fumaric acid derivatives, Hautarzt, 1987;38:279–85.
  9. Kolbach DN, Nieboer C, Fumaric acid therapy in psoriasis: results and side effects of 2 years of treatment, J Am Acad Dermatol, 1992;27:769–71.
  10. Altmeyer PJ, Matthes U, Pawlak F, et al., Antipsoriatic effect of fumaric acid derivates. Results of a multicenter double-blind study in 100 patients, J Am Acad Dermatol, 1994;30:977–81.
  11. Mrowietz U, Christophers E, Altmeyer P, Treatment of psoriasis with fumaric acid esters: results of a prospective multicentre study, Br J Dermatol, 1998;138:456–60.
  12. Prinz JC, The role of T cells in psoriasis, J Eur Acad Dermatol Venereol, 2003;17:257–70.
  13. De Stefano N, Naroyoanan S, Matthews PM, et al., In vivo evidence for axonal dysfunction remote from focal cerebral demyelination of the type seen in multiple sclerosis, Brain, 1999; 122:1933–9.
  14. Ferguson B, Matyszak MK, Esivi MM, Axonal damage in acute multiple sclerosis lesions, Brain, 1997;120:393–9.
  15. Silber E, Sharief MK, Axonal degeneration in the pathogenesis of multiple sclerosis, J Neurol Sci, 1999;170:11–18.
  16. Trapp BD, Peterson J, Ransohoff RM, et al., Axonal transaction in the lesions of multiple sclerosis, N Engl J Med, 1998;338:278–85.
  17. Kermode AG, Thompson AJ, Tofts P, et al., Breakdown of the blood-brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis, Brain, 1990;113:1477–89.
  18. Kraus J, Oschmann P, The impact of interferon-beta treatment on the blood-brain barrier, Drug Discov Today, 2006;11:755–62.
  19. Raine CS, The Dale E McFarlin Memorial Lecture: the immunology of the multiple sclerosis lesion, Ann Neurol, 1994;36:S61–S72.
  20. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG, Multiple sclerosis, N Engl J Med, 2000;343:938–52.
  21. Gilgun-Sherki Y, Melamed E, Offen D, The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy, J Neurol, 2004;251:261–8.
  22. Imitola J, Chitnis T, Khoury SJ, Insights into the molecular pathogenesis of progression in multiple sclerosis: potential implications for future therapies, Arch Neurol, 2006;63:25–33.
  23. Asadullah K, Schmid H, Friedrich M, et al., Influence of monomethylfumarate on monocytic cytokine formation–eplanation for adverse and therapeutic effects in psoriasis? Arch Dermatol Res, 1997;289;623–30.
  24. de Jong R, Bezemer AC, Zomerdijk TP, et al., Selective stimulation of T helper 2 cytokine responses by the antipsoriasis agent monomethylfumarate, Eur J Immunol, 1996;26:2067–74.
  25. Schilling S, Goelz S, Linker R, et al., Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration, Clin Exp Immunol, 2006; 145:101–7.
  26. Schimrigk S, Brune N, Hellwig K, et al., Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-contrilled pilot study, Eur J Neurol, 2006;13:604–10.
  27. Litjens NH Rademaker M, Ravensbergen B, et al., Monotheylfumarate affects polarization of monocyte-derived dendritic cells resulting in down-regulated Th1 lymphocyte responses, Eur J Immunol, 2004;34:565–75.
  28. Loewe R, Holnthoner W, Groger M, et al., Dimethylfumarate inhibits TNF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells, J Immunol, 2002;168:4781–7.
  29. Loewe R, Pillinger M, de Martin R, et al., Dimethylfumarate inhibits tumor-necrosis-factor-induced CD62E expression in an NF-κB-dependent manner, J Invest Dermatol, 2001;117:1363–8.
  30. Wierinckx A, Breve J, Mercier D, et al., Detoxification enzyme inducers modify cytokine production in rat mixed glial cells, J Neuroimmunol, 2005;166:132–43.
  31. Chen XL, Dodd G, Thomas S, et al., Activation of Nrf2/ARE pathway protects endothelial cells from oxidant injury and inhibits inflammatory gene expression, Am J Physiol Heart Circ Physiol, 2006;290:H1862–H1870.
  32. Ockenfels HM, Schultewolter T, Ockenfels G, et al., The antipsoriatic agent dimethylfumarate immunomodulates T-cell cytokine secretion and inhibits cytokines of the psoriatic cytokine network, Br J Dermatol, 1998;139:390–95.
  33. Itoh K, Chiba T, Takahashi S, et al., An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements, Biochem Biophys Res Commun, 1997;236:313–22.
  34. Venugopal R, Jaiswal AK, Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes, Oncogene, 1998;17:3145–56.
  35. Lukashev M, Zeng W, Ryan S, et al., Activation of Nrf2 and modulation of disease progression in EAE models by BG00012 (Dimethyl Fumarate) suggests a novel mechanism of action combining anti-inflammatory and neuroprotective modalities. Presented at: 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis, Prague, October 12, 2007.
  36. Calabrese V, Ravagna A, Colombrita C, et al., Acetylcarnitine induces heme oxygenase in rat astrocytes and protects against oxidative stress: involvement of the transcription factor Nrf2, J Neurosci Res, 2005;79:509–21.
  37. Li J, Johnson D, Calkins M, et al., Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells, Toxicol Sci, 2005;83:313–28.
  38. Satoh T, Okamato SI, Cui J, et al., Activation of the Keap1/Nrf2 pathway for neuroprotection by electrophillic phase II inducers, Proc Natl Acad Sci, 2006;103:768–73.
  39. Shih AY, Li P, Murphy TH, A small-molecule-inducible Nrf2- mediated antioxidant response provides effective prophylaxis against cerebral ischemia in vivo, J Neurosci, 2005;25:10321–35.
  40. Vargas MR, Pehar M, Cassina P, et al., Fibroblast growth factor-1 induces heme oxygenase-1 via nuclear factor erythroid 2-related factor 2 (Nrf2) in spinal cord astrocytes: consequences for motor neuron survival, J Biol Chem, 2005;27:25571–9.
  41. Zhao C, Zawadzka M, Roulois AJ, et al., Promoting remyelination in multiple sclerosis by endogenous adult neural stem/precursor cells: Defining cellular targets, J Neurol Sci, 2007; epub ahead of print.
  42. Hubbs AF, Benkovic SA, Miller DB, et al., Vacuolar leukoencephalopathy with widespread astrogliosis in mice lacking transcription factor Nrf2, Am J Pathol, 2007;170:2068–76.
  43. Thimmulappa RK, Lee H, Rangasamy T, et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Invest 2006;116:984–995.
  44. Ma Q, Battelli L, Hubbs AF. Multiorgan autoimmune inflammation, enhanced lymphoproliferation, and impaired homeostasis of reactive oxygen species in mice lacking the antioxidant-activated transcription factor Nrf2. Am J Pathol 2006;168:1960–1974.
  45. Kappos L, Miller DH, MacManus DG, et al., BG00012, a novel oral fumarate, is effective in patients with relapsing-remitting multiple sclerosis, Mult Scler, 2006;12(Suppl. 1):S85.
  46. Gold R, Havrdova E, Kappos L, et al., Safety of a noval oral single-agent fumarate, BG00012, in patients with relapsingremitting multiple sclerosis: results of a phase 2b study, J Neurol, 2006; 253(Suppl. 2):ii144–ii145.
  47. Kappos L, Safety and tolerability results of a phase 2b extension study of the novel oral fumarate BG00012 for the treatment of relapsing-remitting multiple sclerosis, Neurology, 2007;68 (Suppl. 1):A276.
  48. Rudick RA, Baier M, Cutter G, et al., Estimating long-term effects of disease-modifying drug therapy in multiple sclerosis patients, Mult Scler, 2005;11:626–34.
  49. Johnson KP, Brooks BR, Ford CC, et al., Glatiramer acetate (Copaxone): comparison of continuous versus delayed therapy in a six-year organized multiple sclerosis trial, Mult Scler, 2003;9: 585–91.
  50. McDonald WI, Compston A, Edan G, et al., Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis, Ann Neurol, 2001;50:121–7.

Copyright® 2012 Touch Group PLC. All rights reserved.
Touch Neurology is for informational purposes and should not be considered medical advice, diagnosis or treatment recommendations.