Emerging Therapeutic Applications for Fumarates

Abstract

Fumarates are successfully used for the treatment of psoriasis and multiple sclerosis. Their antioxidative, immunomodulatory, and neuroprotective properties make fumarates attractive therapeutic candidates for other pathologies. The exact working mechanisms of fumarates are, however, not fully understood. Further elucidation of the mechanisms is required if these drugs are to be successfully repurposed for other diseases. Towards this, administration route, dosage, and treatment timing, frequency, and duration are important parameters to consider and optimize with clinical paradigms in mind. Here, we summarize the rapidly expanding literature on the pharmacokinetics and pharmacodynamics of fumarates, including a discussion on two recently FDA-approved fumarates Vumerity^TM and Bafiertam^TM. We review emerging applications of fumarates, focusing on neurological and cardiovascular diseases.

Keywords: atherosclerosis; fumarates; ischemia-reperfusion injury; neurodegenerative disease; neuropathic pain.

Fig. 1. Hydrolysis pathways of fumarates.

MMF is the major metabolite, along with the cleaved prodrug fragments methanol (DMF), 2-hydroxyethyl succinimide (DRF) and N,N-diethyl-2-hydroxyacetamide (TPF). DMF is a symmetrical diester and leads solely to MMF and methanol. For DRF, 2-hydroxyethyl succinimide and methanol formation occurs asymmetrically in a 9:1 ratio [18]. The biologically inert 2-hydroxyethyl succinimide is eliminated primarily through the renal system (58–63%) and the small amount of RDC-8439 formed is presumably converted to FA and 2-hydroxyethyl succinimide in the liver [17]. It is expected that TPF undergoes similar asymmetric cleavage and clearance, given its bioequivalent MMF production (Table 1), even though its spontaneous hydrolysis is not asymmetric [19].

Fig. 2. Intracellular mechanisms of action of MMF and fumarate prodrugs.

Fumarates impose their effects via three main pathways: a) the NRF2 pathway; b) the HCAR2 pathway; and c) via immunomodulation. a) Both MMF and fumarate prodrugs can induce activation and nuclear translocation of NRF2 by succination of Keap-1. Once inside the nucleus, NRF2 promotes transcription of cytoprotective genes, including those encoding antioxidants. The pro-inflammatory transcription factor NFkB can be inhibited by the NRF2 pathway both via a reduction in ROS levels and via competition with NRF2 over CREB-binding proteins. b) MMF is a full agonist of HCAR2. Activation of this Gi-protein coupled receptor results in release of the Giα and Gβƴ proteins. This leads to inhibition of NFkB activation and lipase activity. Via PKC and ERK1/2, PPARƴ-mediated transcription of LXRα is thought to be upregulated, which in turn promotes transcription of ABC transporters. β-arrestin binding to HCAR2 is important in receptor regulation by promoting desensitization and internalization via clathrin-coated pits, and it can inhibit NFĸB activity. β-arrestin is also involved in prostanoid production mediated by cyclo-oxygenase (COX) 1/2 in keratinocyte and Langerhans cells. c) Independent of the NRF2 and HCAR2 pathways, MMF and prodrugs can reduce inflammation by blocking glycolytic metabolism via succination and thus inactivation of GADPH, which favors differentiation of macrophages and T-cells to an anti-inflammatory phenotype. In general, of note, the pharmacodynamics of MMF are likely to be most clinically relevant. PIP2: phosphatidylinositol biphosphate; DAG: diacylglycerol; ATP: adenosine triphosphate; HSL: hormone-sensitive lipase. *Hypothesized.