**5. Safety profile**

By and large, the short-term safety profile for DMF in patients with RMS is highly favorable [64, 65] and long-term safety analyses from the ENDORSE study sustains a favorable benefit: risk ratio [94]. The most common adverse events observed in patients receiving DMF include flushing, gastrointestinal (GI) events (e.g., diarrhea, nausea, abdominal pain, and vomiting), proteinuria, and pruritus [64, 65]. Aspirin pretreatment has been shown to reduce DMF induced adverse GI events [95]. Additionally, the leukotriene-receptor antagonist montelukast has been shown to help as well [96]. Further, it has been observed that consuming a high fat

**213**

*Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation…*

and high protein meal just before DMF administration may reduce GI and flushing side effects by delaying its intestinal absorption. Notably, the risk of lymphopenia is higher in adults older than 55 years, in those with lower baseline lymphocyte counts, and those switching from natalizumab [97]. Cases of multifocal leukoencephalopathy (PML) following DMF treatment have also been reported [98–107]. Highly worthy of mention, however, is the fact that each of the affected patients detailed above had well-known pre-existing risk factors for PML including lymphocytopenia, sarcoidosis, cancer history, and/or prior efalizumab use. Thus, the negative effects of MMF treatment on PML should be interpreted very carefully. Like other pharmacological therapies, DMF/MMF treatment is associated with some side effects importantly however, advancements toward developing improved formulations minimize these events without losing efficacy are already being realized. For example, Alkermes, Inc. has developed diroximel fumarate (DRF), also known as ALKS8700, a novel MMF prodrug. Importantly, this new formulation has been shown to yield bioequivalent levels of MMF at the cellular level when compared directly to DMF (**Figure 1**) [108] while interacting less with off-target proteins and therefore producing fewer unwanted side effects [109]. Indeed, interim findings from EVOLVE-MS-1 and EVOLVE-MS-2 which demonstrate that DRF has a favorable safety and efficacy profile and is well-tolerated in MS patients [108, 110].

Drug repurposing is a very viable therapeutic strategy [18]. Many agents approved for other uses already have been tested in humans, so detailed information is available on their pharmacology, formulation and potential side effects. Since repurposing expands upon past innovative endeavors, hopeful new treatments could be prepared for clinical trials rapidly. Historically, pharmaceutical companies have achieved a number of successes via drug repositioning (e.g., for Viagra, thalidomide, metformin, etc.). Based on the literature available, DMF/MMF has been

shown to protect against a variety of diseases other than MS and psoriasis.

FAE are perhaps most noted for the robust antioxidant effects that they elicit via Nrf2 induction. A number of additional (non-FAE based) Nrf2 inducing drugs have been developed and tested in experimental and clinical systems in recent years (e.g., resveratrol, sulforaphane, etc.) and several have been with considerable success with regard to potential for clinical development [111]. However, the multimodal actions of FAE make this emerging drug stand out among the rest. It is commonly said that oxidative stress and inflammation go hand-in-hand, meaning that one potentiates the other in somewhat of a cyclic manner. Thus, it can only be hoped that in turn, if one is suppressed then the other similarly complies. However, things are usually not that simple. In the case of FAE, there are two arms of action: one induces Nrf2 and the other interacts with the anti-inflammatory hydroxycarboxylic acid receptor (HCAR2 or HCA2; **Figure 2**). Thus, the compound has a direct impact on inflammation independent of its actions on oxidative stress. The fascinating thing about these two mechanistic arms, is that they appear to act simultaneously in many cell and tissue systems. This may explain why FAE has exceled in so many variable pathologic conditions. MMF through its interaction with HCAR2, which is expressed by primary immune cells and a multitude of accessory immune cells (i.e., those that initiate the immune response and those cells like retinal pigment

*DOI: http://dx.doi.org/10.5772/intechopen.91915*

**6. Conclusions**

**7. Future perspectives**

*Repurposing Fumaric Acid Esters to Treat Conditions of Oxidative Stress and Inflammation… DOI: http://dx.doi.org/10.5772/intechopen.91915*

and high protein meal just before DMF administration may reduce GI and flushing side effects by delaying its intestinal absorption. Notably, the risk of lymphopenia is higher in adults older than 55 years, in those with lower baseline lymphocyte counts, and those switching from natalizumab [97]. Cases of multifocal leukoencephalopathy (PML) following DMF treatment have also been reported [98–107]. Highly worthy of mention, however, is the fact that each of the affected patients detailed above had well-known pre-existing risk factors for PML including lymphocytopenia, sarcoidosis, cancer history, and/or prior efalizumab use. Thus, the negative effects of MMF treatment on PML should be interpreted very carefully. Like other pharmacological therapies, DMF/MMF treatment is associated with some side effects importantly however, advancements toward developing improved formulations minimize these events without losing efficacy are already being realized. For example, Alkermes, Inc. has developed diroximel fumarate (DRF), also known as ALKS8700, a novel MMF prodrug. Importantly, this new formulation has been shown to yield bioequivalent levels of MMF at the cellular level when compared directly to DMF (**Figure 1**) [108] while interacting less with off-target proteins and therefore producing fewer unwanted side effects [109]. Indeed, interim findings from EVOLVE-MS-1 and EVOLVE-MS-2 which demonstrate that DRF has a favorable safety and efficacy profile and is well-tolerated in MS patients [108, 110].
