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  • Swiss Archives of Neurology, Psychiatry and Psychotherapy is published by MDPI from Volume 176 Issue 1 (2026). Previous articles were published by another publisher in Open Access under a CC-BY (or CC-BY-NC-ND) licence, and they are hosted by MDPI on mdpi.com as a courtesy and upon agreement with Editores Medicorum Helveticorum (EMH).
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1 January 2015

Oral therapies for relapsing- remitting multiple sclerosis

and
Department of Neurology, University Hospital Basel, Basel, Switzerland
*
Author to whom correspondence should be addressed.
Swiss Arch. Neurol. Psychiatry Psychother.2015, 166(5), 170-175;https://doi.org/10.4414/sanp.2015.00349
Version Notes

Abstract

During the past 4 years the first oral treatments for relapsing-remitting multiple sclerosis have become available. These agents differ from previous therapies for multiple sclerosis in their mechanisms and safety profiles. Fingolimod (Gilenya®), a sphingosine-analogue, was found to reduce the relative relapse rate by 54% compared with placebo. Supposedly its main effect is the inhibition of lymphocyte egress from the thymus and secondary lymphoid organs. In addition to this immunomodulatory action neuroprotective effects of fingolimod have been discussed. Alongside benign side effects, rare cases of serious herpetic infections, bradyarrhythmia and macular oedema were observed. Teriflunomide (Aubagio®) was proven to relatively reduce the relapse rate by 31% to 36%. It inhibits the proliferation of activated lymphocytes by blocking the biosynthesis of pyrimidines. Slight gastrointestinal problems can occur under teriflunomide treatment. Liver enzymes and blood counts need to be monitored during treatment. Dimethylfumarate (Tecfidera®) is associated with a relative reduction of the relapse rate by 44 to 53%. Several immunomodulatory and neuroprotective mechanisms may account for this effect: dimethylfumarate induces an antioxidant response and interacts with candidate pathways for lymphocyte proliferation in in-vitro experiments. The most frequent side effects – flushing and gastrointestinal discomfort – predominantly occur in the initial treatment phase. Scarce cases of serious infections seem to correlate with lymphopenia.
Multiple sclerosis is the most common cause of disability in young adults in the Western Hemisphere. As an immune-mediated demyelinating disease of the central nervous system, its epidemiology and pathophysiology have been studied extensively. Nevertheless, neither a conclusive concept of aetiology nor curative treatment has yet been discovered [1].
Most patients are initially diagnosed with the relapsing-remitting form of multiple sclerosis with disease-modifying therapies (DMTs) available. Until recently any DMT required (self-administered) injection or intravenous infusion. Throughout the last 4 years the first oral DMTs have been registered for the treatment of relapsing-remitting multiple sclerosis (RRMS) and considerably broadened our treatment options. This article reviews data on the proposed mechanisms of action and possible safety concerns of these three agents – fingolimod, teriflunomide and dimethylfumarate.

Fingolimod (Gilenya®)

After detection of the immunosuppressant ciclosporin from Tolypocladium inflatum a range of further fungi have been assessed for similar properties. In this context fingolimod emerged from studies on Isaria sinclairii – a fungus used as an ‘eternal youth’ agent in traditional Chinese medicine [2].
Fingolimod’s immunomodulatory effects, as well as its small size and lipophilic properties allowing for penetration across the blood–brain barrier, made it an aspirant for multiple sclerosis treatment. Large trials proved it beneficial in terms of relapse rate and magnetic resonance imaging (MRI) outcomes: The relative relapse rate was reduced by 54% compared with placebo and brain volume loss under fingolimod treatment was significantly lower than under an interferon regimen [3,4]. These findings led to its approval as the first oral agent for RRMS in Switzerland in 2011.

Mode of action

Fingolimod is a structural analogue of sphingosine. Sphingolipids are ubiquitous cell membrane components. They bind to specific receptors and are responsible for a range of functions in intercellular communication. Fingolimod is hepatically phosphorylated to fingolimod-phosphate. This active metabolite acts as a functional antagonist of sphingosine-1-phosphate receptors (S1PR). These receptors of sphingosine-1-phosphate (S1P) are particularly involved in cell movement, adaptive immunity, calcium homeostasis and tissue regeneration, among other activities [5]. By modulating S1PRs, fingolimod-phosphate influences the trafficking of lymphocytes between bone marrow, lymphoid system and periphery. It inhibits the egress of naïve and memory T- and B-cells from lymph nodes, which leads to their sequestration in secondary lymphoid organs. The numbers of naïve and memory T-cells in blood and cerebrospinal fluid decrease, while effector T-cells remain almost stable and fully functional. In particular, T-cells that produce the cytokine interleukin-17 (IL-17) and that are regarded as key players in the pathogenesis of MS were found to be decreased in the periphery [6]. Fingolimod-phosphate influences the trafficking of lymphocytes between bone marrow, lymphoid system and periphery.
In addition to this immunomodulatory mechanism, animal experiments suggest that fingolimod may have additional beneficial effects in the central nervous system. Specific patterns of S1PRs are found on neurones, astrocytes, oligodendrocytes and microglia, enabling a range of effects [7]. S1PRs play an important role in neurogenesis, and treatment with fingolimod protected neurones from excitotoxic death in an in-vitro model [8]. This protective effect on neurons might be direct or through reduction of NO production by astrocytes [9]. At least in the animal model, the non-immune central nervous system (CNS) effect of fingolimod could be ascribed to astrocytes using conditional knock-out models of S1PR specifically targeted to astrocytes [10]. A part of the neuroprotective effect might also be mediated by increased brain-derived neurotrophic factor (BDNF) production [11,12]. The CNS protective effect is not limited to CNS inflammatory diseases but is also seen in models of neurodegeneration and vascular CNS damage [12,13,14]. This experimental evidence already translated into a positive phase II trial testing fingolimod in patients with intracerebral haemorrhage [15]. In addition to its effects on neurons and astrocytes, fingolimod might also act on oligodendrocytes to enhance remyelination as has been shown in models of toxic demyelination [16,17,18]. Despite all this experimental evidence of a CNS protective effect independent of the immunomodulatory impact, the situation in MS is less clear. The robust reduction of brain atrophy seen in phase III trials of RRMS seemed to support the hypothesis of neuroprotection [3,4]. However, a recent large phase III trial in the primary progressive form (PPMS) does not reveal any beneficial effect of the drug [19].

Long-term safety

In a recent analysis of patients with up to 7 years of fingolimod treatment the most common side effects were found to be back pain, gastrointestinal discomfort (diarrhoea, nausea), moderately elevated liver enzymes, headache, raised arterial blood pressure and respiratory tract infections (nasopharyngitis, bronchitis and pneumonia) [20]. The list of rarer, but relevant effects comprises serious herpetic infections (including herpes zoster, generalised varicella-zoster virus (VZV) infections and herpes simplex virus type 1 (HSV-1) encephalitis), bradyarrhythmia, macular oedema and malignancies (mainly basaliomas) [3,4]:
Scarce serious viral infections in fingolimod- treated patients have been described to be caused by human herpesviridae 1, 2 (herpes simplex) [4] and 3 (varicella zoster) [21]. It is therefore recommended to check for VZV antibodies before treatment start. In patients without detectable VZV-antibodies a vaccination is recommended before start of fingolimod [22]. In addition to herpesviral infections, few cases of progressive multifocal leukoencephalopathy (PML) have been reported. All but two of these cases were associated with previous natalizumab treatment [23,24,25,26]. In contrast to classical immunosuppressive treatments the status of the immune response cannot easily be monitored by means of lymphocyte counts. Despite a dramatic decrease of lymphocytes during fingolimod treatment, the degree of lymphopenia does not correlate with the risk of infections [27]. This is probably due to the peculiar mode of action of fingolimod, which induces redistribution but not deletion of lymphocytes and which is fundamentally different from classical immunosuppressants. It has therefore been argued that a strict cut-off for lymphopenia at 200/μl as has been used in clinical trials might not be needed and a lower cut-off of 100/μl might be a more pragmatic approach in order to avoid treatment interruptions and re-dosing [28].
Another area of clinical awareness are dose- dependent changes in heart rate that are understood to be functionally induced by fingolimod (via local S1PR interaction). Occurring within the first 5 hours after administration, these symptoms are reduced over time owing to internalisation of the affected receptors. Symptomatic bradycardia was rare (0.5% of study population) with most chronotropic effects remaining asymptomatic. Even in a population at higher risk for cardiac side effects (with pre-existing cardiac conditions or concomitant medications affecting cardiac rhythm) fingolimod appeared to be well-tolerated [29]. Practical recommendations for cardiac monitoring adapted to the situation in Switzerland were summarised recently [30]. Another supposedly S1PR-mediated side effect is macular oedema manifesting with decreased visual acuity or distorted vision. Fingolimod-associated macular oedema was observed in less than 0.5% of the study population and associated with concomitant diabetes mellitus or uveitis [31]. In the large majority of cases macular oedema was reversible. It is recommended to check the retina after 4 months of therapy and continue monitoring of patients at risk.
Although the absolute incidence of malignancies is not reported to be affected, basal cell carcinomas appeared to be more frequent under fingolimod albeit not statistically significantly [3]. Patients with increased risk for cutaneous malignancies (positive family history, fair skin) should therefore be checked routinely by a dermatologist.

Teriflunomide (Aubagio®)

When Hoechst investigated potential pesticide compounds in the early 1980s, isoxazole derivates were tested among many others. Concurrently, one agent was found to act as an anti-inflammatory drug. It was consecutively developed as leflunomide (Arava) and licensed for rheumatoid arthritis [32]. Initially thought to work like common nonsteroidal anti-inflammatory drugs (NSAIDs), its properties were soon discovered to exceed the inhibition of cyclooxygenases (COX) and rather to be immunosuppressive [33]. Leflunomide has been in use in rheumatoid patients for 15 years with a well-established side effect profile.
Since leflunomide was a promising prodrug, its active metabolite, teriflunomide, was tested for treatment in other diseases. Trials in RRMS showed that teriflunomide reduces the relative relapse rate by 31% to 36% compared with placebo [34,35] and ultimately led to its approval as an oral drug (Aubagio®) in Switzerland in 2013.

Mode of action

Teriflunomide is assumed mainly to inhibit rapid proliferation of activated immune cells. It does so by specifically blocking the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), which catalyses the antigen-induced biosynthesis of pyrimidines. Pyrimidines (thymine and cytosine) are essential components for DNA assembly [36]. Inhibition of DHODH therefore disenables mitosis and teriflunomide acts as a leucocytic cytostatic rather than cytotoxic. Activated T- and B-cells in multiple sclerosis will hence arrest in the early phase of synthesis in the cell cycle [37]. Leucocyte cell division at an ordinary frequency is still possible [38]. Thus teriflunomide primarily affects lymphocytes in rapid proliferation. Due to a compensating salvage pathway, proliferating cells in other tissues, such as gastrointestinal mucosa, appear to be less affected by this cytostatic effect [39]. Teriflunomide is assumed mainly to inhibit rapid proliferation of activated immune cells.
Teriflunomide is generally classified as a selective immunosuppressant. Nevertheless alternate mechanisms have been discussed: experimental evidence reveals that teriflunomide is able to exert various effects, comprising inhibition of major janus tyrosine kinases (JAK1 and 3), inhibition of proteins in the mitogen-activated protein kinase (MAPK) pathway and targeting of COX-2 and epidermal growth factor receptor (EGFR). All these could possibly account for further immunomodulatory properties on immune cell activation and cytokine synthesis [40]. Their clinical relevance, however, is questionable since these effects depend on higher doses than DHODH inhibition.

Long-term safety

Common (>10% incidence) side effects of teriflunomide are gastrointestinal discomfort (diarrhoea, nausea), moderately elevated transaminase levels and hair thinning or alopecia, the latter being generally reversible within weeks to months. All of these rarely led to discontinuation of treatment [34]. However, in long- term observation period of over 8.5 years, alanine transaminase (ALAT) increases were detected in a large majority (>70% of patients); 12% of patients showed ALAT levels elevated by three-fold or more above the upper limit [41], suggesting that liver enzymes should be measured regularly throughout the treatment. High Child-Pugh scores are considered a contraindication for teriflunomide.
Since teriflunomide is the active metabolite of the well-established antirheumatic leflunomide, some safety data can be extrapolated and exceed the limited timespan of studies for teriflunomide. In 1.5 decades since leflunomide approval only sporadic cases of opportunistic infections have been reported. Progressive multifocal leukoencephalopathy (PML) was observed in two cases, one of which had rituximab treatment concomitantly [42]. For teriflunomide, both large phase III trials (TEMSO [34] and TOWER [35]) alike showed no increase in serious adverse events, particularly no increase of serious infections or neoplasia. To our knowledge no case of PML has yet been observed.

Dimethylfumarate (Tecfidera®)

Dimethylfumarate (DMF), formerly used as a fungicide and desiccant on seating furniture, became infamous for its irritation potential, when customers complained about eczemas associated with contact with their newly purchased couch or chair [43]. Surprisingly, and by serendipity, it was found out that DMF also has therapeutic effects. Fumaric acid esters comprising dimethylfumarate were first discovered to improve symptoms of psoriasis in 1959 – through self-administration by a biochemist suffering from the dermatological disease himself [44]. Their use in patients affected from psoriasis and concomitant multiple sclerosis suggested a beneficial impact on both entities alike. Subsequent studies of dimethylfumarate in RRMS revealed significantly reduced relapse rate (by 44% to 53%) compared with placebo [45,46]. Tecfidera® was approved for use in Switzerland in 2014.

Mode of action

Dimethylfumarate (DMF) is the diester of fumarate, an intermediate substrate in the Krebs cycle. In aqueous solutions – such as blood plasma – it is rapidly hydrolysed to the monoester monomethylfumarate (MMF). A range of immunomodulatory and neuroprotective mechanisms contributing to the effects of DMF and its metabolite MMF have been proposed.
Fumaric acid esters like MMF are potent agonists of hydrocarboxcylic acid receptor 2 (HCA2, also GPR109a) formerly known as nicotinic acid receptor [47]. As such, they may induce downstream effects of HCA2. The exact profile of these effects after stimulation by MMF is not yet known, though HCA2 activation might account for important immunomodulatory effects of Tecfidera ®. HCA2 is found to down-regulate NFκB (nuclear factor κ-light chain enhancer in B-cells) significantly. This leads to a decreased production of proinflammatory cytokines and a reduction of chemotaxis [48,49]. Cutaneous flushing, one of the major side effects of Tecfidera®, also occurred in treatment with other HCA2-agonists like nicotinic acid and was found to be prostaglandin D2 (PGD2) mediated [50].
Linker et al. [51] showed that fumaric acid esters evoke an intracellular antioxidant state via nuclear factor erythroid-derived 2-related factor 2 (Nrf2). It is thought to modify an Nrf2-binding protein (Keap-1) in such manner that Nrf2 is released and down-stream genes (NQO1 and HMOX1) are expressed. This causes cytoprotective effects. The balance of thiols is shifted towards a higher amount of glutathione associated with an elevated intracellular redox potential. ATP levels and mitochondrial membrane potentials were also found to be increased [52]. In an Nrf2 knock-out mouse model these changes could not be found, indicating that the neuroprotective effects of DMF are mediated via this pathway.
Experimental data suggest that both pathways, HCA2 and Nrf2, can be activated independently [53]. However, further mechanisms may be responsible for other effects observed. Fumaric acid esters were found to augment vascular endothelial growth factor (VEGF) with potentially neuroprotective effect [54]. They induce type II dendritic cells and also Th2 cells in trade for lowered Th1 and Th17 cell numbers, which are thought to be key players in multiple sclerosis and psoriasis [49]. Moreover, in-vitro findings suggest that DMF is a potent inducer of apoptosis in T-cells [55] as well as mast cells [56].

Long-term safety

Safety analysis from current data on Tecfidera® (up to 4 years of treatment) [57] and a retrospective analysis of fumaric acid esters (up to 14 years of treatment) [58] reveal similar common side effects: flushing, gastrointestinal discomfort (diarrhoea, nausea, abdominal pain), elevated liver enzymes, leuco- and lymphopenia, upper respiratory tract infections, proteinuria, headache and fatigue. While flushing and gastrointestinal discomfort are reported to decrease rapidly after 1 month, blood cell count aberrations usually stabilise after 6 to 12 months and remain low under treatment [46,58].
Several previously reported cases of PML related to fumaric acid ester treatment were correlated to low lymphocyte levels or other predisposing factors for PML [59]. Although no opportunistic infections in Tecfidera ®-induced lymphopenia were reported in phase III trials, a recent case of PML during the extension phase of phase III trials will necessitate revision [60]. Current guidelines suggest frequent blood count checks (every 6–8 weeks) and pausing treatment if leuco- or lymphocyte counts decrease below 3000/μl or 500/μl, respectively [61].
Cutaneous flushing and gastrointestinal problems are considered the main side effects in the initial phase of treatment [46]. Although dimethylfumarate is administered in capsules resistant to gastric acid, notable gastrointestinal irritation is observed in a large share of patients and leads to early withdrawal from therapy [46]. As described above, flushing is thought to be PGD2-mediated and therefore can be alleviated by simultaneous intake of COX-inhibitors such as aspirin [62]. The gastrointestinal irritation is, however, not influenced by aspirin.

Conclusions and outlook

The therapeutic spectrum for MS is currently dramatically evolving. With the three new oral compounds our chances to control disease in the majority of MS patients are further increasing. Well-designed large phase III trials provided excellent evidence of their efficacy and safety. When introduced to the market, these new compounds had a far more comprehensive safety record than the previous DMTs. Nevertheless, the herpes viral infections and PML cases in fingolimod-treated patients and the PML cases during treatment with fumaric acid esters show that these treatments also have their costs. Unfortunately, no biomarkers have yet been found that could identify patients at higher risks. This reminds the practising neurologist to keep up clinical vigilance. It is the key to diagnosing these complications early and influencing the outcome of these adverse effects.
Despite the promising progress made with these antiinflammatory compounds there is still a lot to achieve in the treatment of MS. So far, no evidence exists that any of the new oral drugs has a direct impact on neurodegeneration. As outlined above, there are preclinical data indicating a potential effect. However, fingolimod failed to show an impact on primary progressive MS in a clinical trial. Currently, studies testing siponimod, a follow-up compound of fingolimod, and DMF in secondary progressive MS are on the way. Although often promoted and proposed for many MS drugs, the goal of a dual mode of action – anti-inflammatory and neuroprotective – has not been reached yet. Maybe we have to give up the idea that these two very different goals will be achieved with the same drug. Several new and older compounds on the horizon are solely aimed at tackling the problem of neuroprotection. We know from the stroke field how hard this will be. Nevertheless, neuroprotection is the unmet need in MS treatment nowadays. We have to achieve this if we want to further advance MS treatment.

Conflicts of Interest

T. Derfuss serves on scientific advisory boards for Novartis Pharma, Merck Serono, Biogen Idec, Genzyme, Mitsubishi Pharma, TEVA Pharma, and Bayer Schering Pharma; has received funding for travel and/or speaker honoraria from Biogen Idec, Genzyme, Novartis, Merck Serono, and Bayer Schering Pharma, and receives research support from Biogen Idec, Novartis Pharma, the European Union, the Swiss National Science Foundation, and the Swiss MS Society. M. Diebold declares to have no potential conflict of interest.

Abbreviations

BDNFbrain-derived neurotrophic factor
COXcyclooxygenase
DHODHdihydroorotate dehydrogenase
DMFdimethylfumarate
DMTdisease-modifying therapy
EGFRepidermal growth factor receptor
HCA2niacin receptor 1
JAKjanus kinase MMF monomethylfumarate
NF-κBnuclear factor kappa-light-chain-enhancer of activated B cells
Nrf2nuclear factor (erythroid-derived 2)-like 2
PMLprogressive multifocal leukoencephalopathy
PPMSprimary progressive multiple sclerosis
RRMSrelapsing-remitting multiple sclerosis
S1Psphingosine-1-phosphate
VEGFvascular endothelial growth factor

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