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Mode of action and clinical studies with fumarates in multiple sclerosis
Multiple sclerosis (MS) as a chronic neuro-inflammatory and neurodegenerative disease of the central nervous system is frequently associated with severe disability and impairment in quality of life.
Early disease-modifying treatment options have mainly focused on inflammatory aspects of the disease. Recently, the neurodegenerative features have received more attention in experimental models, paraclinical assessments and the evaluation of drug effects. Fumaric acid esters (FAEs) as orally available immunomodulatory and neuroprotective compounds have thus advanced to a highly interesting MS treatment option.
Here, we will review the pharmaceutical history of FAEs, their immunomodulatory and putative neuroprotective mechanisms of action and clinical trial data in relapsing MS.
- Dimethyl fumarate (DMF) is a novel oral agent in multiple sclerosis (MS) therapy.
- DMF and its metabolites exert potent anti-inflammatory and anti-oxidative effects.
- Two pivotal phase-III trials have demonstrated efficacy in relapsing–remitting MS.
- Experimental and MRI data support the hypothesis of neuroprotective effects.
- Safety and tolerability profile is favorable, but therapy monitoring is required.
Keywords: RRMS, Dimethyl fumarate, DMF, Immunomodulation, Neuroprotection.
In contrast to several other neuroimmunological disorders with involvement of the central nervous system (CNS), multiple sclerosis (MS) is a commonly occurring disease with prevalence estimates up to more than 200 per 100,000 in distinct regions of Europe ( Kingwell et al., 2013 ).
MS is frequently associated with disability that demands management of various symptoms including spasticity, ambulation, bladder and sexual symptoms, fatigue and cognition ( Thompson et al., 2010 ). This impacts quality of life and working capacity and results in high socioeconomic burden of the disease ( Flensner et al., 2013 ). Yet, variability of disease courses ( Lublin and Reingold, 1996 ), gender and geographical distribution (Evans et al, 2013 and Kingwell et al, 2013) underscore the heterogeneity of MS which is so far not well explained.
Consensus exists about an autoimmune pathology finally composed of both inflammatory and neurodegenerative features. Importantly, the latter seem to be a distinct characteristic of the disease itself (Hafler et al, 2005 and Hohlfeld and Wekerle, 2004). Mechanisms may include oxidative stress and both axonal and neuronal damage (Hafler et al, 2005 and van Horssen et al, 2011).
Yet, both treatment of relapses via steroids ( Burton et al., 2012 ) or plasma exchange techniques (Koziolek et al, 2012, Magana et al, 2011, and Schroder et al, 2009) and early disease-modifying treatment options (beta-interferons, glatiramer acetate) (Comi et al, 2001, Comi et al, 2009, Jacobs et al, 2000, and Kappos et al, 2006) focused on inflammation via immunomodulation and/or immunosuppression (e.g. mitoxantrone) ( Hartung et al., 2002 ).
The concept of neuroprotection has recently attracted more attention and has been evaluated on both (para-)clinical (e.g. MRI, optical coherence tomography (OCT)) and experimental level for different substances (reviewed by Stroet et al., 2013 ).
Fumaric acid esters (FAEs) were initially used in the treatment of an immunological skin disorder — psoriasis. Because of their potent anti-inflammatory effects, they have been introduced in MS. Their further investigation revealed not only anti-inflammatory, but also putative neuroprotective mechanisms of action which made them a highly interesting treatment option for MS.
We will here review the history, the preclinical data on FAEs and the relevant data of clinical MS trials with FAEs, especially with regard to safety and efficacy aspects.
History of fumarates
By the end of the 1950s the German chemist Schweckendiek topically applied FAEs on his own psoriatic lesions as he assumed an underlying metabolic disorder of the citric acid cycle which may be restored by FAE supplementation ( Schweckendiek, 1959 ). Extending this approach, he swallowed oral FAEs and subsequently these drugs were offered to patients with psoriasis, yet on an off-label basis.
More than 30 years later, two double-blind trials were performed in psoriasis (Altmeyer et al, 1994 and Nieboer et al, 1990). These resulted in the approval of Fumaderm®, an oral mixture of dimethyl fumarate (DMF) and ethylhydrogen fumarate (EHF), for the treatment of severe therapy-refractory psoriasis in Germany in 1994 ( Mrowietz et al., 1999 ).
This compounded fumarate was then used in a pilot study on ten patients with relapsing–remitting MS (RRMS) and MRI activity ( Schimrigk et al., 2006 ). Although three patients withdrew, significant results on MRI outcome parameters (number and volume of gadolinium-enhancing lesions) were shown. In general, the safety profile of Fumaderm® was favorable in this study. Yet gastrointestinal side effects and flushing — known from dermatological populations — diminished the tolerability of the drug.
The advancement to “BG12” is composed of only DMF and different galenics to improve tolerability. This compound has been further evaluated on the experimental level and in clinical trials.
Preclinical data on DMF and its mode of action
DMF is the di-methylester of fumaric acid and chemically named trans-1,2-ethylenedicarboxylic acid dimethyl ester. Intestinally localized esterases cleave DMF to monomethyl fumarate (MMF), the main active metabolite that is absorbed and distributed including passage of the blood–brain-barrier. Yet, there is data on faster, but short-lived activity of low concentrations of DMF with both anti-inflammatory and anti-oxidative effects ( Albrecht et al., 2012 ).
After metabolism in the citric acid cycle, MMF is eliminated primarily via exhalation and only to small extents via urine and feces ( Litjens et al., 2004 ).
Effects of FAEs on the immune system are manifold. Using a comparable dosage (120 mg DMF plus other FAEs to a lesser extent) to DMF as designated for MS treatment, they have been shown to induce T cell apoptosis in healthy individuals ( Litjens et al., 2004 ) and to reduce peripheral CD4 + and CD8 + lymphocytes in psoriasis patients ( Hoxtermann et al., 1998 ).
Intracellular ATP levels of CD4 + cells — as a potential surrogate parameter for T cell function ( Haghikia et al., 2011 ) — showed no differences in psoriasis patients with or without DMF treatment ( Gambichler et al., 2012 ). This may be a first hint aiming rather at an immunomodulatory than immunosuppressive effect of FAEs.
This is further supported by experimental data that FAE can induce a Th2 cytokine shift with an interleukin (IL)-4 and IL-5 dominated cytokine response and reduced interferon-gamma production (Ockenfels et al, 1998 and Zoghi et al, 2011). Effects on other immune cells and CNS cells have been described (Lin et al, 2011, Vandermeeren et al, 1997, and Wierinckx et al, 2005). In addition to immunomodulatory properties, further mechanisms of action can thus be postulated.
Interactions with nuclear factor-kappa B (NF-κB) and nuclear (erythroid-derived2)-related factor (Nrf2) will be further elucidated in this context.
DMF inhibits the translocation of NF-κB and thus suppresses NF-κB-dependent transcription. This results in anti-inflammatory effects by reduction of pro-inflammatory cytokines, adhesion molecules and induction of apoptosis, but also in a regulation of cell survival by interfering with cellular redox-systems (Mrowietz and Asadullah, 2005, Stoof et al, 2001, and Vandermeeren et al, 1997). Reduced NF-κB activation results in reduced activity of nitric oxide synthase 2 (NOS-2) and thus reduced nitrite accumulation, but increased mRNA levels of enzymes involved in glutathione synthesis ( Lin et al., 2011 ). Anti-oxidative mechanisms and putative cytoprotective properties of DMF have therefore been further investigated. In this context, Nrf2 is of interest as it induces the transcription of several anti-oxidative genes. Among these genes are pathways that reduce oxidative stress and may thus preserve myelin integrity (Linker et al, 2011 and Papadopoulou et al, 2010).
On a cellular level, the application of DMF (or MMF) leads to intranuclear translocation of Nrf2, and enhances Nrf2-dependent transcription and thus the expression of anti-oxidative enzymes in experimental models (Linker et al, 2011 and Liu et al, 2007). This hypothesis was further supported by in vitro studies documenting prolonged survival of neurons and glial cells, an effect that was lost in Nrf2-deficient cells ( Scannevin et al., 2012 ).
Experimental autoimmune encephalomyelitis (EAE) is a widely used murine model of MS. It can be induced by injection of myelin oligodendrocyte glycoprotein (MOG) ( Gold et al., 2006 ). In this model, DMF treatment also augments Nrf2 levels in the CNS and results in an ameliorated disease course, especially in late stages of EAE ( Linker et al., 2011 ).
These experimental data will have to be further confirmed by human data and long-term data, especially on disability progression in later stages of MS to prove significant neuroprotective effects in human disease.
Clinical trials and efficacy outcomes
DMF in enteric-coated capsules (“BG12”) was investigated in a multicenter, randomized, double-blind phase-II trial with an initial placebo-controlled phase followed by an extension phase with different dose regimens ( Kappos et al., 2008 ).
The trial investigated a once daily (120 mg) versus two different thrice daily dosages of FAE (3 × 120 mg vs. 3× 240 mg). During the extension phase, the placebo group was switched to the high-dose thrice daily regimen.
After the double-blind study period of 24 weeks, a significant reduction of new gadolinium-enhancing MRI lesions, of new/enlarging T2-hyperintense and new T1-hypointense lesions was only shown comparing the high-dose group vs. placebo. These positive results were corroborated by post hoc and subgroup analyses (Kappos et al, 2012 and MacManus et al, 2011). Interestingly, the evolution of T1-hypointense lesions from gadolinium-enhancing lesions seemed to be specifically suppressed by the high-dose regimen ( Kappos et al., 2012 ). This may argue for reduced sustained tissue destruction and reflect putative neuroprotective mechanisms.
The randomized, double-blind DEFINE trial investigated twice and thrice daily DMF in a dosage of 240 mg vs. placebo with the primary endpoint of the proportion of relapse-free patients after 2 years ( Gold et al., 2012 ). Secondary endpoints included further clinical measures (annualized relapse rate (ARR), time to confirmed disability progression) and MRI parameters (new/enlarging T2 lesions, and gadolinium-enhancing T1 lesions).
Seventy-seven percent of 1237 randomized patients completed the study. Baseline demographics and therapy discontinuation as well as study withdrawal were similar between the three groups. DEFINE met its primary endpoint by showing a significant reduction of the proportion of patients with relapse(s) (46% placebo vs. 26% twice daily DMF vs. 27% trice daily DMF). ARR was reduced by 53% (twice daily DMF) and 48% (thrice daily DMF) vs. placebo. Disability progression (measured by expanded disability status scale (EDSS)) could be reduced to 16% (twice daily DMF) and 18% (thrice daily DMF) compared to 27% progression in the placebo group.
Also, the numbers of both new/enlarging T2 and gadolinium-enhancing T1 lesions on MRI were significantly reduced by both dosage regimens vs. placebo over a study period of 2 years.
The randomized CONFIRM study additionally included an active comparator, glatiramer acetate (GA), but was not designed to test superiority or inferiority between the active treatment arms (GA, 2 × 240 mg DMF, 3 × 240 mg DMF) ( Fox et al., 2012 ).
Primary endpoint was the ARR after 2 years; secondary endpoints included again clinical parameters (time to first relapse, proportion of relapsing patients, and confirmed disability progression by EDSS) and MRI parameters (new/enlarging hyperintense T2 lesions, gadolinium-enhancing T1 lesions, and new hypointense T1 lesions).
Eighty percent of 1430 randomized patients completed the study. Yet, the therapy discontinuation rate and the rate of patients switching to an alternative MS treatment, respectively, were slightly higher in the placebo vs. all active treatment groups.
ARR was significantly reduced by all active treatment arms as compared to placebo (0.29 GA, 0.22 2 × 240 mg DMF, 0.20 3 × 240 mg DMF vs. 0.40 placebo). This corresponds to a relative reduction of relapses of 44% and 51% for the two DMF dosages and 29% for GA. This was also reflected by a longer time to the first confirmed relapse (25th percentile: 30 weeks placebo, 72 weeks 2 × 240 mg DMF, > 96 weeks 3 × 240 mg DMF (no exact estimate available), 57 weeks GA) and a significantly lower proportion of patients with relapse(s) during the trial (32% GA, 29% 2 × 240 mg DMF, 24% 3 × 240 mg DMF vs. 41% placebo).
The estimated proportion of patients with confirmed disability progression in the CONFIRM trial was 16% GA, 13% 2 × 240 mg DMF, and 13% 3 × 240 mg DMF vs. 17% placebo. Due to the low progression rate in the placebo group, this did not result in a statistically significant reduction of disability progression for neither of the active treatment arms. In terms of MRI, all secondary endpoints were met by all active treatment arms vs. placebo by the end of the study (new/enlarging T2 lesions, new hypointense T1 lesions, and gadolinium-enhancing T1 lesions).
Confirming the observations of the phase-II trial, again a lower proportion of new hypointense T1 lesions evolving from initially T2 hyperintense lesions was detected in CONFIRM emphasizing possible tissue protective effects of DMF in terms of a reduction of brain atrophy.
For both the DEFINE and the CONFIRM trial, further analyses were performed to test clinical efficacy of DMF in different patient subgroups (Bar-Or et al, 2013 and Hutchinson et al, 2013). The latter were stratified by baseline demographics, disease history (McDonald criteria, relapses, previous treatment, and EDSS) and MRI parameters. Efficacy of DMF treatment was confirmed in these analyses without identification of distinct subgroups benefiting more or less from the treatment.
Safety data of the pivotal clinical trials and beyond
The overall occurrence of adverse events (AE) and serious adverse events (SAE) was similar between the study groups in both phase-III trials ( Table 1A ) (Fox et al, 2012 and Gold et al, 2012). Mainly mild or moderate severity of AEs was described.
|Placebo [%]||2 × 240 mg DMF [%]||3 × 240 mg DMF [%]||Glatiramer acetate [%]|
|A) Adverse event|
|Death||0||< 1||< 1||0||< 1||< 1||< 1|
|Gastroenteritis||0||0||< 1||< 1||< 1||< 1||0|
|Ovarian cyst||< 1||–||< 1||–||< 1||–||–|
|Pneumonia||< 1||< 1||< 1||0||0||0||< 1|
|Other serious infection||2||–||2||–||2||–||–|
|Malignant neoplasm||< 1||–||< 1||–||< 1||–||–|
|Cellulitis||–||0||–||< 1||–||< 1||0|
|Abdominal pain, back pain, muscle strain||–||0||–||0 to < 1||–||0 to < 1||0|
|Depression||–||0||–||0||–||< 1||< 1|
|Spontaneous abortion||–||< 1||–||0||–||0||0|
|Anaphylactic reaction||–||0||–||0||–||0||< 1|
|B) Efficacy parameters|
|Clinical parameters as measured after 2 years|
|(Estimated) patients with relapse(s) [%]||46||41||27||29||26||24||32|
|(Adjusted) annualized relapse rate (95% CI)||0.36 (0.30–0.44)||0.40 (0.33–0.49)||0.17 (0.14–0.21)||0.22 (0.18–0.28)||0.19 (0.15–0.23)||0.20 (0.16–0.25)||0.29 (0.23–0.35)|
|(Estimated) patients with sustained disability progression [%]||27||17||16||13||18||13||16|
|MRI parameters as measured after 2 years|
|Adjusted mean no. of new/enlarging T2 lesions (95% CI)||17.0 (12.9–22.4)||17.4 (13.5–22.4)||2.6 (2.0–3.5)||5.1 (3.9–6.6)||4.4 (3.2–5.9)||4.7 (3.6–6.2)||8.0 (6.3–10.2)|
|Mean no. of gadolinium-enhancing T1 lesions ± SD||1.8 ± 4.2||2.0 ± 5.6||0.1 ± 0.6||0.5 ± 1.7||0.5 ± 1.7||0.4 ± 1.2||0.7 ± 1.8|
|Adjusted mean no. of new T1 hypointense lesions (95% CI)||–||7.0 (5.3–9.2)||–||3.0 (2.3–4.0)||–||2.4 (1.8–3.2)||4.1 (3.2–5.3)|
AE — adverse event, CI –, confidence interval, MS — multiple sclerosis, SAE — serious adverse event.
Gastrointestinal events, flushing, proteinuria, pruritus ( Gold et al., 2012 ) as well as upper respiratory tract infections and erythema ( Fox et al., 2012 ) were more frequently observed in the DMF groups. The incidence of flushing and gastrointestinal symptoms decreased after 1 month of treatment in both trials. The so-called “hot flush” entails redness and itching of the body. Flushing seems to be a dose-dependent and habituating side effect. Dose titration over the first weeks of treatment is thus recommended.
Importantly, an increase of the occurrence of malignancy or opportunistic infections was not observed for DMF treatment. Serious gastrointestinal events were rare, but slightly more frequent in the DMF groups.
Monitoring of the study participants revealed a decrease of white blood cell and lymphocyte counts over the first year of DMF treatment with a plateau afterwards. Leukocyte counts decreased by 10–12% from baseline, and lymphocyte counts by 28–32%, respectively. In up to 5% of patients, a grade 3 or higher lymphopenia (according to National Cancer Institute Common Toxicity Criteria) was detected.
European prescription guidelines will probably account for this effect on white blood cell counts in terms of a recommendation for regular, e.g. every 8 weeks, performance of blood cell counts over the first year of treatment. This is of even more importance as two of the few described cases of PML on FAEs seemed to be partially promoted by lymphopenia.
Early asymptomatic increases of liver enzymes were identified (up to month 6).
It is thus reasonable to control for liver enzymes and proteinuria regularly before and at least during the first year of treatment, too.
Besides the described laboratory and gastrointestinal findings, no other organ system seemed to be specifically affected by DMF treatment in the pivotal trials.
Data of the phase-III trials therefore suggest a favorable safety profile and good tolerability of the enteric-coated DMF capsules.
The summary of product characteristics (SPC) of the FDA categorizes DMF as “pregnancy category C” due to thus far lacking human data, but adverse effects in animal reproduction studies. Cautious evaluation of the individual risk–benefit profile is thus mandatory when considering DMF use in pregnant women.
So far, four reports of progressive multifocal leukoencephalopathy (PML) with Fumaderm® and self-compounded FAEs for psoriasis have been published.
In two of these cases, persistent lymphopenia was described that was not followed by treatment interruption or adaption (Ermis et al, 2013 and van Oosten et al, 2013). This emphasizes the rationale for the regular performance of full blood counts before and during DMF therapy and indicates violation of prescription rules. In the other two cases, predisposing factors for PML development were identified in the patients' medical history: co-morbidities and co-/previous treatments: sarcoidosis and immunosuppressive therapy via methotrexate in one patient, previous monoclonal antibody therapy with efalizumab and diagnosis of a malignancy in the other ( Sweetser et al., 2013 ). To the authors' knowledge, there have thus far been no published reports of PML without such pre-disposing factors.
Disease-modifying treatment of RRMS mainly aims at a reduction of relapses and thus prevention of disability accumulation. Anti-inflammatory properties have therefore been in the focus of early trials.
Yet, long-term clinical data, MRI data and neuropathological studies show that neuronal and axonal damage occurs i) in absence of acute relapses, ii) outside MS lesions on MRI and iii) in chronic progressive stages of the disease without relapse activity hinting at independent neurodegenerative features of the disease.
Cytoprotective properties have therefore been investigated for both established and advancing therapeutic options.
An oral compound serving as first-line therapy with favorable safety and efficacy profiles is therefore still needed. DMF may serve as such a treatment alternative as the available data from both phase-III clinical trials in MS and previous experiences in dermatological populations support these two characteristics.
Tolerability of the drug has been improved by an adapted formulation. Still, transient flushing and/or gastrointestinal symptoms may occur and require both a dose titration over 4 weeks to the full dosage of 2 × 240 mg DMF and proper counseling of patients to prepare them for the possible occurrence of these side effects.
The overall promising clinical data is complemented by experimental data supporting the hypothesis of neuroprotective properties of DMF, especially via modulation of the Nrf2 pathway and thus reduction of oxidative stress. Hypothetically, this may result in reduced axonal and neuronal damage. However, these features will have to be confirmed by human data in large, long-term observations.
DMF (Tecfidera®) is licensed for treatment of RRMS in the US and soon expected in the EU. Supposedly, it is an attractive first-line treatment option due to its favorable efficacy and safety profile, its route of application and putative neuroprotective attributes. The latter may also support the use of DMF in other disease courses such as primary or secondary progressive MS. Yet, it has thus far not been tested on the basis of clinical trials.
Acknowledgments and disclosures
This work was supported by the German Bundesministerium für Bildung und Forschung (BMBF), German Competence Network Multiple Sclerosis (KKNMS), 01GI0914.
A. Salmen has received personal compensation for activities with Novartis, Sanofi and Almirall Hermal GmbH.
R. Gold has received personal compensation for activities with Bayer Healthcare, Biogen Idec and Teva Neuroscience and in an editorial capacity from Therapeutic Advances in Neurological Disorders, and also received patent payments from Biogen Idec and research support from Bayer Healthcare, Biogen Idec, Merck Serono, Teva Neuroscience, Novartis and from the German Ministry for Education and Research (BMBF, “German Competence Network Multiple Sclerosis” (KKNMS), CONTROL MS, 01GI0914).
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