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HIGHLY EFFECTIVE AND YET NON-HARMFUL: FUMARIC ACID ESTERS TO FIGHT MS
Research made in Bochum: successful treatment of relapsing-remitting multiple sclerosis
Ralf Gold, Gisa Ellrichmann and Ralf Linker
Multiple sclerosis is a disease for which no cure has yet been found. Its progression may be delayed thanks to new
drugs, but the active ingredients in those drugs are either only partially effective or may lead to severe side effects.
New discoveries in the field of dermatology have given rise to hope. Researchers in Bochum have discovered that MS
symptoms are considerably alleviated through the application of an active pharmaceutical ingredient on the basis of
fumaric acid that has long been successfully used against psoriasis.
A chronic disease of the central nervous system, the autoimmune disease multiple sclerosis (MS) is the most
common neurological cause of disabilities in young adults. At present, the number of MS patients in Germany is
calculated to amount to 130,000, with some 70 per cent of them being women.
In MS patients, the body’s own immune system attacks the nerve fibres’ “insulating layer” (myelin sheath) and
destroys it. Early MS symptoms, so-called episodes, frequently include impairment of visual functions caused by
optic neuritis, paralysis of the arms and legs caused by inflammations in the brain or in the spinal cord, and
paraesthesia (fig. 1). These episodes last for over 24 hours and are usually treated with cortisone in high doses to
encourage remission. In case of severe flare-ups that do not remit after cortisone treatment, patients have the
option to undergo plasmapheresis in specialised centres.
Typically, all regions of the central nervous system – brain and spinal cord – are affected as the disease progresses.
The inflammations result in ataxia, impairment of fine motor skills, as well as concentration loss, bladder function
impairment, fatigue and depressive episodes.
Disease progression varies from person to person: some 90 per cent of all patients suffer from relapsing-remitting
MS, with symptoms initially remitting after an episode. Without proper treatment, the disease evolves into the
secondary (chronic) progressive form, where patients experience no symptom relief between episodes. Some 10 per
cent of all patients suffer from primary progressive MS, which means they have never experienced symptom relief
between episodes (fig. 2). This form of MS affects men and women equally.
Despite intensive research into and the development of new therapy methods, there is, as yet, no cure for MS.
Nonetheless, considerable progress has been made regarding the treatment of relapsing-remitting MS in the last 20
years. In the 1990s, injectable drugs were released to the market that modulate the immune system: interferon beta
and glatiramer acetate reduce the frequency of the episodes by one-third and suppress the formation of new
inflammatory foci in the brain and in the spinal cord. As a result, MRI scans (fig. 3 and 4) show 70 per cent fewer
newly formed inflammatory foci in patients undergoing this type of treatment. These drugs are not harmful, but at
the same time, their efficacy is quite limited.
Particularly severe cases are treated with the chemotherapeutic agent Mitoxantron. Originally developed to treat
cancer, it may cause severe side effects such as cardiac insufficiency, secondary leukaemia and infertility. Released in
2006, the monoclonal antibody Natalizumab has proved efficient in reducing MS episodes by up to 68 per cent.
Biocellular and biomolecular engineering methods are deployed for the production of this antibody that binds to
certain structures on the surface of white blood cells, thus stopping them from migrating through vascular walls into
inflamed tissue. Consequently, the agent inhibits the leukocytes’ destructive effect that, in case of MS, is directed
against the insulating layer of the nerve fibres. But because the destruction of harmful foreign bodies such as viruses
and bacteria is what white blood cells are all about, this therapy method results in a weakening of the body’s
immune defences. The after effects may include so-called opportunistic viral infections of the brain, such as the
frequently fatal progressive multifocal leukoencephalopathy (PML).
Available in capsule form, the recently approved drug Fingolimod, which likewise suppresses the immune system,
boasts a similar effectiveness; however, here, too, comprehensive measures must be taken to prevent opportunistic
infections. In view of all this, the demand for highly efficient and non-harmful immune therapeutics has never faded.
There are new grounds for hope, and they derive from a wholly unexpected field: namely dermatology. Here,
fumaric acid esters have long been successfully used in psoriasis therapy (info) – likewise an auto-immune disease.
Fumaric acid is a fruit acid found in numerous plants, fungi and lichens and an approved food acidulant that also
occurs naturally in the human body. In its pure form, the substance is not effective against psoriasis; it is not until the
acid is condensed with alcohol that esters are formed which have a therapeutic effect against autoimmune diseases.
The application of fumaric acid esters to fight autoimmune diseases has been the result of the collaboration
between the dermatology and neurology departments at the RUB clinic St. Josef Hospital in Bochum. It all began
when patients suffering from both MS and psoriasis who were treated with fumaric acid esters experienced a
remission of their MS symptoms. The physicians at the RUB clinic thus made surprising discoveries regarding the
neuroprotective properties of fumaric acid esters. Currently, their therapeutic effect against multiple sclerosis has
caused a considerable stir on an international level.
A blend of several fumaric acid esters has been available in the German market under the brand name Fumaderm®
since the 1990s. The agent is absorbed by the body through the small intestine; small amounts are excreted through
urine and faeces. The half-life of the double ester dimethyl fumarate (DMF) is only a few minutes. By splitting
enzymes, so-called esterases, DMF is rapidly metabolised into mono-methyl fumarate (MMF) whose half-life in
human blood is 60 minutes. A small molecule, MMF can actually permeate the protective blood-brain barrier that
separates the brain from various agents: in an experimental model, the local effective concentrations of fumaric acid
ester measured in the brain reached up to three micromol that may have a therapeutic effect in the inflamed regions
caused by MS.
In the field of dermatology, a broad range of immune mechanisms had been researched. It has been postulated
that key cells of the immune system, so-called dendritic cells, use fumaric acid ester to process white blood cells
(lymphocytes) of the aggressive TH1 type into the TH2 type that modulates immune activity and, in a manner of
speaking, soothes auto-aggressive cells through various messenger substances. An autoimmune disease, psoriasis is
mediated by the T cells of the immune system, which is why it is reasonable to assume that the symptoms may be
reduced or even entirely suppressed if the immune system is reprogrammed.
During our initial research into the effect of fumaric acid esters on a disease similar to MS (Experimental
Autoimmune Encephalomyelitis, EAE) conducted on mice in an experimental model at the MS Institute in Göttingen
in 2004, we observed that the migration of the phagocytes of the immune system (macrophages – microglia) into
the mice’s inflamed spinal cord was inhibited to a considerable degree. At the same time, we discovered that the
damage to the myelin sheath of neurons (demyelination) was reduced: a larger number of myelin sheaths
surrounding nerve fibres remained intact. Eventually, we also demonstrated a higher density of nerve fibres (axons),
thus providing an explanation of why mice treated with fumaric acid ester showed less severe symptoms.
At that point, the cause underlying these findings was still unclear: we suspected that fumaric acid ester reduced
the damage to the nervous system in the first place and, consequently, fewer phagocytes migrated there as
“cleaners”. This would indicate that the agent had a protective effect on neurons, in addition to providing immune
modulation, as had been postulated in the field of dermatology. This hypothesis was supported by the fact that the
number of inflammatory T cells of the immune system was only slightly reduced.
Further research showed that protective antioxidant metabolic pathways were triggered in cell cultures through
the addition of fumaric acid esters. The transcription factor Nrf2 (nuclear factor derived-E2-related factor 2, fig. 5), a
modulatory protein in neurons, acts as the molecular mediator. Typically, this factor is suppressed within the cytosol
by its counterpart Keap. By sulphidising Keap, fumaric acid esters dissolve the blockage, allowing Nrf2 to migrate into
the nucleus and to trigger a number of antioxidant pathways (fig. 5). These, in turn, neutralise various cytotoxins that
are formed due to oxidative stress, for example through so-called free radicals.
This is very clearly demonstrated in an experimental model: the process of Nrf2 permeating the nucleus in nerve
cells as well as in myelin sheath-forming oligodendrocytes and in astrocytes that surround brain neurons can be
observed under the microscope. Thus, it became obvious that nerve cells are protected, as if by a firewall, from
inflammatory agents, mainly from free radicals and nitrogen monoxide. The implementation of a protective
mechanism in the nervous system through therapeutic measures would constitute a wholly new approach in MS
treatment; however, conducting the necessary studies in humans is possible only to a limited extent, and such
hypotheses can be only indirectly verified, for example through MRI scans (fig. 3 and 6).
Further examinations in experimental models demonstrated, moreover, that fumaric acid esters had a protective
effect on nerve cells in patients suffering from Huntington’s, a most severe neurodegenerative disease. In
Huntington’s patients, genetic defects lead to cellular metabolism dysfunctions, thus causing nerve cells to die off. In
Germany, 10,000 people suffer from this hereditary disease whose progression is unstoppable and which causes
severe disabilities that last for the rest of the patients’ lives. Treated with fumaric acid ester, Huntington’s mice with
a similar genetic defect live a longer and more active life, and a higher number of neurons survive in them than in
untreated Huntington’s mice.
Current neuroimmunologic studies have shown that, in EAE, a disease with MS-like symptoms, the effect of
fumaric acid esters could be enhanced if they were applied in combination with interferons – chemical messengers
of the immune system. Fumaric acid esters also proved effective in the treatment of spontaneously progressing
genetic EAE diseases.
The then-managing director at the neurology clinic, Prof Dr Horst Przuntek, observed significant MS symptom relief
in MS patients who also suffered from psoriasis after they had been undergoing fumaric acid ester treatment carried
out by -Bochum-based dermatologists. Accordingly, a small-scale study was conducted with ten patients suffering
from relapsing--remitting MS. In the course of 70 weeks, the researchers observed that the frequency of the
episodes decreased considerably and that changes typical for MS were reduced by up to 90 per cent, as evident in
MRI scans. What followed was a phase 2 dose-finding study (clinical study with several hundred patients) sponsored
by Biogen-Idec. The result was: a single dose of the drug has to contain at least 240 mg DMF, also known as ‘BG-12’.
Subsequently, phase 3 studies with more than 2,400 patients were conducted, comparing treatment groups of
patients who took daily doses of 2 x 240 mg or 3 x 240 mg DMF respectively in form of tablets, as well as control
groups of patients undergoing placebo therapy or a proven basic treatment (glatiramer acetate). Fumaric acid esters
reduced the episode frequency by up to 50 per cent and the number of active inflammatory foci that were visible in
MRI scans by up to 90 per cent. Two daily doses offered results comparable to three daily doses.
The side effects of fumaric acid ester treatment include gastrointestinal problems that have been observed in
some 20 per cent of patients taking the drugs as part of their dermatological therapy. The reason is: when fumaric
acid esters are absorbed through intestinal mucosa, locally irritating inflammatory cytokines are released.
Therefore, the BG-12 compound has a delayed-release formula. As a result, gastro-intestinal intolerances occurred
considerably less frequently in phase 3 trials than they had done with the dermatological drug, amounting to a mere
three to five per cent. Apart from digestive disorders, the second most common side effect was the so-called flush
syndrome, which occurred in some 40 per cent of all patients. This reaction is certainly quite unpleasant, but it is by
no means dangerous. The symptoms disappear some four to six weeks into the treatment. There was no evidence of
any immunosuppressive effects, opportunistic infections or cancerous cell growth such as may develop following a
reprogramming of the immune system whose functions include protecting the body from cancer. Blood-counts that
were routinely conducted in two-month intervals showed no abnormalities. Highly efficient and yet non-harmful – a
wholly new experience in MS therapy!
Fumaric acid esters enhance the therapy spectrum for relapsing-remitting MS. The new drugs are an interesting
treatment alternative as they combine high efficacy and safety such as have long been achieved with the old formula
in the field of dermatology and are supported with data corresponding to more than 150,000 patient years.
Moreover, the oral formulation is a relief for many MS patients who have long developed ‘injection fatigue’. Market
authorisation being scheduled for spring 2013, the substance will then be ‘officially’ available to patients; at present,
the only option are so-called off-label prescriptions.
Considering the evidence of their protective efficacy for nerve cells gathered in experiments as described above, it
is possible that fumaric acid esters might also prove effective in case of other neurodegenerative diseases for which
no treatment has yet been found. A study regarding the application of fumaric acid esters to treat motor neuron
diseases, a group of disorders affecting the nerve cells that control locomotion, is forthcoming. Motor neuron
diseases include, for example, amyotrophic lateral sclerosis (ALS). It is imperative to conduct individual studies for
each and every one of the disorders.
Already, we can confidently state that fumaric acid esters have found their way from Bochum into the world of MS
therapy!
Prof Dr Ralf Gold, Dr Gisa Ellrichmann and PD Dr Ralf Linker (currently Neurological University Clinic, University of
Erlangen), Neurological Clinic, St. Josef Hospital, Clinic of the Ruhr-Universität Bochum
INFO
HISTORY OF FUMARIC ACID ESTERS IN THE FIGHT AGAINST AUTOIMMUNE DISEASES
The development of fumaric acid esters as autoimmune disease therapeutics has --been marked by many happy
coincidences. It all began when biochemist Dr -Walter Schweckendiek, himself a psoriasis patient, and general
practitioner Dr Günther Schäfer postulated the substance’s efficacy in the 1950s and 1960s: in case of autoimmune
diseases, the T cells of the immune system require an energy input and what fumaric acid esters do is manipulate
the citric acid cycle – a series of biochemical reactions in cells that generates energy. After successful external
application of a fumaric acid cream, both researchers went a step further and began developing a variety of fumaric
acid ester mixtures which they tested on themselves. In the following years, Dr Schäfer successfully treated
numerous psoriasis patients in his surgery, which in those days constituted a huge progress. Bochum-based medical
researchers, Prof Dr Peter Altmeyer and Dr Uli Matthes, then took up fumaric acid ester research in the academic
context and established the substance firmly as the primary psoriasis therapy method – thus going against the
contemporary ‘dermatological mainstream’.