First described in 1868, multiple sclerosis is a debilitating disease that still has scientists baffled. Only now are we getting to grips with its method of attack and Dr Sarah Houlton reviews the latest drugs offering some alleviation
Multiple sclerosis is a progressive central nervous system condition, and is the most common disabling neurological disease in young adults. Many of the symptoms result from nerve damage, caused by inflammation in the central nervous system. This can result in the myelin sheath surrounding the nerve fibres in the brain and spinal cord being destroyed, stopping them working and leaving the nerves themselves unprotected, and exposing channels in the axons.
Potassium channels create the electrical signals by which the nerve axons communicate with each other, and when the potassium channels are damaged the ions can leak out and signalling is disrupted. While the damaged nerves are able to regenerate themselves up to a point, the damage builds until they are no longer able to function. This can result in persistent symptoms, including pain and weakness or even loss of control of bodily functions.
The disease affects different people in different ways, and is completely unpredictable. Some will experience a very rapid decline, while in others the progression is slow and their functions take decades to deteriorate. Most patients, however, develop a relapsing-remitting form of the disease, where the relapses of short-term flare ups of their symptoms are punctuated by periods of calm. However, it is now believed that the neurodegenerative processes continue unabated between the relapses.
The processes have now been classified into four main forms: as well as relapsing-remitting, there is primary progressive, where there is a steady increase in disability without these relapses; secondary progressive, where the patient starts off with relapses but then moves to a progressive form of the disease; and progressive relapsing, the most unusual form, where there is a steady decline with clear neurologic attacks.
cause unknown
The precise cause of the disease is as yet unknown, but one theory that is gaining supporters is that the initial trigger for the autoimmune response could be a virus. It may attack the CNS directly, or perhaps its surface may resemble myelin, which confuses the immune system into making myelin-destroying antibodies. Two possible culprits are Epstein-Barr and human herpes virus-6. However, these are very common infections, so it may be that a genetic susceptibility is also required before the disease is triggered. Various other factors may also be involved, including exposure to sunlight (it may be that exposure as a child has a protective effect), components of the diet, physical trauma, stress or even cigarette smoking.
Acute exacerbations are generally treated with short courses of the corticosteroid methyl-prednisolone. Other symptoms of the disease, such as pain, incontinence and depression, can also be treated with drugs. While there is no cure for MS, a number of drugs are used to try and reduce the number of relapses, and many others are under development, including some that are aimed at modifying the course of the disease.
Six drugs are licensed: three different forms of interferon beta (Avonex from Biogen Idec), Merck Serono's Rebif and Betaferon from Bayer Schering), glatiramer acetate (Teva's Copaxone), the monoclonal antibody natalizumab (Tysabri, Biogen Idec), and mitoxantrone (Novantrone, from Merck Serono and OSI). Clinical trials have shown the interferons reduce the frequency of relapses by about a third over two years.
Several potential mechanisms have been suggested for the interferons" activity. They may reduce the activation and proliferation of lymphocytes, reduce the expression of VLA4 adhesion molecules on lymphocytes lowering their ability to cross the blood-brain barrier, or they may reduce the activity of matrix metalloproteases which weaken the blood-brain barrier. Other possibilities involve cytokines: they may either increase the production of anti-inflammatory cytokines such as interleukins in the CNS, or reduce the release of pro-inflammatory ones, such as interferon-gamma.
Glatiramer acetate is a synthetic polypeptide made up of glutamic acid, alanine, lysine and tyrosine residues as an acetate salt. It has many possible mechanisms of action, including desensitising the lymphocytes that cross-react with myelin, and increasing the number of anti-inflammatory and reducing the number of pro-inflammatory T-cells and hence affect the cytokines they produce. Again, it may reduce relapses by a third over two years.
Natalizumab works in a very different way, as it prevents inflammatory lymphocytes entering the CNS by stopping VLA4 antigen from binding to receptors on the surface of epithelial cells within the blood brain barrier. Recent trial results indicate that five times as many MS patients treated with the antibody were free from disease activity than those given placebo. Two years after starting treatment, 37% of 596 patients being treated with the antibody were free from disease activity compared with 7% of the placebo group of 311, while 64% showed no sign of relapse or sustained disability progression.
Another different mechanism is behind the action of mitoxantrone. A topoisomerase II inhibitor that is used to treat cancer also has some activity in MS. It acts on the inflammatory backdrop to the disease, inserting itself into the DNA, decreasing cell division and protein production. It has been shown in vitro to reduce the proliferation of damaging B cells, T cells and macrophages. This lowers the production of the cytokines that cause the damage. It is indicated for reducing neurologic disability and the frequency of clinical relapses in patients with secondary progressive and progressive relapsing forms of MS, and also relapsing-remitting MS that is getting worse; it can slow the progression of the disease and increase the time between relapses.
wealth of possible mechanisms
Because MS is such a complex disease, there are many different points at which there could be potential targets for drugs, and a wealth of mechanisms of action are being investigated in clinical studies. The following represent just some of these that have made it to the later stages of trials.
One of the furthest advanced is Fampridine-SR, a sustained release form of 4-aminopyridine, from Acorda Therapeutics and Elan. In the lab, it has been shown to improve impulse conduction in nerve fibres whose myelin sheath has been damaged by blocking the exposed channels, allowing electrical signals to pass through.
In a Phase III trial, it had a positive impact on the walking ability of people with MS.1 A total of 301 patients with MS and some degree of walking disability were given the drug either in doses of 10mg twice a day or placebo for 14 weeks. Significantly more of those taking the active had a consistent improvement in walking speed compared with those on placebo, and it improved walking ability in all forms of MS. Adverse events were generally mild to moderate, and included urinary tract infection, falls and insomnia.
Another potential treatment has recently been submitted to the regulatory authorities for approval in patients with relapsing forms of the disease, and is one of several drugs that reduce the number of lymphocytes that could cross the blood-brain barrier. Merck Serono's cladribine has been in use for many years to treat leukaemia. The oral drug inhibits the enzyme adenosine deaminase, and interferes with the proliferation of lymphocytes and monocytes; it is selectively toxic to these cells.
In a two-year, randomised, double blind placebo-controlled Phase III trial in 1,326 patients with relapsing-remitting MS, subjects were given one of two different dose regimens of cladribine, or placebo. In the first year, they were given either two or four treatment courses of four or five consecutive days of doses depending on weight. In the second year, they were all given two treatment courses.
The active reduced the annualised relapse rate significantly compared with placebo, and this effect was significant after just 12 weeks of the study. The effects were sustained throughout the 96 weeks of the trial, with a relative reduction in annualised relapse rates greater than 50% for both dose regimens compared with placebo. In addition, lower mean numbers of different types of brain lesions were evident in the cladribine group. Adverse event profiles were similar across both treatment groups and those given placebo. The most common side-effects were headache, naso-pharyngitis, upper respiratory tract infections and nausea.
leukemia drug
Another leukaemia drug is also being investigated in MS. Alemtuzumab (Bayer Schering Pharma and Genzyme) is a recombinant humanised monoclonal antibody directed against the cell surface glycoprotein CD52 on lymphocytes and monocytes. In a Phase II randomised, double blind trial in previously untreated patients in the early stages of relapsing-remitting MS, 334 patients were given either interferon beta-1a three times a week, or annual intravenous cycles of alemtuzumab at doses of either 12 or 24mg a day for 36 months.2
At the end of the trial, the risk of relapse in those given antibody was reduced by 74% compared with those given the interferon, and the risk of sustained accumulation of disability was reduced by 71%. Mean disability also improved from baseline, whereas it got worse in the interferon group. Aside from normal infusion- related side effects, the antibody group were more likely to experience infections, and 3% of this group developed the potentially serious autoimmune condition immune thrombocyto-poenic purpura, where a low platelet count leads to an increased risk of uncontrolled bleeding. Phase III trials are now under way.
A different cancer drug under MS trials is rituximab from Roche, which is currently used for non-Hodgkin's lymphoma and to treat rheumatoid arthritis. The chimeric monoclonal antibody is directed against the CD20 protein on the surface of B lymphocytes, and thus depletes the number of lymphocytes in the bloodstream.
In a Phase II double blind 48 week trial, 104 patients with relapsing-remitting MS were given either 1,000mg of intravenous rituximab or placebo on days 1 and 15.3 The total count of gadolinium-enhancing lesions seen on MRI scans of the brain was lower in those given the antibody than in the placebo group. After the first infusion, more patients in the antibody group had adverse events within the first day, but the rates were similar after the second infusion. Most of these adverse events were mild to moderate.
Novartis" fingolimod is also designed to reduce circulating lymphocytes. The oral drug has a different mechanism: rather than killing lymphocytes, it prevents them from leaving the lymph nodes in the first place by modulating the sphingosine-1-phosphate receptors. In a two-year extension to a Phase II trial, 250 of the original 281 patients continued after the initial six months of therapy.4 In the first part of the randomised, double blind, placebo-controlled study, subjects were given 1.25 or 5.0mg of the drug a day; the trial remained blinded during the extension, when the placebo group was re-randomised to one of the two dose regimens. A total of 189 patients continued therapy for the full duration of the trial.
In the core study, the drug significantly reduced gadolinium-enhanced lesions and the annualised relapse rate compared with placebo, with no difference between the two doses. In the extension stage, those who switched from placebo showed clear reductions in both, and they remained low in those who had been taking the drug throughout. After two years, 79-91% of patients were free from lesions, and up to 77% remained relapse free.
FDA submission
Initial results of a Phase III trial showed that fingolimod reduced the relapse rate by 54% at 0.5mg doses, and 60% at the higher dose of 1.25mg. It also reduced the progression of disability by about 30% in both doses compared with placebo over two years. Novartis plans to submit the drug for FDA approval by year-end.
While reducing the number of lymphocytes appears to be an effective strategy in reducing the number of both lesions and relapses, it does open the door to a potential increase in the risk of infection. An alternative would be to change the way the lymphocytes behave using immuno-modulatory drugs. One of these is Teva's laquinimod, which reduces the ability of the lymphocytes to pass into the CNS, and alters the cytokines they release.
Positive results were seen in a 36 week double blind, placebo-controlled Phase IIb trial.5 Subjects had had at least one relapse in the previous year, and at least one gadolinium-enhancing lesion. A total of 720 patients were given 0.3 or 0.6mg of the drug a day, or placebo. The higher dose gave a 40% reduction in lesions compared with placebo, while the lower dose had no effect. It was well tolerated, and Phase III trials are under way using the higher dose.
A more specific method is to target only those lymphocytes that react against myelin basic protein. One drug had made it to Phase III - BioMS Medical Corp's dirucotide, being developed with Eli Lilly - but it was discontinued because it did not delay disease progression. However, another treatment that works on this protein is still undergoing trials - BHT-3009 from Bayhill Therapeutics. This is a vaccine that encodes for myelin basic protein, and is designed to reprogramme the immune system not attack it.
In a Phase II trial, patients were randomised to 0.5 or 1.5mg of the vaccine or placebo, given intramuscularly on weeks 1, 2, 4 and every fourth week thereafter until week 44.6 The mean volume of enhancing lesions at week 48 was 51% lower in the 0.5mg group than for placebo, but no significant improvement was seen with the higher dose. In addition, dramatic reductions in 23 myelin specific autoantibodies were seen in the 0.5mg group, but not in those given 1.5mg. In the follow-up period, there was also a trend to a reduction in relapse rates.
Another strategy is to reduce inflammation within the CNS. Many such drugs have reached trials only to fail, and one that had positive Phase II results, MN-166, has been parked by Medicinova, because of a lack of funding. This is used in Japan as an asthma treatment where it is better known as Kyorin's ibudilast, and inhibits leukotriene activity, phosphodiesterases and nitric oxide synthase, all of which are inflammatory mechanisms involved in MS.
In a two-year Phase II trial, patients were given 30 or 60mg of the drug a day or placebo.7 Brain volume loss was significantly lower after two years in those given the higher dose, and the relative risk for conversion of new inflammatory lesions into persistent black holes also reduced. Sustained disability progression was about half as likely in those given either dose for 24 months compared with those who received it for just 12. It was well tolerated.
There remains no cure for MS, but increasing understanding of how the disease progresses has led to a substantial amount of research, and many other mechanisms are in the early stage of investigation. The new disease-modifying agents may go a long way to improving the prognosis for patients with this degenerative disease.
Blood test predicts the course of MS
Scientists have discovered a blood test that could predict the course of multiple sclerosis (MS), or even indicate who is likely to develop the condition after a first MS-like attack.
The results of a recent study suggest that differing antibody levels produced in response to the common Epstein Barr Virus (EBV), may predict the course of MS. Further studies are being carried out to assess whether the biological indicator, or biomarker for MS could predict disability progression from a simple blood test.
The innovative work was carried out at the Institute of Neurology, UCL and the Institute of Cell and Molecular Biology, Barts & The London School of Medicine & Dentistry and was funded by the MS Society.
It is hoped the findings will aid the development of better ways to predict who goes on to develop MS after initial MS-like symptoms and help in identifying more effective therapies for the 100,000 people living with MS in the UK.
The paper's lead author, clinical research fellow Dr Rachel Farrell, said: 'All the participants in our study had previous history of infection with EBV, which has been shown in other studies and is not surprising given that a large majority of the adult population is infected with EBV.
'What was surprising is that the levels of a molecule in the blood called anti-EBNA-1 IgG, induced by the virus, were associated with the activity of MS. The results of this work show that participants who had new areas of MS damage in the brain also had high levels of the anti-EBNA-1 IgG molecule in their blood.
'In addition, participants with higher levels of EBNA-1 in the bloodstream were more likely to have an increase over time in the disability associated with MS.'
The authors of the study, published in the journal Neurology, concluded that anti-EBNA-1 IgG is a potential biomarker in MS that might be useful in predicting disability and progression. They added that the work needed to be validated in larger studies and in combination with other as yet unidentified biomarkers.
