Current developments in MS research: new drugs reduce frequency of attacks in MS and improve walking ability
Berlin, 21 June 2010
ENS 2010: 3,000 neurologists meet in Berlin
Current developments in MS research: new drugs reduce frequency of attacks in MS and improve walking ability
Good news for patients with multiple sclerosis: the range of treatments for MS has been further expanded: the active ingredients cladribine and fingolimod induce a significant reduction in MS attacks. As these drugs can be taken orally, time consuming transfusions are no longer necessary. And the active ingredient Fampridine offers relief from symptoms. 43% of participants in a study saw improvements in their ability to walk. Neurologist Prof. Klaus V. Toyka (Würzburg) speaks of "another successful step in the treatment of MS." MS is not a disease of old age. It appears most commonly between the ages of 20 and 40, and women are more than twice as likely to contract it as are men.
Berlin, 21 June 2010 - "Major advances have been made in the treatment of multiple sclerosis. The most recent examples are the active ingredients cladribine and fingolimod, which can be taken orally," says Prof. Klaus V. Toyka (Director of the Neurology Clinic, University Clinic Würzburg) at the Meeting of the European Neurological Society in Berlin (19-23 June, 2010). Test results from three studies demonstrate that the two active ingredients significantly reduce the frequency of attacks of MS. While drugs used until now had to be administered by transfusion, cladribine and fingolimod can be taken in pill form, as a short course treatment with time dependent effect, or as a daily dosage. "With this we have achieved an important expansion of treatment options for relapsing-remitting MS," says Prof. Toyka. Many patients who find regular injections burdensome prefer to take the drug in the form of a pill. "We hope that tests planned on these substances for advanced stages of MS such as secondary progressive MS will also soon deliver positive results."
Novel active mechanisms
Cladribine, which has already been approved for cancer treatment, is a small molecule which may influence the behaviour and cell division of certain white blood cells which are probably involved in the pathological processes of MS. It was already tested for MS in a small study many years ago, but not to the standards of quality and effectiveness demanded today.
Fingolimod prevents potentially damaging immune cells from the lymph nodes from reaching the bloodstream. They are thus prevented from contributing to the development of inflammations in the central nervous system, which are considered responsible for the majority of symptoms in MS. Furthermore, it has been demonstrated by experiment that fingolimod reacts directly with central nervous system cells, where it displays a protective effect and can promote the regeneration of tissue. The clinical significance of this 'neuroprotective active aspect' of fingolimod has however not been investigated.
Although the active mechanisms of cladribine and fingolimod are different, they deliver similar therapeutic results. The test phases have taken place over the past two years and have delivered very satisfactory results with respect to reducing attacks of MS.
Frequency of attacks reduced by up to 60%
The results of the (Phase III) cladribine study ("CLARITY") involving over a thousand relapsing-remitting MS patients are very good: after 96 weeks the annual rate of attacks compared to placebo was reduced by over 50% and almost 80% of those treated with cladribine remained free of attacks until the end of the study. Most importantly, the worsening of MS related disabilities among those receiving treatment was a third less pronounced than among the placebo group. The positive therapeutic effects also appeared in MRT examinations.
In the two year clinical Fingolimod study ("FREEDOMS") with over a thousand relapsing-remitting MS patients, it was demonstrated that Fingolimod also reduced the frequency of attacks by over 50% in comparison to placebo. There was likewise a reduction of MS related disabilities of around 30%. Using MRT, it could be shown that the number of inflammation sites declined and depletion of brain tissue was delayed. A further one year study comparing fingolimod with interferon demonstrated the marked superiority of fingolimod.
Fewer undesired effects - longterm investigations needed
The two new drugs are in general well tolerated. However doctors have diagnosed an increasing incidence of Herpes zoster infections (shingles) among cladribine patients as well as with fingolimod, and a temporary decline in the heart rate with initial doses of fingolimod. In both studies the development of a small number of rare tumors was also noted. "Though the results of the studies are very promising, we can assess rare and serious side effects only after approval and general use. Thus follow-up studies after they are introduced to the market are extremely important," says Prof. Toyka. Follow-up studies on the risk-benefit ratio for the two drugs are underway at the moment. Fingolomod was recommended for approval by United States regulatory authorities on June 11th, 2010. The European EMEA may take a little longer. Cladribine is also in the approval process. It can be expected to take some months to receive approval here.
Fampridine allows MS patients to run again
Doctors and researchers have been able to achieve a degree of progress in treatment of MS symptoms. Patients can now hope for some relief in the treatment of symptoms triggered by MS such as limited strength and mobility. Treatment of these restrictions in function has been unsatisfactory until now. Fampridine, from a group of substances tested by experiment some years ago by Prof. Toyka's team in Würzburg and also in Amsterdam, has been shown in a small study to have an effect on around 40% of participants: it improved their ability to walk. Fampridine works as a potassium channel blocker to improve signal transmission in demyelinised nerve tracts. The active substance has meanwhile been licensed in the US under the name "Ampyra". Europe and Canada will follow suit in the coming months.
Recommendation for treatment of progressive multifocal leukoencephalopathyPML(PML) with Natalizumab
In the name of the Medical Advisory Board of the German Multiple Sclerosis Society (Deutschen Multiple Sklerose Gesellschaft, DMSG), together with the neurological professional associations and in agreement with the Swiss and Austrian MS societies, Prof. Toyka and the board of directors have for the first time issued a recommendation on the use of the MS drug Natalizumab (Tysabri). The drug was withdrawn from the market in the US in 2005 and then reintroduced the following year. This was because patients contracted progressive multifocal leukoencephalopathy (PML), a serious and formerly often fatal virus infection of the central nervous system with severe neurological complications. The grounds for the recommendation were MS patients treated with Tysabri who then fell ill with PML. "All doctors treating MS patients with Natalizumab should have PML in mind if new neurological or psychiatric symptoms develop. Our specialists have worked out clear recommendations to ensure the safety of patients. First and foremost, every patient receiving treatment for a period of 24 months must once again be fully informed and monitored at very close intervals, should treatment be continued," says Prof. Toyka.
The German Multiple Sclerosis Society recommends magnetic resonance imaging as a first step in diagnosis. Should this not deliver definitive results, analysis of cerebrospinal fluid to ascertain the presence of the JC virus should be undertaken. Should this prove positive, the German Multiple Sclerosis Society and "Working group Immune Therapy" initiated by Prof. Gold and other colleagues recommends plasmapheresis treatment "so that the active agent is eliminated from the body as quickly as possible."
"Despite the serious and grave risks, we consider there are still no grounds to generally limit treatment with Tysabri strictly to two years," says Prof. Toyka. "The expert group led by Prof. Wiendl is also of this opinion."
Compromised blood flow in the veins is not the cause of MS
A highly controversial current theory on the possible cause of MS has been rejected by Prof. Toyka and members of the Medical Advisory Board and representatives of the new specialist network set up in the ministry of education and research; "The theory of chronic cerebro-spinal venous insufficiency (CCSVI), which is again under discussion in specialist circles as a cause of MS, is a theory which at the moment has no scientific basis." This theory proceeds from the idea that compromised blood flow increases the vascular pressure in the brain, possibly leading to increased deposits of iron in blood vessels triggering inflammation. Prof. Toyka say that ultrasound diagnostic findings presented as evidence do not give clear cut results. Prof. Toyka: " Unfortunately, the only study done so far, by Dr. Paolo Zamboni, which was strongly criticised for its methods, has already led to operations to expand 'affected' veins in the brain with stents, which in the US has led to fatalities. The Medical Supervisory Board has described the study as ethically questionable."
MS onset usually between the ages of 20 and 40 - clarification by neurologists
While many neurologcal diseases such as neuropathic pain, stroke, Parkinson's or Alzheimer's are primarily diseases of advanced phases of life, MS is a disease of the young and young adults (between the ages of 20 and 40), occasionally occuring even in childhood and youth.
Indications can include disturbances in sensation, visual or speech disorders, or tremors, but also unsteady gait and walking disabilities extending to paralysis of one or more extremities, coordination problems, bladder and bowel incontinence, and impairment of muscle and of body image perception. Sexual function can also be affected in MS patients. The length of duration of MS has a negative impact on performance. "MS fatigue" is a special form of rapid exhaustion.
Here neurologists in acute clinics and private practices need to link up with neurologists expert in rehabilitation, to work together to offer multimodal treatment of symptoms, and at least bring some relief.
In summary Prof. Toyka views the future of MS treatment and the latest scientific findings as a success story, but warns against ignoring immunomodulators which have proven value and low risk, even when they must be administered by injection.
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Dr. Birgit Kofler
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