Research news - January 2010
Way Ahead 2010;14(1):2-4
- ECTRIMS report
- Securing ethical approval in the UK
- Fingolimod
- PreCISe study
- Fampridine
- CCSVI research
ECTRIMS report
A speaker addressing the ECTRIMS conference
The European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) hosts the world's largest annual international conference devoted to basic and clinical research in multiple sclerosis.
This year's conference took place in Dusseldorf, and boasted an attendance of 5,000 health professionals from 86 countries including 275 from the UK. The following summary aims to capture the key messages of the four day conference.
Existing disease modifying drugs - the story so far
While a large proportion of the conference programme focused on the latest developments relating to emerging therapies for multiple sclerosis, it was useful to set the backdrop against which these new treatments are coming into focus.
The existing disease modifying drugs are accepted as the first and safest line of treatment with a consensus that a therapeutic window affords optimum benefit from early intervention in appropriate patients. The patient population receiving disease modifying drugs is changing; they are less disabled and diagnosed earlier in the course of the condition than the early recipients of the drugs over a decade ago.
Importantly, the less visible symptoms of MS are beginning to receive greater recognition and the World Health Organisation's shift from cause to impact has changed the focus of disability from the medical or biological function, to one that takes into account the social and contextual aspects of disability.
Emerging therapies
Data was presented on the following emerging therapies:
Cladribine
Data on the oral MS drug Cladribine was submitted to the European drug regulator last year. The 96-week data shows a 55-58% reduction in relapses. Dosage varies according to body weight and in trials has been given as two or four treatment courses consisting of once daily administration for four to five consecutive days, meaning study participants took Cladribine tablets for 8 to 20 days during the year. It is not known how many courses can be safely administered.
Towards the end of 2009, the US drugs regulator the Food and Drug Administration (FDA) 'refused to file' a license application for Cladribine. The FDA usually issues such a response when it finds applications to be incomplete.
Fingolimod
Results of the FREEDOMS trial were released just after ECTRIMS and are reported in greater detail on page 4. The phase III efficacy and safety data confirm a positive benefit-risk profile for the lower 0.5mg dose of fingolimod and support the planned EU licence submission.
Laquinimod
Laquinimod is currently being investigated in two phase III trials. Both studies are fully recruited and there are in excess of 1,000 people with relapsing remitting MS participating in each. Interferon beta 1a is being used as a comparator in one of these studies.
Alemtuzumab
The data for alemtuzumab remains encouraging in terms of the impact it has on the course of MS. There is now four year follow-up data for patients from the trial, the majority of whom received only two years of therapy consisting of five consecutive days of alemtuzumab at the start of each year. Alemtuzumab was shown to be 70% more effective than high dose interferon beta 1a using relapse rate and disability progression as the marker of effectiveness.
The seriousness of the side effects means that close monitoring of patients is necessary and the optimum number of cycles for the best outcome has yet to be established.
Failed studies
Data was presented to demonstrate how the following drugs had failed to meet their primary outcome measures in studies: lamotrigine, atorvastatin and dirucotide.
Oral treatments; first or second line therapy?
With several oral therapies moving ever closer to clinical use, questions have arisen over appropriate and safe administration of the drugs. A session addressing these questions saw debate over when to consider oral preparations and for which clinical presentations. Consideration was also given to the impact of emerging oral therapies on the current organisational structures and how a new line of drugs may affect the way in which MS services are managed. The impact emerging oral therapies may have on the dialogue between patient and clinician was also explored.
Primary progressive MS; not the forgotten few
As far as research is concerned, people with primary progressive MS are not the forgotten few, and this particular subtype of MS is moving fast up the research agenda.
A key study in this area is the INFORMS (FTY720 in patients with primary progressive multiple sclerosis) study which is investigating the effects of fingolimod in primary progressive MS. This is a three year placebo controlled study with a primary outcome measure defined as delaying time to sustained disability progression. There are three sites around the UK participating in the study.
Amongst the challenges that research into primary progressive MS poses is the selection of responsive and appropriate outcome measures and the selection of reliable predictors of progression.
Closing questions
Whilst the range and diversity of the conference was both encouraging and inspiring, there remain further questions about the future direction of research and the gaps in our knowledge about MS. The key questions that were posed as ECTRIMS 2009 drew to a close were:
- Are there bio-markers which will predict which people will respond to drug treatment?
- What happens when natalizumab is discontinued? Does disease activity return and is it at a higher level?
- Who will be appropriate to receive stem cell therapy?
- What is driving the apparent increase of MS in women?
- Why is there a clustering of MS in people born in the summer months?
- How important is the interaction between vitamin D and MS genes?
- Is there a role for anti-infective agents?
Securing ethical approval in the UK
There is a growing perception that the UK's ethical approval processes are stifling rather than improving the quality of research. Accepting this view, but offering practical advice and guidance on how to overcome the obstacles posed by regulatory approval, is a recently published paper in the British Medical Journal, 'Applying for ethical approval for research in the United Kingdom.'
This Practice Pointer discusses the practicalities of preparing an application for ethical review and the processes by which decisions are made. It explains exactly what ethics committees are looking for in an application and offers advice on how to avoid common problems. It also offers some general pointers for writing participant information sheets and guidance on using the integrated research application system.
Smajdor A, Sydes MR, Gelling L, et al.
Applying for ethical approval for research in the United Kingdom [cited 2009; October 28].
Available from: URL: www.bmj.com/cgi/content/extract/339/oct16_1/b4013?papetoc
Fingolimod
Adding to the positive data that was released early in 2009, initial results from the two year Phase III FREEDOMS (FTY720 Research Evaluating Effects of Daily Oral therapy in Multiple Sclerosis) study have been released. 1,272 people with relapsing remitting MS in 22 countries took part in the study and received one of two doses of fingolimod or placebo over two years. The results show that fingolimod reduced the relapse rate by 54% for the lower dose (0.5 mg) and by 60% for the higher dose (1.25 mg) compared to placebo. The reduction of progression of disability was 30% and 32% respectively compared to placebo.
Novartis announced it's intention to apply for a licence for the lower dose of fingolimod in both the USA and Europe towards the end of last year. The drug is also currently under investigation in primary progressive MS.
PreCISe study
Results of the PreCISe study (Study to Evaluate Early Glatiramer Acetate Treatment in Delaying Conversion to CDMS of Subjects Presenting With CIS), a randomised, double blind, placebo controlled study investigating the effects of glatiramer acetate (Copaxone) in patients presenting with a clinically isolated syndrome (CIS), were recently published. In the study, 481 people presenting with CIS were randomly assigned to one of two groups; to receive either daily injections of Copaxone or daily injections of a placebo for up to three years. The two groups were monitored for the occurrence of a second attack confirming a definite diagnosis of MS. The results of the study indicate that over a period of three years, the group receiving Copaxone were 45% less likely to convert from CIS to a clinically definite diagnosis of MS. These results are consistent with the results of previous studies which have shown interferon beta to delay progression from CIS to clinically definite MS.
Comi G, Martinelli V, Rodegher M, et al.
Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial.
Lancet 2009; 374 (9700):1503-1511.
Fampridine
The US medicines regulator the Food and Drug Administration (FDA) is due to make a ruling on the approval of Fampridine SR, an oral, sustained-release drug designed to improve walking ability in people with MS. There had been indications that the drug would be approved by the FDA panel last October, but following the submission of new information on the manufacturer's risk evaluation strategy for the drug, the FDA extended the review date. Fampridine remains an unlicensed drug treatment in the UK but in July 2009 the manufacturer, Acorda, announced it would submit a licence application in Europe during 2010.
CCSVI research
In November last year, research conducted by an Italian vascular surgeon was widely reported in the media. Chronic cerebro-spinal venous insufficiency (CCSVI) is the name given to a phenomenon whereby stenosis (an abnormal narrowing or obstruction) in blood vessels that take blood from the brain allows a build up of iron. This is then able to cross the blood-brain barrier and cause inflammation and damage to cells in the central nervous system.
In the 2 small studies of 116 people so far published, Dr Zamboni reports that the abnormality is present in people with MS but not in a healthy control group or in people with other neurological conditions. Surgery can relieve the blockage and appears to reduce MS symptoms.
The evidence has yet to demonstrate whether the association between MS and CCSVI is cause or effect or how CCSVI affects the long-term course of MS. Dr Zamboni's theory will need further investigation in larger groups before any firm conclusions can be drawn.
Zamboni P, Galeotti R, Menegatti E, et al.
Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis.
Journal of Neurology, Neurosurgery & Psychiatry 2009;80(4):392-399.
Zamboni P, Galeotti R, Menegatti E, et al.
A prospective open-label study of endovascular treatment of chronic cerebrospinal venous insufficiency.
Journal of Vascular Surgery 2009;50(6):1348-1358.
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