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Summary
Hundreds of multiple sclerosis clinicians and investigators convened to present findings and develop collaborations at one of the top MS-focused conferences in the world. The 25th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) was held September 9-12, 2009, in Dusseldorf, Germany. Here is just a sample of these presentations, full details of which are available online at http://www.akm.ch/ectrims2009/.

Details
As several oral treatments wrap up phase III studies and prepare to submit data to the FDA, investigators reported on additional safety and effectiveness data from phase II and III studies:

•Dr. Mark Freedman and colleagues reported on phase II results of a study in which two doses of oral teriflunomide (sanofi-aventis), an immune modulator, or placebo, were added to ongoing interferon beta-1a therapy in 116 people with relapsing-remitting MS. Disease activity as observed on MRI scans was reduced by 56% over placebo in the lower dose group, and by 81% over placebo in the higher dose group. Phase III studies of teriflunomide are underway in relapsing MS and in people at high risk for developing  MS. (#P878)

•Dr. Gavin Giovannoni and colleagues analyzed data from the CLARITY study, a phase III trial of oral cladribine (EMD Serono). Cladribine – a drug that interferes with the immune cells that underlie the attack in MS – as reported previously reduced the relapse rate significantly more than inactive placebo in 1,326 people with relapsing-remitting MS (RR MS). Now the team reports that treatment with cladribine resulted in a greater proportion of people with no new disease activity (44.3% on a higher dose, 43% on a lower dose) than inactive placebo (16%). The company plans to submit to the FDA for approval of cladribine to treat MS in 2009. (#P471)

•Dr. Frederik Barkhof and colleagues presented MRI findings from the TRANSFORMS study that compared two different doses of oral fingolimod (FTY720) with Avonex® (interferon beta-1a, Biogen Idec) over a one year period. Previous results reported significant reductions in relapse rates with the study treatment; now the team reports as that fingolimod reduced active areas of tissue damage observed on imaging scans. Phase III studies are ongoing. (#89)

•Dr. Giancarlo Comi and colleagues reported on a long-term extension of the phase II study of laquinimod (Teva Pharmaceutical Industries), an oral immune modulator now in phase III trials. Laquinimod reduced disease activity by 40.4% compared with placebo in a study of 306 people with RR MS treated for 18 months; 155 of 209 patients who entered the extension have been treated for an additional 24 months. The “annualized” relapse rate for this group is 0.46, compared with 0.53 in the original study; 10.5% of participants have shown progression on the EDSS disability scale, compared with 14.8% during the first 18 months; and 61% have not had new active areas of tissue damage on MRI scans. The most common side effects include nasopharyngitis (25.8%), back pain (12.4%), and headache (8.1%). (#P443)

Some Success, Some Failures in Novel Strategies

ECTRIMS featured mixed results on novel therapeutic strategies:

•One experimental strategy under study for treating MS is cell transplants, such as “mesenchymal stem cells,” which are derived from bone marrow. Dr. Mark Freedman and colleagues reported on the formation of the International Mesenchymal Stem Cell Therapy Study Group. This group – which includes many of the world’s experts in this type of cell therapy – met in 2009 to develop a protocol for propelling this research forward. They formed a consensus on numerous issues related to study design, and have agreed to begin studying this strategy in active forms of MS, including RR MS, secondary progressive MS with ongoing relapses or primary progressive MS with disease activity on MRI scans. (#49)

•Dr. Frederik Barkhof and colleagues administered the immunosuppressive drug temsirolimus or placebo to 297 people with RR MS for nine months. Temsirolimus reduced the rate of brain tissue volume loss significantly more than placebo, as measured by two separate methods. The results suggest that this drug may protect nerve tissue from damage in MS, as well as suppress the immune attack. (#P481)

• Dr. Raj Kapoor and colleagues reported on a study of the epilepsy (and potentially neuroprotective) drug lamotrigine in 120 people with secondary-progressive MS. The primary goal of the study was to determine the treatment’s effect on brain tissue volume loss; the results show tissue loss increased, in fact, although losses were recovered when treatment was stopped. Surprisingly, participants taking lamotrigine improved in walking speed, although the study was not designed specifically to measure this as a primary outcome. (#135)

•Dr. Emanuelle Waubant and colleagues reported on a study of atorvastatin and interferon beta or placebo in 81 people with Clinically Isolated Syndrome (CIS, a single, isolated neurologic event suggesting loss of nerve-insulating myelin). Previous studies have suggested that cholesterol-lowering “statins” can alter immune responses in a way that may hold promise in treating MS. The study was designed for 152 people, but enrollment stalled at 81, and thus it was not possible to detect if the primary endpoints – to decrease or delay clinical and MRI disease activity – were reached. However, the proportion of people who did not develop new tissue damage up to month 12 was 55.3% in the atorvastatin group and 27.6% in the placebo group, indicating a trend toward effectiveness. (#132)

Tysabri® and PML

There continues to be considerable interest in determining how to lessen the risk of PML (progressive multifocal leukoencephalopathy, a viral infection of the brain that usually leads to death or severe disability) in people treated with Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals).

•Dr. Richard Rudick and colleagues (Poster 883) found, in a large group of people tested before and after initiating therapy, that the frequency of detection of JC virus (the virus that causes PML) in blood or urine in those treated with Tysabri over 48 weeks was no different from that seen in healthy controls. This suggests that these tests are not helpful in screening people on treatment for risk of PML.

•Another approach under discussion has been to consider instituting a “drug holiday” at some point after being on Tysabri therapy. However, data presented by Dr. Paul O’Connor and colleagues indicated that MS disease activity rapidly begins to return after cessation of Tysabri, whether or not another disease modifying agent is being used (Poster 793).

Improving MS Symptoms

Several teams addressed the variety of symptoms experienced by people with MS:

•Dr. Z. Ambler and colleagues reported on a study of an oral spray drug derived from whole cannabis plants (Sativex® -- GW Pharmaceuticals, Salisbury, UK) in 572 people with all types of MS. Of this group, a four-week preliminary study targeted 241 as “responders” who then enrolled in a 12-week study in which the drug was compared with placebo. In this second phase, Sativex significantly improved spasticity compared with placebo. In the first phase, the most common adverse effect was dizziness (14% of those taking Sativex), and in the second phase, urinary tract infection (7% of the Sativex group). (#P844)

•Dr. John Zajicek reported results from the MUSEC study, which evaluated oral cannabis extract for treating muscle stiffness in 400 people with all types of MS. In this study, muscle stiffness improved by almost twofold in the group taking cannabis extract compared to placebo, and improvements were also noted in body pain, spasms and sleep quality. The most frequent adverse events were urinary tract infections, dizziness, dry mouth, and headache. (#881)

•Dr. N. Sharafaddinzadeh and colleagues administered low dose naltrexone (an opioid antagonist used to treat addictions to opioids and alcohol) or placebo to 50 people with MS to determine its effect on quality of life. Using a scale that measures physical and mental aspects of health status (MSQLI), the group found no significant difference between the naltrexone and placebo groups. (#P865) Read more about naltrexone research in MS.

•Dr. Charles Bombardier and colleagues used counselling to improve the participation of 102 people with MS and major depression in an exercise program. One face-to-face and five telephone sessions were conducted to promote motivation and commitment to the program. After 12 weeks, the group receiving the counselling showed significant improvements on several scales including those rating depression and fatigue, compared with a group not receiving the counselling. Those who improved also showed benefits in pain symptoms and community integration. (#P841).

Exploring the Underpinnings of MS

ECTRIMS featured some novel insights into the development of MS:

•Among many presentations focusing on genes that make people susceptible to developing MS and that may dictate its variability among people, Dr. M. Vellinga and colleagues reported on a study of focused on determining whether genetic variations could explain differences in the location of MRI-detected brain lesions in 208 people with MS. They found three gene variations that were associated with tissue damage located near the ventricular system of the brain (a set of structures containing cerebrospinal fluid). These gene variations occurred in the MHC or “major histocompatibility complex,” which helps determine immune responses and has shown definite links MS. Further research along these lines may provide valuable insight into why MS can be so different among individuals. (#p258)

•In the annual Charcot Award Lecture, Dr. John Prineas reviewed what has been learned in recent studies of MS pathology, and offered predictions for the next major insight in MS research. He discussed the fact that in a related disease, neuromyelitis optica (NMO), the aquaporin 4 antibody used to help diagnose NMO was recently discovered to be targeting astrocytes, star-shaped cells that support brain structure and function and which are known to be involved in creating scar tissue in MS. Dr. Prineas showed evidence of astrocytic involvement and reduced aquaporin 4 levels in tissue from people with MS, and suggested these cells may play a major role in MS damage. (#79, p585)

Source: ECTRIMS, Multiple Sclerosis Society of Canada and National MS Society (USA) (16/10/09)

About 50 million people in the EU suffer from neurological diseases such as epilepsy, migraines, multiple sclerosis, Parkinson's disease, strokes and dementia. These disorders account for 35 percent of the total health care burden in this region. That means not only a lot of human suffering but also a burden of some Euro130 billion on the European economies, noted Professor Ionnis Milonas, chairman of the annual Congress of the European Neurological Society at Rhodos. The latest research findings are also being discussed at the ENS Congress. Researchers are presenting innovative methods for repairing nerve damage and reporting about their studies on the therapeutic potential of stem cells in treating multiple sclerosis.

Rhodos, 18 June 2007 - "Neurological diseases are increasingly widespread throughout the world, especially in Europe, and incur heavy costs," warned Professor Dr. Ioannis Milonas at the annual Congress of the European Neurological Society (ENS) on the Greek island of Rhodos. "According to WHO data, neurological diseases as well as mental and neurosurgical suffering account for no less than 35 percent of the health care burden in European countries," noted Professor Milonas, head of the Department of Neurology at the University of Thessaloniki and chairman of the ENS Congress.

Elaborating on current data, Professor Milonas noted that there are about 46 million cases of neurological diseases such as epilepsy, migraines, multiple sclerosis, Parkinson's disease and stroke among the 466 million inhabitants in the EU (excluding the two new members Romania and Bulgaria, but including the non-members Iceland, Norway and Switzerland). A further five million people suffer from dementia, a disease classified both as a neurological and a mental disorder.

Professor Milonas added: "Neurological diseases incur costs of Euro84 billion a year. Migraines account for about Euro27 billion of the total, strokes for about Euro22 billion, epilepsy for about Euro15.5 billion, Parkinson's for about Euro10.5 billion and multiple sclerosis for about Euro9 billion." Dementia, for its part, is associated with financial outlays of Euro55 billion. For brain and nervous system diseases as a whole, i.e. including mental illnesses such as depression, addiction and anxiety disorders and neurosurgical diseases such as brain injuries and tumors, the costs in Europe total a staggering Euro386 billion.

Repairing Damage from Brain and Spinal Cord Injuries

Professor Milonas: "Events like this Congress of the European Neurological Society are so significant because they showcase and discuss new research findings that can help to bring about substantial progress in the prevention, diagnosis, treatment and rehabilitation of neurological diseases." One priority topic of the ENS Congress is devoted to possible ways of repairing damage from brain and spinal cord injuries. About 710,000 people suffer traumas of these kinds in Europe every year, incurring subsequent costs of some Euro2.9 billion.

An Antibody as an Enabler of New Nerve Growth

"A scientist at the University of Zurich is presenting promising research at the ENS Congress. In experiments on animals, he has succeeded in restimulating nerve growth following nerve injuries and strokes," explained Professor Milonas. In the human brain and spinal cord, nerve fiber growth is basically restricted to distances of 0.2 to 2 millimeters. It is inhibited by several substances contained in the myelin sheaths, the coverings on the nerves in the central nervous system. One such substance is the highly potent membrane protein Nogo-A.

In a study presented at the ENS Congress, researchers developed an antibody to counter the growth inhibitor Nogo-A and tested its effect on nerve injuries and strokes in animal experiments. The authors of the study reported success in stimulating nerve fiber growth over comparatively long distances and "substantial improvement in functional restoration" as regards activities such as running, swimming or gripping. Professor Milonas: "The new agent is currently being tested in a phase 1 clinical study in a European network of centers for spinal cord injuries."

Preventing Scar Tissue Formation On Nerves 

A researcher at the University Clinic in Aachen, Germany, is presenting a research study at the ENS Congress on ways of preventing the formation of scar tissue following nerve injuries. "The German colleague suggests that agents originally created or tested for other applications be examined to determine their usefulness in this special area," explained Professor Milonas. "Partial successes were achieved with the anti-inflammatory agents Rolipram and Thalidomide in animal tests, bringing about improved motor functions following nerve injuries."

Aligning Rehabilitation with Recovery Phases Following Nerve Injuries

Following brain injuries, skills that initially appear to have been lost can often be restored to a suprisingly great extent. This comes about from a reorganisation of nerve structures in the brain that compensate for the functions of the failed parts of the brain. The process proceeds quite differently from one individual to the next depending on the area of the brain injured and the functions impaired, e.g. motor or language skills, and can be divided into different phases. These phases are also proved in current data presented at the ENS Congress by a researcher from the Neurological University Clinic in Freiburg.

The data shows, for example, that patients suffering from speech impairments after a brain injury go through an initial shock phase followed by a phase of hyperactivity and finally a normalisation phase. This time sequence can also be verified with magnetic resonance examinations of nerve cell activity in the affected areas of the brain. The idea the German scientist put up for discussion is that the various phases of recovery should be accompanied by different medicinal therapies and treatment methods specially geared to each phase.

Stem Cells as Possible Therapy for Multiple Sclerosis

The possible therapeutic uses of stem cells are now under investigation in a wide variety of medical fields. Stem cells are cells capable of unlimited cell division and of differentiating into a diverse range of cell types. Stromal cells, for their part, form the support structure of an organism. Bone Marrow Stromal Cells (BMSCs) are non-hematogenic (non-blood-building) stem cells, which can become, inter alia, cells of the central nervous system. Greek scientists at the University of Thessaloniki have conducted in vitro examinations to determine whether these BMSCs can survive in the presence of cytokines, a group of proteins and peptides that play a role in human immune and special inflammatory responses.

These types of inflammatory environments are present for example in patients with multiple sclerosis. "The basic experiment was highly encouraging, which is why bone marrow stromal cells were tested as a cell-based therapy for treating multiple sclerosis," explained Professor Milonas and noted that the transplantation of neural stem cells has already been tested in an animal study conducted by a Greek-Israeli team of researchers: "The possible effect of stem cells on multiple sclerosis was also tested in this model experiment. They were shown to bring about a reduction in inflammations in the brain and tissue injuries."

Source: Congress of the European Neurological Society (19/06/07)

Gordon Brown MP said: "I would like to welcome delegates to the MS Society's Frontiers research conference in London. Multiple sclerosis is a devastating condition and it is vital that the UK plays a lead in promoting high quality research in a bid to improve our understanding of the disease. People with MS, their families and carers greatly value your efforts."

Frontiers is a two-day event bringing together MS researchers from across the world. Questions up for discussion include possible causes of MS, why it varies so much in geographical impact - (MS is twice as common in Scotland as in England, for example) and the origins of the condition. Experts will look into the potential of cutting edge treatments like stem cell therapy, risks involved in more aggressive treatments, and a range of possible rehabilitation approaches to tackle MS.

MS Society chief executive Simon Gillespie, who opens the event today, said: "Research offers the greatest hope of beating MS, which is our vision as a charity. We have more than GBP14 million invested in projects across the UK trying to figure out what causes this appalling condition, and looking at how we can fight its symptoms in the here and now.

"MS Frontiers brings together some of the best brains in the research business so that they can share ideas, challenge one another and push forward the MS research agenda.

"The MS Society is doubling its research spending over the next year and we want the research community to be in no doubt that we are 100% behind them. We welcome Gordon Brown's support."

Frontiers 2007 features 28 international speakers, including representatives from the USA, Australia and Canada. This year's keynote presentation on the future of MS therapies is by Professor Larry Steinman MD of Stanford University.

Source: The MS Society(13/06/07)