Global MS Research Efforts Shared at ECTRIMS/ACTRIMS Meeting - National Multiple Sclerosis Society

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Global MS Research Efforts Shared at ECTRIMS/ACTRIMS Meeting

November 10, 2011

EXECUTIVE SUMMARY

More than 7,000 investigators convened in Amsterdam on October 19-22, 2011 to present findings at a joint congress of ECTRIMS (European Committee for Treatment and Research in MS) and ACTRIMS (Americas Committee for Treatment and Research in MS). Over 1100 scientific presentations and display posters covered virtually every aspect of research to stop MS, restore function, and end MS forever. Among these were the latest results from pivotal clinical trials of emerging MS therapies, possible risk factors, underlying disease mechanisms, rehabilitation approaches, CCSVI, and much more.

Below are highlights and a more extensive summary. Free access to the conference abstracts are available at the ECTRIMS/ACTRIMS 2011 Website. Read on-site commentary on the National MS Society’s Blog. View videos of select researchers.

Highlights:

STOPPING MS

  • First results from late-phase clinical trials of new agents, some of which, if found to be safe and beneficial, may come on the market in 2012 and 2013.
  • Progress toward more individualized approaches to treating MS, or “personalized medicine” was evident, including efforts to find non-invasive signals or biomarkers that may be predictive of treatment response and disease course and may speed up clinical trials.

RESTORING

  • The full potential of a variety of rehabilitation and exercise regimens to help restore function to people with MS were presented, including approaches to address troubling symptoms including pain, cognitive issues, fatigue and tremor. In addition, 19 presentations focused on Chronic Cerebrospinal Vascular Insufficiency and MS. Many reported on the prevalence of CCSVI in people with MS compared to controls, with conflicting results. Others reported new findings related to imaging techniques and pathology findings.

ENDING

  • Genes that make people susceptible to MS contribute only about 30% of the risk – the remainder may be contributed by factors in the environment. Results on possible risk factors – and protective factors – were featured, including new information about how our intestines influence immune activity, as well as levels of vitamin D in the bloodstream. New studies are getting under way to identify risk factors in children with MS and to test whether vitamin D supplements added to ongoing therapy can reduce MS severity.

Summary:

RESEARCH TOWARD STOPPING MS IN ITS TRACKS
-- Experimental Treatments in the Pipeline

Among studies reported were these first results from late-phase clinical trials. If these treatments are found to be safe and beneficial, some of them may come on the market in 2012 and 2013. The more that ongoing studies reveal about the modes of action as well as potential benefits and risks of these and other emerging therapies, the clearer it should become regarding how they might be used either alone or in combination, if and when they are approved for use.

  • BG-12 (Biogen Idec) – Results from the DEFINE phase III trial of this oral therapy in relapsing-remitting MS, tested at two or three times a day against placebo over two years, achieved statistical significance on all primary and secondary outcomes measured, including reducing the proportion of patients who experienced relapse after two years (as low as 26% in treated groups versus 46% of those on placebo -- a reduction of up to 50%), reducing the risk of disease progression (by up to 38% over placebo), and reducing disease activity seen on MRI. The most common adverse events were flushing (in about 35% of those on BG-12) and bowel problems such as diarrhea and cramping (2 to 3% on BG-12) (Abstract 95).
  • Laquinimod (Teva Pharmaceuticals and Active Biotech) – The phase III BRAVO clinical trial tested oral laquinimod against inactive placebo in people with relapsing-remitting MS. Participants received either one daily capsule of laquinimod, inactive placebo, or standard dosing of Avonex® (interferon beta-1a, Biogen Idec) for 24 months. Laquinimod did not reduce the annualized relapse rate significantly more than placebo. According to the presentation, there were differences in MRI characteristics between the treatment groups at the beginning of the study, and when the data were adjusted to account for these differences, laquinimod was found to reduce annualized relapse rate by 21%, reduce the risk of progression by 33.5%, and reduce the rate of brain tissue volume loss by 27.4%, over placebo. The most common adverse events were elevated liver enzymes, back pain, joint pain and depression. (Abstract 148)
  • Alemtuzumab (Genzyme) -- The two-year CARE-MS-I phase III trial compared intravenous alemtuzumab against standard dosing of Rebif® (interferon beta-1a, EMD Serono Inc. and Pfizer) in early relapsing-remitting MS. The study met one of two primary endpoints by reducing relapse rates by 55 percent over Rebif. The study did not meet its second primary endpoint of slowing disease progression compared to Rebif; after two years, 8 percent of those on alemtuzumab had an increase in their EDSS score (a standard scale of physical disability) compared to 11 percent on Rebif – a difference that was not statistically significant. MRI results showed benefit, including a reduction of the risk of brain volume loss. The most common adverse event included reactions associated with infusions (such as headache, rash, fever, flushing, hives and chills). There were more infections in those taking alemtuzumab, predominantly mild to moderate, but there were no fatal infections. Less than 20 percent on alemtuzumab developed autoimmune thyroid-related problems. (Abstract 151)
  • Daclizumab HYP (Biogen Idec and Abbott Pharmaceuticals) – The Phase II SELECT study tested monthly, under the skin injections of a low (150 mg) and high (300 mg) dose of the monoclonal antibody compared to placebo in relapsing-remitting MS over 48 weeks. The trial met its primary endpoint by reducing the average annual relapse by 50 to 54% over placebo. The therapy also decreased new or enlarging MRI brain lesions, improved a measure of quality of life, and reduced disease progression by as much as 57% over placebo. The role of daclizumab could not be ruled out in one death that occurred from a complication that occurred during the person’s recovery from a serious skin-related adverse event. Serious infections, serious skin events and liver function test abnormalities occurred more frequently in the DAC HYP groups than in the placebo group. (Abstract 149)
  • Botox® (Botulinum toxin type A, Allergan) – Dr. A. van der Walt and colleagues (Royal Melbourne Hospital, Australia) presented positive results from a small phase II, six-month study supported by the investigators’ institution, testing the ability of Botox injections to control upper limb tremor, an MS symptom that can be difficult to treat effectively. Significant improvements over placebo were seen in writing, drawing and other tests at 6 and 12 weeks. Many (42.2%) of those on Botox experienced mild to moderate weakness after injections, which resolved within two weeks. (Abstract 50)
  • Omega-3 Fatty Acids – A placebo-controlled trial by a multi-center team across Norway, involving 92 people with relapsing-remitting MS, tested the ability of daily omega-3 oil capsules or placebo corn oil capsules to alter disease activity over 6 months. Using measures of disease activity as seen on MRI, and also relapse rates, fatigue, quality of life and other measures, the team was unable to detect any benefits of the treatment over placebo. (Abstract P919)

RESEARCH TOWARD STOPPING MS IN ITS TRACKS

Current MS Therapies

Many presentations focused on follow-up safety and benefits of approved therapies, generally supporting and expanding on original findings of their benefit for treating MS. Of note:

  • The question of what happens to disease activity when a person stops taking Tysabri® (natalizumab, Biogen Idec and Elan Pharmaceuticals) was addressed in the 24-week RESTORE trial of people with relapsing MS who had been relapse-free for at least 12 previous months while taking Tysabri. They were randomly assigned to be switched to placebo or to other disease-modifying therapy for 24 weeks, or continue on Tysabri. After the 24-week observation period, Tysabri was reintroduced unless criteria for “rescue” therapy had been met during the observation period by those experiencing relapse or significant MRI activity. Overall, 30% of patients were rescued with Tysabri due to resumed disease activity. The investigators found that the first signs of disease activity detected with MRI returned at 12 weeks after Tysabri interruption. The results may offer clinicians practical clues as to the appropriate timing for starting a person’s next treatment regimen. (Abstract 150)
  • Exposure to interferons, ranging from three months to up to 12 years, does not increase the risk of cancers, according to preliminary results from an ongoing study presented by Drs. E. Kingwell, Helen Tremlett and colleagues (University of British Columbia, Vancouver, Canada). The study used a health database including 5157 people with MS, and compared cancer rates in people taking interferons to cancer rates in matched controls. (Abstract 140)

RESEARCH TOWARD STOPPING MS IN ITS TRACKS

“Personalized medicine”

The way individuals experience MS -- the course of their disease and response to treatments -- varies considerably. Personalized medicine is the concept of being able to determine in advance, based on sophisticated analyses, the likely prognosis and best personal treatment plan for any individual. Right now it’s only a dream in MS, but research efforts are advancing to find non-invasive “biomarkers,” such as signals in the blood or other fluids, or clues in MRI scans, which may be predictive of treatment response and disease course:

  • Hi-tech analysis of blood from people with MS enrolled in Harvard’s CLIMB study (Comprehensive Longitudinal Investigation of MS at Brigham & Women’s Hospital), by Drs. L. Ottoboni, Philip De Jager and colleagues, has identified two subsets of people with MS based on profiles of immune cell gene signals. The subjects included 141 untreated patients, 94 treated with glatiramer acetate, and 128 treated with interferon beta. In all groups, the team was able to identify a subset of people who had more active disease whether treated or untreated. The second subset had a profile of less active disease, remission, and better response to treatments. If this research is validated, it may lead to earlier ways to identify people less likely to respond to “first-line” therapies than is now possible. (Abstract 57)
  • An invited talk by National MS Society Harry Weaver Neuroscience Scholar Sergio Baranzini, PhD (University of California, San Francisco, California) described progress toward using discoveries from gene screens in clinical practice. His team has been following gene activity in people at high risk for MS and tracking signals in the genes of specific immune cells in people who progress. They identified preliminary findings on a gene called Tob1 that may be linked to the likelihood of MS progression and more immune activity. He also cited some progress in identifying signals in the blood that identify people who are less likely to respond to therapy with interferon beta. “With the advent of newer sequencing technologies, the search for biomarkers will explode,” he remarked. (No abstract)
  • The risk of MS relapse is generally lower during pregnancy, but rises after delivery. Finding a way to predict who is more likely to relapse after delivery could help guide treatment decisions. Dr. E. Portaccio and members of The MS Study Group of the Italian Neurological Society looked for possible predictors of postpartum relapse and progression of disability after delivery in 349 pregnancies in women with MS. The risk of relapse was higher in women who had higher EDSS scores (a scale of physical disability) at conception and more relapses the year before and during pregnancy. Progression of disability was linked to the occurrence of postpartum relapses, and those who resumed disease-modifying therapy within three months of delivery were less likely to experience a postpartum relapse. (Abstract 130)
  • An award-winning presentation by young investigator Dr. Leonard Verhey (University of Toronto, Ontario, Canada) described an extensive study of MRI scans of children who had experienced a neurological problem that had not yet been diagnosed. Looking back at the scans of children who later went on to be diagnosed with MS, the Canadian Pediatric Demyelinating Disease Network team found that specific characteristics of brain MRIs (periventricular lesions, black holes and contrast-enhancement on initial MRI) increased the risk that those children would later be diagnosed with MS, especially if two or more of those characteristics were present. (Abstract 62)
  • The experimental MS treatment alemtuzumab (see above) can cause autoimmunity, usually directed against the thyroid gland, months or years after its use. A prize-winning poster by Drs. Joanne Jones, Alisdair Coles and colleagues at Cambridge University, where this therapy originated, explored the idea that this autoimmunity is caused by a genetically determined reaction that can be measured in serum levels of an immune messenger called IL-21 even before treatment begins. They analyzed messenger chemicals in samples from 130 people, finding that those who developed autoimmunity during or after alemtuzumab had higher levels of IL-21. They also found that another immune messenger, IL-7, seemed to protect against autoimmunity. This approach could be used to identify good candidates for treatment with alemtuzumab if it is eventually approved for use in people with MS. (Abstract P1009)
  • The use of Tysabri has been linked to the development of PML (progressive multifocal leukoencephalopathy). Recent research suggests that individuals whose blood does not carry antibodies against the JCV virus that causes PML are at low risk for developing it while taking Tysabri. Drs. T. Olsson (Karolinska Hospital, Stockholdm Sweden) and international colleagues tested the prevalence of anti-JCV antibodies in six countries. They found, similar to prior reports, that 50 to 60% of most of the national populations had the antibodies. Women tended to have lower prevalence compared to men, and the prevalence of antibodies increased with age. This information contributes to efforts to understand and reduce the risk of PML in people taking or considering taking Tysabri. (Abstract P338)

RESEARCH TOWARD RESTORING WHAT’S BEEN LOST
-- Rehabilitation: Providing Help Now

Understanding how MS damages the nervous system and how symptoms impact daily life are important aspects of using the full potential of a variety of rehabilitation and exercise regimens to help restore function to people with MS.

  • Despite active MS destruction to the nervous system, the brain of a person with MS has the power to rewire itself to compensate, according to research described by Dr. Paul Matthews (GlaxoSmithKline, London, United Kingdom) during an invited talk on central nervous system plasticity. He noted an important factor that contributes to disability is “learned disuse,” and that nervous system plasticity remains even in advanced MS. This provides a rationale for rehabilitation even in later stages of disease. (Abstract 49)
  • Drs. A. Tacchino, G. Brichetto and colleagues (Italian MS Foundation, Genoa, Italy) conducted a small study based on recent evidence suggesting that mental imagery of specific movements may enhance rehabilitation in people with MS. First the participants, 14 people with MS and 19 healthy controls, mentally imagined doing a task with a pencil, and later actually performed the task physically. They found that the mental practice sped up the time it took to physically perform the task, and suggest that this technique could be applied to rehabilitation in people with MS. (Abstract P574)
  • A survey conducted by Harris Interactive on behalf of Acorda Therapeutics and the National MS Society, and presented by Dr. Nicholas LaRocca, suggested that difficulty walking substantially interferes with activities of daily living and quality of life in a majority (65% of those surveyed) of people with MS, even in those who have had MS five or fewer years. Of those who had MS-related walking difficulty, 70% called it the most challenging aspect of MS, yet 40% of those surveyed “rarely or never” discussed walking problems with their doctors. The survey involved 1,246 people who reported that they had been diagnosed with MS. The results support the need for early recognition and management of mobility problems experienced by people with MS. (Abstract P1130)
  • A portion of the memory problems experienced by people with MS involves inadequate acquisition of information. Using stories to weave better memories is the idea behind the “modified story memory technique,” being explored to treat learning and memory deficits in people with MS by Dr. John DeLuca and team (Kessler Foundation Research Center, West Orange, New Jersey). This experimental treatment involves 10 sessions that teach patients to put things into context and to use imagery to cement learning elements. The team found evidence that the technique is beneficial, especially for people who have normal information processing speeds, and it also appears to activate more regions of the brain during performance of memory tasks, as seen on functional MRI scans. (Abstract 117)

RESEARCH TOWARD RESTORING WHAT’S BEEN LOST
-- CCSVI

Nineteen platform or poster presentations related to Chronic Cerebrospinal Vascular Insufficiency and MS. Most reported on studies of the prevalence of CCSVI in people with MS compared to various types of controls, using different imaging technologies, with conflicting results. Some reported that venous abnormalities are common and equally prevalent in patients and controls (for example, Abstracts P1105 and P1108) and others found higher prevalence in people with MS compared to healthy controls (for example, Abstract P631 and P1106-pediatric MS). Presentations of note included:

  • A platform presentation of preliminary results from an ongoing study of vein structure in autopsy specimens (by Claudiu Diaconu, Dr. Robert Fox and colleagues, Cleveland Clinic, Ohio) from seven people who had MS in their lifetimes, compared to six people who did not have MS. In this unblinded study, funded by the National MS Society, so far they have identified abnormalities inside the vein tubes (lumen) that drain the brain and found a variety of structural abnormalities and anatomic variations in both groups. However, they reported higher frequency of abnormalities in those who had MS (2 abnormalities in 2 out of 6 controls versus 9 abnormalities in 6 out of 7 MS patients). They noted that MR venography may be less effective than ultrasound for identifying these venous abnormalities, and that ultrasound that examines only vein wall circumference may miss some intraluminal abnormalities. (Abstract 134)
  • A platform presentation by Dr. Florian Doepp (Charite University Medicine Berlin, Germany), describing the lack of a gold standard for evaluating cerebral venous flow and summarizing findings by his team, which includes vascular experts, that directly challenge and conflict with the original findings reported by Dr. Zamboni. (No abstract)
  • A poster describing a controlled Italian multi-center study (CoSMo Study) currently in process that will ultimately evaluate venous abnormalities in 2,000 people. (Abstract P634)
  • A poster by Drs. Kresimir Dolic, Robert Zivadinov and colleagues (University of Buffalo, NY) exploring results in 252 people who had undergone evaluation for CCSVI. They were evaluated for possible risk factors for being diagnosed with CCSVI. The investigators found that 27.8% of the pooled group met CCSVI criteria. In this group, factors in their medical history that were more frequent than in those who did not meet the CCSVI criteria included heart disease (especially murmurs), infectious mononucleosis, and irritable bowel syndrome. (Abstract P1128)

RESEARCH TOWARD ENDING MS FOREVER
-- Risk Factors

What triggers MS? As was pointed out by one presenter, the genes that make people susceptible to MS contribute only about 30% of the risk – the other 70% possibly contributed by factors in the environment. Results showing progress in understanding some possible risk factors – and protective factors – were prominent at the conference.

  • The Charcot Satellite Symposium before the start of the ECTRIMS/ACTRIMS meeting focused on the potentially colossal role that tiny colonies of bacteria inside our intestines may play in determining a person’s susceptibility to MS. The ‘hygiene hypothesis’ of MS suggests that the reduced exposure to microbes in countries with higher sanitation standards may make the immune system over-react to infections, possibly leading to MS. Dr. Valerie Gaboriau-Routhiau (INSERM, Paris, France) described how the trillions of bacteria in the gut engage in interactions with the immune system, and can in fact influence the balance of that system. She suggested that improving our understanding of gut immunity can have major implications for developing new therapies for MS and other autoimmune diseases. (No abstract)
  • At the same symposium, Dr. Hartmut Werkerle (Max Planck Institute of Neurobiology, Martinsried, Germany) described a genetically engineered mouse model that develops spontaneous MS-like disease without injections of myelin components or immune cells that are normally needed to stimulate this disease in rodents. His group discovered that if these mice are housed in a germ-free environment, they do not develop the disease, and discovered that gut bacteria are required for spontaneous disease to occur. (No abstract)
  • Dr. Jorge Correale (Institute for Neurological Research, Buenos Aires, Argentina) described ongoing work by his team related to how intestinal parasites in the Helminth family of worms may shift the immune balance to reduce MS disease activity. (Abstract 88) This approach is being tested in clinical trials. For example, the National MS Society is funding a small clinical trial at the University of Wisconsin, Madison, testing whether feeding harmless Helminth eggs to people with MS can reduce disease activity.
  • Insufficient vitamin D has been linked to a higher risk of developing MS, but its possible link to ongoing disease activity has not been fully explored. Dr. Ellen Mowry (Johns Hopkins University, Baltimore, Maryland) and colleagues described the five-year EPIC study at the University of California, San Francisco (funded by Glaxo-Smith Kline and Biogen Idec) involving 469 people with CIS (with early signal but not yet diagnosed with MS) or relapsing-remitting MS who had annual MRI scans, blood draws and clinical exams. Among their findings, they reported that higher blood vitamin D levels lowered the risk of MS activity seen on MRI; each 10 ng/mL increase in the blood level of vitamin D was linked with a 32% lower risk of developing a new, active (gadolinium-enhancing) brain lesion. Dr. Mowry and team are beginning a National MS Society-funded clinical trial to test whether vitamin D supplements added to standard therapy can reduce relapses and other disease activity. (Abstract 129)
  • The possibility that children diagnosed with MS may offer a better opportunity to early triggering events was discussed at a popular session devoted to pediatric MS. Dr. Emmanuele Waubant (University of California, San Francisco, California), who heads one of six centers in the network of Pediatric MS Centers established by the National MS Society, provided an overview of what is known about MS in children and the open question as to why these children get MS so much earlier than adults. She is leading a study that will investigate possible environmental triggering factors in children with MS, including common viral infections, vitamin D levels, exposure to smoking and others. (Abstract 58)

These and many other presentations reflect the rapid pace of MS research today.

-- with special thanks to members of the Executive Committee of the Society’s National Clinical Advisory Board.

Botox is a registered trademark of Allergan
Rebif is a registered trademark of EMD Serono, Inc.
Tysabri is a registered trademark of Biogen Idec and Elan

About Multiple Sclerosis

Multiple sclerosis, an unpredictable, often disabling disease of the central nervous system, interrupts the flow of information within the brain, and between the brain and body. Symptoms range from numbness and tingling to blindness and paralysis. The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, but advances in research and treatment are moving us closer to a world free of MS. Most people with MS are diagnosed between the ages of 20 and 50, with at least two to three times more women than men being diagnosed with the disease. MS affects more than 2.3 million people worldwide.

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